Introduction

On May 20, 2026, Engage Biologics announced a definitive agreement to be acquired by Eli Lilly and Company for up to $202 million in cash, including an upfront payment and subsequent payments upon achievement of specified development milestones. This acquisition centers on Engage’s Tethosome platform, a novel non-viral DNA delivery system designed to “overcome key limitations in DNA delivery, including potency, tolerability, and redosability.”

Here, we dive into founding journey of Engage Bio and explore how its Tethosome platform could advance the frontier of genetic medicine.

A Founder-led Platform Company

The rapid trajectory of Engage Bio, from its 2021 founding to its $202 million acquisition by Eli Lilly on May 20, 2026, was heavily driven by the distinct, complementary skill sets of its co-founders. Will Olsen (CEO) brought a track record of operational agility, lean startup execution, and clinical project management, while Kathryn Strobel Kwant (CSO) provided the deep, sophisticated protein engineering and drug platform expertise required to invent the Tethosome platform.

Will Olsen graduated with a B.S. in Economics from the University of Florida before shifting toward life sciences, completing a Post-baccalaureate program in Premedical Sciences at Columbia University. He began his career in clinical execution, working as a research associate within the Mount Sinai Health System before moving to Biorasi, a contract research organization (CRO). At Biorasi, he served as a Senior Program Manager, designing and driving clinical programs and managing business development. In 2015, he co-founded and served as Chief Operating Officer (COO) of Luminist Labs, a diagnostic platform aimed at screening for liver disease and early-stage cancer. Luminist was later acquired by DiscernDx, with its technology assets eventually integrated into Viome. From 2019 to 2021, he served as the Vice President of Development Operations at Rejuvenation Technologies, a Stanford University mRNA spinout developing telomere-extending therapeutics. This role solidified his operational mastery of mRNA therapeutics development and manufacturing logistics. In parallel to his operator roles, Olsen joined the Pioneer Fund as a Venture Partner in 2019, giving him insight into early-stage biotech deal-making. His co-founder is equally as impressive.

Kathryn Strobel Kwant completed her Ph.D. in Chemical Engineering at UC Berkeley under the co-direction of pioneering biochemical engineers Harvey Blanch and Douglas S. Clark. Her doctoral research focused on enzyme mechanics, directed evolution, and altering carbohydrate-binding modules to optimize performance and reduce inhibition in complex environments. Before founding Engage Bio, Dr. Kwant was a vital scientific force at Harpoon Therapeutics (acquired by Merck for $650 million in 2024), a company celebrated for pioneering multi-specific T-cell engagers (TCEs). During her tenure, she specialized in designing complex, multi-functional biologics. She was a lead inventor and architect behind TriTAC-XR (an extended-release, trispecific T-cell activating construct) and ProTriTAC (a protease-activatable prodrug platform). These technologies were specifically designed to minimize systemic maximum drug concentration (C_max) to reduce Cytokine Release Syndrome (CRS) while expanding the therapeutic window for solid tumors. Furthermore, Kwant is a named inventor on numerous foundational biopharmaceutical patents covering conditionally activated target-binding molecules, EpCAM-binding proteins, and trispecific protein constructs for oncology.

The pairing of Olsen and Kwant perfectly mirrored the dual requirements of the Tethosome platform. Olsen’s background at Rejuvenation Technologies provided the operational blueprints for handling lipid nanoparticles (LNPs) and mRNA chemistry. Meanwhile, Kwant’s deep expertise in engineering multi-functional proteins allowed Engage Bio to design the proprietary DNA-binding protein encoded by that mRNA, the vital bridge that shields the therapeutic DNA payload from innate cellular immunity and tethers it within the nucleus for sustained expression.

The founders sought to engineer a solution to the two biggest bottlenecks plaguing non-viral gene therapy:

• Nuclear localization: Getting large DNA payloads across the nuclear membrane without a viral vector.

• Innate immune sensing: Preventing the cell from detecting and destroying foreign DNA.

Unlike highly capitalized biotech startups that launch with massive Series A rounds and public relations blitzes, Engage Bio operated as an ultra-lean, stealth-mode organization. The company relied on a mix of modest seed capital and highly competitive translational grants. They went through Y Combinator and secured early venture backing from ecosystem micro-VCs and angel networks including SciFounders, Pioneer Fund, and the Cal Innovation Fund.

To advance the science without excessive dilutive equity, Engage Bio secured non-dilutive grants through the National Institutes of Health (NIH) and the Bill & Melinda Gates Foundation. Crucially, they also received financial backing from the Cystic Fibrosis Foundation (CFF), signaling that their delivery platform had potential therapeutic viability in difficult-to-target mucosal tissues like the lungs.

During this period, the team (which later included key RNA scientists like CTO Ben R. Hawley, Ph.D.) quietly developed and patented the Tethosome platform. Instead of relying purely on standard DNA or standard mRNA, they built a dual system: using an LNP to co-deliver a therapeutic DNA payload alongside an mRNA strand that codes for a proprietary DNA-binding protein, enabling the DNA to safely enter and “tether” inside the nucleus for sustained expression.

Engage Bio never publicly disclosed a formal, single pipeline indication or internal drug asset. Instead, they focused entirely on validating the modular nature of the Tethosome platform. This strategy culminated on May 20, 2026, when Eli Lilly and Company announced an agreement to acquire Engage Biologics for up to $202 million in cash. The transaction suggests that Lilly intends to integrate Engage Bio into its broader genetic medicines organization, potentially utilizing the Tethosome platform as a modular, non-viral delivery system for its own expanding portfolio of redosable DNA therapies. It’s a rare moment where a major pharmaceutical player may have gained conviction in a platform’s capabilities, rather than a specific pipeline asset.

The Platform that Olsen & Kwant Built

In the modern era of genetic medicine, the industry has become incredibly proficient at gene editing machinery, the DNA encoding enzymes that can correct the root cause of disease. However, the field continues to stall at the last mile: delivering that code safely, effectively, and repeatedly to the right cells. Historically, introducing foreign DNA into the human body has been a high-stakes gamble. The body’s innate immune sensors often identify these genetic payloads as threats, triggering inflammatory responses that can range from neutralizing the treatment to being outright lethal.

The center of the Engage Bio deal is the Tethosome platform, a technology that seeks to bridge the gap between mRNA’s ease of delivery and DNA’s long-term durability. Unlike traditional methods, the Tethosome system utilizes lipid nanoparticles (LNPs) to co-formulate two distinct components: a recombinant therapeutic DNA expression vector and an mRNA that encodes a proprietary “Tethosome” protein.

The mechanics represent a significant technical leap. Once the LNP enters the cell, the mRNA is translated into a protein intended to both shuttle the DNA payload to the nucleus and ‘tethers’ the expression vector within it. This anchoring mechanism is designed to enable durable expression without the need for the DNA to integrate into the host genome. According to Engage Bio, this dual-action approach results in a 100-fold increase in expression compared to traditional non-viral methods.

The “holy grail” of genetic medicine is redosability, the ability to administer multiple doses to titrate a drug to optimal levels, much like a traditional pill. Viral vectors, specifically adeno-associated virus (AAV), have long been the industry standard, but they are plagued by immunogenicity and cytotoxicity. Once a patient receives an AAV-based therapy, their body often develops antibodies that make redosing impossible, effectively making it a one-and-done treatment with no room for error.

Tethosomes are engineered to be “invisible to immune sensors”, according to Engage Bio. By aiming to avoid the innate immune triggers that typically detect foreign DNA, the platform is designed to potentially allow for safe, repeated administration. This addresses the primary limitations found in previous generations of gene therapy, which often struggled with sometimes lethal immune activation or diminished efficacy over time.

While the official acquisition press release remains high-level, a NCATS grant data reveals two potential areas where Engage Bio is focusing its anchoring technology:

• Hemophilia A: A monogenic disease caused by a deficiency in Factor VIII (FVIII). Engage Bio could use Tethosomes to provide a potentially safer, redosable alternative to current AAV therapies, which often suffer from varying expression levels and a lack of redosability.

• Liver Cancer (Hepatocellular Carcinoma): The platform could used to deliver a cocktail of clinically validated pro-inflammatory cytokines, specifically IL-15su (sushi) and IL-12sc (single chain), alongside IL-2 and GM-CSF.

A BioSpace article about the acquisition also indicates that the Cystic Fibrosis Foundation (CFF) was a funding source of Engage Bio, suggesting historical research interest or early-stage exploratory alignment with cystic fibrosis.

Conclusion

From an industry perspective, Eli Lilly’s acquisition of Engage Bio represents a highly strategic move within the competitive gene therapy landscape. Buoyed by the unprecedented weight-loss windfall generated by its GLP-1 portfolio, Lilly is utilizing its massive cash flow to in-house and derisk early-stage platform technologies. The pharmaceutical giant had committed nearly $21 billion to M&A activity in the first four months of 2026 alone. As the industry matures, the delivery platform itself may prove to be the most valuable asset in a pharmaceutical portfolio, the gatekeeper to the last mile of gene therapy.

To contact us, please send us an email at biotechreadout@gmail.com

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Introduction

In Part 1 of this series of CAR-T, we traced the roots of immunotherapy back to Coley’s Toxins, re-lived the Immunology Civil War and its détente with the 1908 Nobel Prize, unraveled the key discoveries that would enable CAR-T (T-cell and TCR), explored the progression from the proto-CAR-Ts of Dr. Yoshikazu Kurosawa and Dr. Zelig Eshhar to the long-liver costim powerhouses crafted by Dr. Michel Sadelain and Dr. Carl June, and lingered a bit on the heartwarming story of Emily Whitehead (the first pediatric CAR-T patient). Lastly and perhaps most importantly, we touched on two critical problems with CAR-T:

1. Access Gap: The month-long logistical obstacle course required to draw T-cells, re-program them, expand them, QC them, and re-infuse them back into a patient. This technically complex process largely restricted access to CAR-Ts to elite academic medical centers like UPenn.

2. Lymphodepleting Chemotherapy: The process of existing T-cells to make room for new CAR-T cells to multiply adds a significant layer sof treatment burden to an already frail patient.

While these barriers remain for “autologous” CAR-T therapy (when a patient’s own T-cells are re-programmed), there are a number of emerging technologies that are specifically designed to be “off-the-shelf” with the following benefits in mind:

• Donor-Derived: Instead of using the patient’s own T-cells, which may be “exhausted” from prior chemotherapy, these cells are harvested from healthy, screened donors.

• Ready for Use: Because the product is pre-manufactured and stored, there is no “vein-to-vein” wait time (the 2–4 week period required to engineer a patient’s own cells).

• Scalability: A single donor’s leukapheresis material can potentially be used to create hundreds of doses, moving the process toward a more traditional pharmaceutical manufacturing model.

In Part 2, we will explore those therapies that push the frontier beyond autologous CAR-T:

1. Allogeneic CAR-T / scroll to section ⬇️

2. In vivo CAR-T / scroll to section ⬇️

3. T-cell engagers (TCE) / scroll to section ⬇️

Allogeneic CAR-T, an “Off-the-shelf” Approach

Before we dive into the history here, it’s important to demystify a bit of industry jargon define the difference between “autologous” and “allogeneic” CAR-T. The fundamental difference between autologous and allogeneic therapy lies in the source of the cells:

• Autologous, Self to Self: In autologous therapy, the patient is their own donor. Cells are collected from the patient via apheresis, sent to a manufacturing facility to be genetically engineered (in the case of CAR-T), expanded in number, and then infused back into the same patient. Since the cells are self, they will not attack the patient’s healthy tissues. These cells can survive for years in the body as living drugs.

• Allogeneic, Donor to Patient: In allogeneic therapy, cells are harvested from a healthy, third-party donor. Cells are collected from a healthy volunteer, engineered to be universal (often by removing the T-cell receptor to prevent graft-versus-host disease), and are frozen. Healthy donors typically have more robust, fitter immune cells than heavily pre-treated cancer patients. This process is, theoretically, more scalable, allowing one donor collection to potentially provide hundreds of doses, significantly lowering costs. These doses are kept in cell banks at hospitals. Patients can be treated within days of diagnosis, as opposed to the months-long vein-to-vein time of autologous CAR-T.

The story of allogeneic CAR-T begins with André Choulika, a researcher in the laboratory of Bernard Dujon at the Pasteur Institute. His work focused on meganucleases, naturally occurring enzymes that can recognize and cut specific DNA sequences. Choulika was among the first to prove that these nucleases could be used to induce homologous recombination (HR) in mammalian cells. In 1995, his paper on I-SceI meganucleases demonstrated that one could create targeted double-strand breaks (DSBs) at a specific coordinate to trigger the cell’s natural repair machinery, potentially enabling the precise deletion or insertion of DNA. Choulika’s predated the more modern CRISPR technology by 17 years (when Jennifer Doudna’s landmark paper was published in 2012). Before Choulika’s discovery, genome modification was largely done by random integration (sticking DNA into the genome and hoping it landed somewhere useful). His paper showed that induced homologous recombination was approximately two orders of magnitude (100x) more frequent than spontaneous recombination, making precise gene editing a viable therapeutic tool rather than a rare laboratory fluke. This specific snip-and-insert logic is exactly what is used today to remove the T-cell Receptor (TCR) from donor cells.

While the Dujon lab was focused on basic biology, Choulika was focused on application. He recognized that if you could make these yeast enzymes work in human cells, you could rewrite the human genome. In 1999, André Choulika spun Cellectis out of the Pasteur Institute, making it the first company in the world dedicated specifically to genome engineering. Choulika’s first major move was securing the exclusive licenses for meganucleases from the Pasteur Institute. Initially, Cellectis didn’t focus on drugs. They functioned more like a tool shop, licensing their meganuclease technology to large pharmaceutical companies and agricultural firms who wanted to modify cell lines or crops.

By 2011, Cellectis faced a crossroad. Meganucleases were hard to engineer for new targets. Each meganuclease is a single protein that both “recognizes” and “cuts” a specific DNA sequence. If you wanted to cut a different part of the genome, you had to redesign the entire protein, a process that was slow, expensive, and often failed. Recognizing that meganucleases were too rigid for mass-scale drug development, Choulika made a aggressive strategic pivot:

• Acquiring TALENs: He secured the rights to TALEN technology (Transcription Activator-Like Effector Nucleases) from the University of Minnesota and Iowa State University. Unlike meganucleases, TALENs were modular. Theoretically, you could snap different codes together to target almost any DNA sequence.

• Betting on CAR-T: Instead of just being a tool company, Cellectis decided to become a therapeutics company. Choulika realized that the killer application for gene editing wasn’t just fixing a broken gene, but engineering donor T-cells to be universal.

Scientists at Cellectis worked tirelessly to engineer allogeneic “off-the-shelf” CAR-T, which they called UCART (Universal Chimeric Antigen Receptor T-cell). These cells are gene-edited to be compatible with any patient, and get around non-self immune rejection. The two key ingredients of their allogeneic CAR-Ts came from different biological threads:

• TRAC (The Safety Switch): The discovery that the T-cell Receptor (TCR) was the culprit behind Graft-versus-Host Disease (GvHD) was well-established in bone marrow transplant science. However, the specific discovery that you could delete the TRAC gene to prevent GvHD in CAR-T was further validated by researchers like Hiroshi Torikai and his team at MD Anderson. In early 2012, they demonstrated that using Zinc Finger Nucleases (ZFNs) to disrupt TRAC did not hurt the T-cell’s ability to kill cancer but did stop it from attacking the host.

• CD52 (The Survival Strategy): The use of Campath/Lemtrada (an anti-CD52 antibody) was already common in oncology and transplants to clear out a patient’s immune system. The discovery here was the clinical observation that Campath/Lemtrada would also kill any donor CAR-T cells. Cellectis researchers realized they could use their gene-editing tools to delete the CD52 target from the donor cells, effectively giving them a bulletproof vest against the patient’s chemotherapy.

By 2012, Cellectis brought these external concepts together and applied their proprietary TALEN technology to create a single, efficient manufacturing process. Cellectis scientists, led by Philippe Duchateau and Laurent Poirot, engineered TALENs to precisely target both the TRAC and CD52 loci in a single manufacturing run. A critical, often overlooked part of the discovery was the acquisition of CytoPulse in 2010. Its PulseAgile technology allowed Cellectis to shock the cells just enough to let the TALEN mRNA inside without killing the delicate donor T-cells. Between 2011 and 2012, Cellectis moved from theoretical editing to showing that these double-knockout cells could still proliferate, survive freezing/thawing, and kill tumor cells in mouse models.

In June 2014, Pfizer and Servier (a major French pharmaceutical firm) partnered with Cellectis in one of the largest early-stage biotech collaborations in history. Cellectis received an upfront payment of $80 million, but the total deal value exceeded $2.9 billion in potential milestone payments. Pfizer underscored its long-term commitment by purchasing a 10% equity stake in Cellectis. Pfizer secured the rights to develop allogeneic therapies for 15 oncology targets, while Servier and Cellectis shared rights to another 12 targets, including the flagship candidate, UCART19 (an allogeneic CAR-T that targets CD19).

With manufacturing and big pharma partnerships in place, UCART19 headed into the clinical trials becoming the first allogeneic CAR-T therapy ever used in a human. One-year-old Layla Richards became the first person in history to receive those gene-edited universal CAR-T cells. Layla had been diagnosed with an exceptionally aggressive form of B-cell Acute Lymphoblastic Leukemia (B-ALL) at just three months old. When all standard therapies (chemotherapy and a bone marrow transplant) failed, her lead clinician at Great Ormond Street Hospital (GOSH), Professor Paul Veys, and the medical team informed her parents that they had run out of conventional options and suggested palliative care. However, they mentioned that a highly experimental “off-the-shelf” treatment was being developed in the hospital’s own labs by Dr. Waseem Qasim, a Professor of Cell and Gene Therapy at University College London (UCL).

Rather than accepting palliative care, Layla’s father, Ashleigh Richards, specifically asked the doctors to pursue the experimental treatment. He is quoted as saying:

“She was sick and in lots of pain so we had to do something... We didn’t want to accept palliative care and so we asked the doctors to try anything for our daughter, even if it hadn’t been tried before.”

Ashleigh Richards, father of Layla Richards, the first person in history to receive allogeneic CAR-T therapy

Once the family gave their consent and expressed their desire to fight, Dr. Waseem Qasim took the initiative to bridge the gap between the lab and the bedside. Dr. Qasim contacted Cellectis (the biotech company that owned the technology) to request a special “compassionate use” license for the single vial of UCART19 that was sitting in the hospital’s freezer. He then led the effort to present the case to an emergency ethics committee to gain legal permission to use a drug that had never been tested in humans. The drug had never been tested in humans, but given Layla’s terminal status, the UK regulatory authorities granted a one-time exception.

Layla’s treatment was performed under a “Special Therapy” regulation at Great Ormond Street Hospital (GOSH). The procedure was technically complex and required a sequence of specific clinical steps:

• Lymphodepleting Chemotherapy: Before the infusion, Layla was given a specific chemotherapy regimen including Campath/Lemtrada. This was intended to wipe out her remaining immune system to create a niche for the donor cells to grow without being immediately rejected.

• The Infusion: Layla received a 1mL dose containing approximately 5 million engineered T-cells per kilogram of her body weight. The infusion itself took only 10 minutes.

• The “Wait and See” Period: Because the TRAC gene was knocked out, doctors were watching specifically for any signs of Graft-versus-Host Disease (GvHD). If the engineering failed, the cells would have attacked her skin, liver, and gut.

The outcome was described by her lead clinician, Professor Paul Veys, as “almost a miracle.” Within 28 days of the infusion, tests showed that the UCART19 cells had successfully expanded in her blood and she was in molecular remission (no detectable cancer cells). About two weeks post-infusion, Layla developed a mild skin rash. While usually a scary sign of GvHD, in this context, it was a positive clinical marker that the donor cells were active and taking in her body. The most critical outcome was that the UCART19 cells cleared the cancer long enough to allow her to receive a second bone marrow transplant from a different donor. This transplant was necessary to provide her with a long-lasting, healthy immune system, as the UCART cells were designed to eventually disappear. Layla’s case study has since been documented in documented in several high-impact journals:

• Qasim, W., et al. Science (2017): This is the definitive paper that details her specific dosage (4.6 x 10⁶ cells/kg), the “Double Knockout” (TRAC and CD52), and the molecular confirmation that the donor cells successfully eliminated her leukemia without causing GvHD.

• Benjamin, R., et al. Lancet (2020): This publication expanded on Layla’s success, showing that the UCART19 platform worked in a larger cohort of 21 patients (7 children and 14 adults). It confirmed a 67% complete response rate in the pediatric group, directly tracing back to the protocol used for Layla.

With the clinical success of Layla Richards, Cellectis and their partners re-architected the future of UCAR19. In 2018, Cellectis’ partner Pfizer decided to shift its oncology strategy. While they remained interested in the technology, they felt the allogeneic portfolio would advance faster within a more agile, dedicated startup environment. Pfizer contributed its entire portfolio of allogeneic CAR-T assets (including the UCART19 rights and 16 preclinical targets) to a newly formed company: Allogene Therapeutics. In exchange for these assets, Pfizer took a 25% ownership stake in Allogene, allowing them to benefit from the upside of the technology without managing the day-to-day R&D. Allogene was founded by Arie Belldegrun and David Chang, the same team that built Kite Pharma and successfully developed the first autologous CAR-T (Yescarta). Their expertise in taking cell therapies through the FDA was seen as the missing piece to move the UCART platform from academic proof-of-concept into a commercial product. Allogene launched with $300 million in Series A funding, ensuring the UCART19 trials (CALM and PALL) would be fully funded without Cellectis having to bear the cost. Cellectis remained eligible for up to $2.8 billion in milestone payments plus royalties.

On April 13, 2026, Allogene announced that the pivotal Phase 2 ALPHA3 trial evaluating UCAR19 (now called cema-cel) versus standard of care as a first-line consolidation therapy for patients with high-risk Large B-cell Lymphoma (LBCL) showed a positive interim signal (press release, slide deck). Approximately 58.3% of cema-cel-treated patients achieved minimal residual disease (MRD) clearance at Day 45, compared to 16.7% MRD clearance among patients in the observation arm. Furthermore, patients receiving cema-cel saw a median 97.7% decrease in plasma ctDNA by Day 45, while the observation arm saw a median increase of 26.6%. In oncology, MRD (Minimal Residual Disease) refers to the small number of cancer cells that remain in the body after treatment. These cells are below the limit of detection (invisible) to standard imaging like PET or CT scans but can be detected through highly sensitive liquid biopsies that track circulating tumor DNA (ctDNA). Achieving MRD clearance is a critical clinical milestone because it indicates that the treatment has eliminated the disease at a molecular level, significantly reducing the risk of a future relapse.

Did cema-cel deliver the logistical gains that were the hope for allogeneic CAR-T? While this trial didn’t compare cema-cel directly against autologous CAR-T, there are some initial observations that we can make:

• Outpatient Management: The primary barrier to outpatient CAR-T is the risk of Cytokine Release Syndrome (CRS) and ICANS (neurotoxicity). The FDA package insert and registration trials for the autologous CAR-T Yescarta reported a 94% incidence of CRS in patients with Large B-cell Lymphoma. Clinical guidelines from institutions like MD Anderson (the CARTOX algorithm) and systematic reviews in PMC confirm that patients are typically monitored inpatient for 7–14 days due to the median onset of CRS occurring within the first week (typically Day 2 to Day 5). On the other hand, allogeneic CAR-T cema-cel reported 0% CRS and 0% ICANS in the outpatient cohort, enabling 83% of patients (10 out of 12) to be managed entirely as outpatients, never requiring a hospital bed for treatment-related issues.

• Community Access: A 2025 report from the University of Kansas Cancer Center, which notes that only 20% to 30% of eligible patients eventually receive therapy. This is primarily because they cannot travel to or stay near a specialized urban transplant center for the required month of monitoring. In contrast, approximately 33% of screening and infusions of allogeneic CAR-T cema-cel took place at community cancer centers, highlighting the potential for this “off-the-shelf” therapy to be administered outside of specialized academic hospitals. By removing the requirement for a 24/7 inpatient oncology ward, the potential addressable market for cema-cel could potentially be significantly larger than for any autologous product currently on the market.

Following the positive interim futility analysis reported in April 2026, Allogene Therapeutics’ next steps are focused on completing the clinical evidence required for a Biologics License Application (BLA), a comprehensive request submitted to the FDA for permission to market a new biological product in the United States. While the interim data focused on MRD clearance (molecular evidence of cancer detection), the FDA requires longer-term clinical outcomes for approval. Allogene expects to present this data on Event-Free Survival (EFS), the ALPHA3 trial’s primary endpoint, in min-2027. If successful, it could support a BLA filing and, if it clears the FDA’s stringent regulatory review process, cema-cel could become the first ever approved allogeneic CAR-T therapy.

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In Vivo CAR-T, Programming T-cells in the Body

Allogeneic CAR-T offered a potential solution to autologous CAR-T’s logistical burden by allowing oncologists to delivering pre-engineered cells from “off-the-shelf” instead of triggering a month-long process of programming the patient’s own T-cells. However, it still requires lymphodepleting chemotherapy, a grueling process for already an already frail patient. In vivo CAR-T, where CAR-T cells are programmed within the body, is a potential solution to both problems.

While this technology is immature (most are preclinical or Phase 1 stage), there had been a spate of acquisitions in the space, totaling nearly $15 billion in deal value over the last 18 months (see table below). Biotech Readout discussed one of these acquisitions, Eli Lilly’s purchase of Kelonia for $3.25 billion and up to $7 billion including clinical, regulatory and commercial milestone payments. This signals unusually high enthusiasm for in vivo CAR-T among big pharma acquirers, who typically prefer to acquire FDA-approved or Phase 3 assets (~61% of acquisitions in our internal dataset) because they generate a better risk-adjusted return on investment, a must-have in order to compensate for impending patent cliffs.

So, how do these companies aim to subvert a long and expensive manufacturing process, and instead create CAR-T within patients themselves? They are undertaking two general approaches:

• Viral Vector Approaches: Kelonia (Eli Lilly), EsoBiotech (AstraZeneca), Interius (Gilead) used hollowed-out lentiviruses that were engineered to be immune-shielded and cell-specific so they can be injected directly into the bloodstream. Their viruses used Nanobodies or scFvs to bind only to specific immune cells (like CD8+ T cells) and insert a chimeric antigen receptor (CAR) gene directly into the patient’s DNA. Since the gene is integrated into the T-cell’s DNA, the resulting CAR-T cells are longer-lasting. When the T cell divides, the CAR gene is passed on, potentially providing durable surveillance against cancer recurrence. Eli Lilly’s $7B acquisition of Kelonia (April 2026) is the current high-water mark for the field. Kelonia’s iGPS system showed 100% minimal residual disease (MRD)-negative response rate across four patients in a small Phase 1 clinical trial, with MRD-negative responses maintained through three months in the two patients with the longest follow up. This result did not require the need for toxic lymphodepleting chemotherapy.

• Non-Viral RNA Approaches: Capstan (AbbVie) borrows the approach used in COVID-19 vaccines. They package mRNA inside a Lipid Nanoparticle (LNP) that has been decorated with antibodies to find T cells. The LNP delivers mRNA into the T cell. The cell’s internal machinery reads the mRNA and temporarily expresses the CAR protein on its surface. Unlike viral vectors, mRNA does not integrate into the DNA. The CAR expression eventually fades away. This could make it safer, but there isn’t data to back this up. Orna (Eli Lilly) and Orbital (Brisol-Myers Squibb) used a similar LNP approach, but loaded it with circular RNA (cRNA) instead of mRNA. Circular RNA (oRNA) has been hailed as the next generation RNA approach. While standard mRNA is a linear strand that the body breaks down quickly, circular RNA is a closed loop, which makes it more challenging for the body’s “trash-collecting” enzymes (exonucleases) to find an end to start chewing it up. Circular RNA can survive in the cell much longer than linear mRNA (one review claimed that cRNAs exhibited protein expression for 7 days compared to less than a full day for mRNA). This could allow for days of CAR expression rather than hours, without permanent DNA integration and other potential safety risks of a viral vector.

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T-cell Engagers (TCE), Antibodies that Rally the Troops

T-cell engagers (TCEs) are specialized types of immunotherapies, typically bispecific antibodies, designed to bridge the gap between a patient’s immune system and a target cell (usually a cancer cell or a pathogenic B-cell). Unlike traditional antibodies that simply flag a target for destruction, a TCE act as a molecular matchmaker: it physically grabs a T-cell and pulls it into direct contact with the target cell to force an immune attack. A T-cell engager has two distinct binding arms:

• The Effector Arm (anti-CD3): This arm binds to the CD3 receptor on the surface of a T-cell. This binding bypasses the normal, complex “recognition” process of the immune system and essentially “hot-wires” the T-cell into an active state.

• The Target Arm (BCMA, CD19, and PSMA are the most common): This arm binds to a specific protein found on the surface of the cell you want to kill.

By bringing these two cells into close proximity, the TCE creates an artificial synapse. The T-cell then releases toxic enzymes (perforins and granzymes) that punch holes in the target cell, causing it to die. T-cell engagers represent a third “off-the-shelf” alternative to CAR-T therapy, an antibody that mimics the function of the cell therapy.

The development of TCE’s occurred in parallel to Dr. Michel Sadelain’s and Dr. Carl June’s development of CAR-T. The foundational spark occurred in 1985 with a landmark paper in Nature by Uwe Staerz and Michael Bevan the Scripps Research Institute in La Jolla, California. They didn’t have bispecific antibodies as we know them. Instead, they took two different monoclonal antibodies, one that targeted the T-cell receptor (TCR) and one that targeted a specific antigen, and chemically cross-linked them into a single “heteroaggregate.” They showed that these hybrid molecules could bypass the need for a T-cell to recognize a cancer cell naturally and forced a physical connection that triggered the T-cell to release its lethal payload (perforins) regardless of the cancer’s attempts to hide.

Two years after the Staerz/Bevan’s chemical heteroaggregate discovery, Mike Clark and Herman Waldmann at the University of Cambridge in the United Kingdom published the first description of a true bispecific antibody (bsAb) created through “hybrid hybridomas” (often called Quadromas). They fused two different antibody-producing cells together. The resulting cell would spit out a “mosaic” antibody that had one arm for the T-cell and one arm for the target. However, their protocol had a critical flaw: it was a manufacturing nightmare. The fused cells produced ten different combinations of antibody arms, and only one of those ten was the correct bispecific molecule. Purifying the intended bsAb was nearly impossible at the time.

In 1990, Dr. Taizo Nitta and his colleagues at the Juntendo University School of Medicine in Tokyo provided the first evidence that these “bridging molecules” could actually shrink tumors in human patients.Their findings, published in The Lancet and the Journal of Neurosurgery, remain a foundational milestone in the history of T-cell engagers (TCEs). The study focused on malignant glioma (an aggressive brain cancer), a disease chosen because it was notoriously resistant to conventional surgery and chemotherapy. They used a bispecific antibody (BsAb) created through the Quadroma (hybrid-hybridoma) method. One arm of the antibody targeted CD3 (on the T cell), and the other targeted a Glioma-Associated Antigen on the tumor cells.

The 1990 Lancet paper, titled “Preliminary trial of specific targeting therapy against malignant glioma,” reported several key findings. In a small pilot group of 10 patients, they observed significant tumor shrinkage (regression) in several cases. They proved for the first time in humans that you could kill cancer cells without the T cell needing to “naturally” recognize the tumor through the MHC system. The antibody bridge was sufficient to trigger the kill. While side effects like fever were noted, the treatment did not cause the catastrophic brain swelling that many had feared would occur when activating T cells in the confined space of the skull.

While the Lancet paper focused on the clinical outcomes, the Journal of Neurosurgery paper titled “Induction of cytotoxicity in human T cells coated with anti-glioma x anti-CD3 bispecific antibody against human glioma cells“ detailed the “how”, specifically the laboratory engineering and the cellular proof-of-concept. Instead of a simple IV drip of the TCE, they infused T-cells that were coated with a CD3 x Anti-Glioma TCE outside of the body. They harvested T cells (specifically Lymphokine-Activated Killer or LAK cells) from the patient, coated them with the bispecific antibody in a lab, and then re-infused these primed cells directly into the tumor cavity or the carotid artery.

Despite Nitta’s success, the field stalled shortly afterwards. Patients had a toxic HAMA (Human Anti-Mouse Antibody) response; their immune systems would recognize the mouse-derived antibodies as foreign and destroy them. The same fate befell Removab (catumaxomab; EpCAM x CD3 TCE). In 2009, Removab became the first TCE approved in the EU for intraperitoneal treatment of malignant ascites in adult patients with EpCAM-positive carcinomas. Being a rat-mouse hybrid, it was highly immunogenic. Patients quickly developed Human Anti-Mouse Antibodies (HAMA) and Human Anti-Rat Antibodies (HARA), which essentially neutralized the drug after a few doses, making long-term treatment difficult. By 2013-2014, marketing of Removab effectively stopped, and in 2017, the marketing authorization was officially withdrawn. The original developer, TRION Pharma, faced significant financial distress and eventually went into insolvency. The partner, Fresenius Biotech, underwent a corporate restructuring and shifted focus away from specialty oncology. Lindis Biotech (founded by the original inventor, Dr. Horst Lindhofer) spent years regaining the rights and modernizing the process. In February 2025, the European Commission granted a new EMA marketing authorization for catumaxomab (under the brand name Korjuny) for the intraperitoneal treatment of malignant ascites, marking a significant comeback for the first-ever approved TCE. Partnering with Pharmanovia, the drug is being relaunched across Europe.

Meanwhile, Patrick Baeuerle and colleagues working at the Institute of Immunology at the University of Munich in Germany had spoun out a biotech company called Micromet in 1993. The aimed to solve the HAMA (Human Anti-Mouse Antibody) problem, though they did it through miniaturization and low dosing rather than full humanization. Micromet developed the Bispecific T-cell Engager (BiTE) platform. By stripping away the bulky Fc region of an antibody and linking only the binding arms (scFvs) with a flexible peptide chain, they created a molecule that was only 55 kDa, about 1/3 the size of a standard antibody. This smaller size was critical. It allowed the T-cell and the cancer cell to get close enough, approximately 15 nanometers, to form an immunological synapse. This helped reduce the toxic HAMA (Human Anti-Mouse Antibody) response in two ways:

• Small Surface Area: By removing the Fc region of the antibody, body’s immune system had less surface area to recognize it as foreign, significantly lowering the HAMA response compared to the 1990-era drugs.

• Less Drug: Since the BiTE platform was so efficient at creating an immunological synapse, it worked at incredibly low concentrations. The body can’t develop an allergic-like response (HAMA) to something that is barely present in the bloodstream. The dose was so small that it often stayed under the radar of the patient’s antibody-producing B-cells.

In 2008, Micromet published a landmark study in Science showing that incredibly low doses of their lead program blinatumomab (then called MT103) could clear tumors in patients with Non-Hodgkin Lymphoma (NHL). Before this publication, the industry was skeptical that a drug with such a short half-life and such low dosing could actually eliminate established tumors in humans. Researchers observed complete tumor regressions at a dose of just 0.005 milligrams per square meter per day. For context, that is roughly 10,000 times lower than the dose of a standard monoclonal antibody like Rituxan. Out of the patients treated at the target dose level, 100% showed a reduction of tumor cells in the blood, and several experienced complete and partial responses, even those who had failed all previous lines of chemotherapy.

Inspired by this initial positive data blinatumomab, Micromet paid to buy back the North American rights for blinatumomab from MedImmune, giving them 100% global rights to the drug. To fund their independent operations, they partnered with Sanofi for other BiTE assets, which provided non-dilutive capital and further validated the platform’s worth to external observers. In 2009, Micromet entered into a large-scale manufacturing agreement with Lonza, dispelling the skepticism that blinatumomab was un-manufacturable at scale.

They also initiated the pivotal Phase 2 BLAST trial in B-cell precursor Acute Lymphoblastic Leukemia (ALL). It was strategically designed around neutralizing Minimal Residual Disease (MRD), shifting the goalposts from treating treatment-resistant tumors to preventing the relapse. Micromet’s internal research suggested that T-cell engagers were most effective when the “T-cell to Tumor cell ratio” was in the T-cell’s favor. In late-stage patients, the sheer mass of the tumor often exhausts the T-cells. In MRD+ patients, the tumor burden is microscopic (less than 5% blasts).

Data from the Phase 2 BLAST trial were released at ASCO 2011 and ASH 2011 conferences. At the time, if a patient was MRD-positive after intensive consolidation chemotherapy, their chances of clearing that disease with more chemo were extremely low (typically <20%). Micromet showed that 16 out of 21 patients (76%–80%) with persistent or relapsed MRD became MRD-negative after just one 4-week cycle of blinatumomab. Crucially, 12 of the 16 responders were “molecularly refractory,” meaning their cancer had already seen and defeated the best chemotherapy cocktails available. Blinatumomab cleared them anyway.

The most “buzz-worthy” part of the 2011 presentation was the early survival curve. The study reported an Relapse-Free Survival (RFS) of 78% at a median follow-up of 405 days (~13.5 months). It solidified that achieving MRD-negativity with blinatumomab was a direct predictor of long-term survival. If the drug made you MRD-negative, your risk of death or relapse dropped by nearly three-fold. Although the 2011 paper was a pilot, it set the stage for the Landmark Analysis seen in the later BLAST study, where the difference in median RFS was 23.6 months for MRD-responders vs. 5.7 months for MRD-non-responders (see Kaplan-Meier curves below).

By late 2011, Micromet had full global rights, pivotal Phase 2 data, and a proven manufacturing process. Amgen, looking to diversify beyond its aging anemia franchise (Aranesp/Epogen), moved quickly. On January 26, 2012, Amgen announced a definitive merger agreement under which to acquire Micromet for approximately $1.16 billion, a roughly 33% premium at the time. The acquisition provided three distinct layers of value:

• The Lead Asset (Blinatumomab): At the time, it was in Phase 2 for acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL). Amgen’s massive regulatory and clinical infrastructure was exactly what was needed to push it through to its 2014 approval.

• The BiTE Platform: Amgen gained proprietary rights to the entire modular system, allowing them to rapidly create new TCEs by swapping out the tumor-binding arm.

• The Munich Center of Excellence: Amgen chose to keep Micromet’s Munich site operational. This ensured that the original brain trust of the BiTE platform remained intact, rather than losing the institutional knowledge through a messy integration.

The Micromet acquisition is often cited as one of the cleanest exits in biotech history because the company successfully solved the three main pillars of risk: Science, Manufacturing, and Legal Rights. It was clean for Amgen as well because, in just two years in 2014, the FDA granted accelerated approval to blinatumomab (marketed as Blincyto) for relapsed/refractory (R/R) B-cell precursor ALL, making it the first FDA-approved T-cell engager (TCE).

Later on, Amgen realized that Blincyto’s real power was not in “salvage” (late-stage) therapy, but in “consolidation” (early-stage). Following the successful Phase 3 E1910 trial, the FDA expanded Blincyto’s label to include frontline consolidation for Ph- B-ALL patients, regardless of their MRD status, effectively moving the ‘molecular matchmaker’ into the earliest stages of treatment. By the late 2010s, competitors were developing TCEs that could be given as a simple weekly injection. Amgen countered by evolving the Micromet platform. Amgen researchers in Munich (the original Micromet site) successfully added a humanized Fc region to the BiTE scaffold. This increased the molecular weight and prevented rapid kidney clearance, extending the half-life from ~2 hours to several days. This paved the way for subcutaneous dosing, removing the need for the continuous infusion pump.

Amgen used the “blinatumomab blueprint” to attack other cancers, leading to the diverse 2026 portfolio you see today, including Imdelltra (tarlatamab, DLL3 x CD3 TCE). This is perhaps the most successful descendant of the Micromet acquisition. It was approved in 2024 for Small Cell Lung Cancer (SCLC), proving the BiTE platform could finally crack the code of solid tumors.

While Amgen’s Blincyto (blinatumomab, CD19 x CD3 TCE) and Imdelltra (tarlatamab, DLL3 x CD3 TCE) paved the way, the 2022–2026 period has seen a Cambrian Explosion of T-cell engagers (TCEs) from other major players. As of May 2026, the market has matured, with several TCEs moving from late-stage salvage into earlier lines of therapy and subcutaneous formats:

• Roche/Genentech’s Lunsumio (mosunetuzumab, CD20 x CD3 TCE): This drug was approved for R/R Follicular Lymphoma (FL) in 2022. In December 2025, the FDA approved Lunsumio VELO, a subcutaneous version that reduced administration time from a 4-hour infusion to a one-minute injection.

• Johnson & Johnson’s Tecvayli (teclistamab, BCMA x CD3 TCE): This drug is the first FDA-approved TCE targeting BCMA (2022). Its March 2026 approval in combination with Darzalex Faspro for R/R MM after just one prior line of therapy has solidified it as a standard of care bridge, similar to how Blincyto moved upstream in ALL.

• Johnson & Johnson’s Talvey (talquetamab, GPRC5D x CD3 TCE): This drug is the first FDA-approved TCE targeting GPRC5D (2023). It is unique because it works for patients who have already failed BCMA-targeted therapies (like CAR-T or other TCEs).

• Pfizer’s Elrexfio (elranatamab, BCMA x CD3 TCE): This drug was approved for R/R multiple myeloma (MM) in 2023. In 2025-2026, it gained traction due to its fixed-dose subcutaneous schedule that moves to every-four-week dosing for responders, potentially increasing convenience for patients.

• Regeneron’s Lynozyfic (linvoseltamab, BCMA x CD3 TCE): This drug was recently approved in 2025 for heavily pre-treated MM. Regeneron is currently betting big on MRD-negativity (Phase 3 data due in 2028) to potentially challenge J&J’s dominance in frontline settings.

While Amgen dominates CD19 and DLL3, J&J and Pfizer have competed for the BCMA space, with J&J carving out a niche in GPRC5D to handle post-BCMA relapses. As of 4Q 2025, there are at least 87 clinical-stage TCE programs. T-cell engagers (TCEs) constitute a blockbuster therapeutic modality, representing an estimated aggregate revenue run rate of more than $4.6 billon as of 4Q 2025 according to quarterly press releases associated with Blincyto, Imdelltra, Tecvayli, Talvey, Elrexfio, Lunsumio, and Lynozyfic* (see below)

The acquisition landscape for T-cell engagers (TCEs) are also quite healthy, representing more than $9 billion in aggregate enterprise value (EV). We recently covered the largest TCE acquisition to date, UCB’s acquisition of Candid Therapeutics for $2 billion in upfront payments and up to $200 million in potential future milestone payments ($2.2 billion total).

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Conclusion

The journey from the first personalized CAR-T infusions to the modern era of allogeneic cells, in vivo engineering, and T-cell engagers represents a significant evolution in how we think about living drugs. We are moving away from the bespoke model of CAR-T, where every treatment is handcrafted for a single patient, and toward an “off-the-shelf“ future that is faster, cheaper, and more accessible. The milestones we’ve witnessed are dismantling of the barriers that have historically kept these treatments confined to elite academic centers:

• Allogeneic CAR-T is proving that we can use healthy donor cells to treat patients in days rather than weeks, as seen with early clinical cema-cel’s success in outpatient management.

• In vivo CAR-T promises to turn the human body itself into a manufacturing plant, potentially removing the need for toxic lymphodepleting chemotherapy.

• T-cell Engagers (TCEs) like Blincyto have brought the power of T-cell recruitment into the realm of half-life extended antibodies that require only weekly subcutaneous injections.

As we look toward Part 3, the CAR-T’s horizon expands even further. The same tools that were built to hunt down aggressive liquid tumors are now being re-tooled to reset the immune system itself. Stay tuned for Part 3 of this three-part Frontiers in Medicine series on CAR-T, where we explore how CAR-T is moving beyond oncology to tackle the challenge of autoimmune diseases, potentially offering a multi-year reset for patients with Lupus, Myasthenia Gravis, and beyond.

To contact us, please send us an email at biotechreadout@gmail.com

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Table of Contents

This week, we discuss…

…key data releases from the 33rd European Congress on Obesity (ECO):

• Eli Lilly / Weight loss maintenance with Foundayo (oral GLP-1 agonist) / Phase 3b ATTAIN-MAINTAIN (obesity) ⬇️

• Eli Lilly / Weight loss maintenance with low dose Zepbound (injectable GLP-1 agonist) / Phase 3b SURMOUNT-MAINTAIN (obesity) ⬇️

…two pathbreaking publications that merit a closer look (round of applause for academia this week!):

• Generic / Metformin (mechanism opaque) / Nature Metabolism paper revealing its mechanism after 70 years of opacity (T2D) ⬇️

• Preclinical proof of concept for rare disease with limited treatment options; Dr. David Liu Lab / ABE8e-V106W-VRQR (base editor) / Preclinical (Dravet syndrome with SCN1A-p.R613X mutation) ⬇️

…and other clinical data releases:

• Potentially best-in-disease; Inhibrx / INBRX-106 (hexavalent OX40 agonist) / Phase 2 (HNSCC) ⬇️

• AstraZeneca / Eneboparatide (PTH analog) / Phase 3 (hypoparathyroidism) ⬇️

• Potentially best-in-class; Regenxbio / RGX-202 (AAV8-microdystrophin) / Phase 3 (DMD) ⬇️

• Alkermes / Lumryz (ER sodium oxybate) / Phase 3 (idiopathic hypersomnia) ⬇️

• Cabaletta / Rese-cel (CD19-CAR T) / Phase 1 (PV) ⬇️

• AstraZeneca / Imfinzi (anti-PDL1 mAb) / Phase 3 (MIBC) ⬇️

Eli Lilly / Weight loss maintenance with Foundayo (oral GLP-1 agonist) / Phase 3b (obesity)

The ATTAIN-MAINTAIN Phase 3b clinical trial evaluated Foundayo (orforglipron), a first-in-class, oral, non-peptide GLP-1 receptor agonist, as a maintenance therapy for individuals who achieved initial weight loss using injectable GLP-1 medications like Wegovy (semaglutide) or Zepbound (tirzepatide). The data was officially presented today (May 12, 2026) at the 33rd European Congress on Obesity (ECO) held in Istanbul and the full study was simultaneously published in Nature Medicine.

• Indication: We covered the obesity in a two-part Frontiers in Medicine series (Part 1, Part 2).

• Mechanism: Foundayo is a small-molecule GLP-1 receptor agonist. Unlike existing peptide-based oral options (e.g., Rybelsus, oral Wegovy), it does not require complex absorption enhancers or strict fasting/water restrictions. It stimulates insulin secretion, suppresses glucagon, slows gastric emptying, and reduces appetite by acting on brain centers that regulate satiety.

• Trial design: The ATTAIN-MAINTAIN trial utilized a “switch” design to test the sustainability of weight loss when transitioning from injectable to oral therapy. It included adults with obesity or overweight (without Type 2 Diabetes) who had completed a 52-week weight loss induction phase on either injectable Wegovy (2.4 mg) or Zepbound (15 mg). After the induction phase, participants were re-randomized to receive once-daily Foundayo (orforglipron) or a placebo for an additional 52 weeks of maintenance. The primary endpoint was the percentage change in body weight from the start of the maintenance period (Week 52) to the end of the trial (Week 104).

• Data (press release, Nature Medicine paper): The trial demonstrated that Foundayo effectively maintained the weight loss achieved on injectables (see table below). Those who switched to Foundayo regained an average of only 0.9 kg over the year, compared to significant weight regain typically seen in placebo groups after stopping injectables. The most common adverse events were gastrointestinal (nausea, vomiting).

• Impact:

  • Foundayo for Weight Loss Maintenance: It provides a clinically viable exit strategy for patients who want to transition off weekly injections but fear the rebound weight gain associated with treatment cessation.

  • Oral Convenience: Foundayo removes the needle phobia and the fasting requirement associated with other GLP-1 therapies. It can be taken at any time of day, with or without food.

• Next steps: Following its FDA approval on April 1, 2026, the manufacturer is pursuing regulatory filings Foundayo in the UK (MHRA) and EU (EMA). The trial sponsor telegraphed than future studies will focus on the 3- to 5-year durability of maintenance to see if patients can remain on a low-dose oral maintenance pill indefinitely. Data from the separate ATTAIN-CVOT trial will be monitored to confirm if Foundayo provides the same heart-protective benefits as injectable Wegovy.

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Eli Lilly / Weight loss maintenance with low dose Zepbound (injectable GLP-1 agonist) / Phase 3b (obesity)

The SURMOUNT-MAINTAIN Phase 3b trial results, officially presented today (May 12, 2026) at the European Congress on Obesity (ECO) and published in The Lancet, provide critical evidence for the “maintenance phase” of obesity treatment. This study addresses a key clinical question: Can patients maintain their weight loss on a lower “maintenance dose” of Zepbound (tirzepatide)?

• Indication: We covered the obesity in a two-part Frontiers in Medicine series (Part 1, Part 2).

• Mechanism: Zepbound (tirzepatide) is a dual GIP and GLP-1 receptor agonist. GIP potentiates insulin secretion and acts on the brain to improve lipid metabolism and potentially reduce the nausea often associated with GLP-1 alone. GLP-1 delays gastric emptying and increases satiety. The combination leads to superior weight loss compared to single GLP-1 agonists by targeting multiple metabolic pathways and appetite centers in the hypothalamus.

• Trial design: The SURMOUNT-MAINTAIN Phase 3b trial focused on dose-reduction as a long-term strategy for weight management. It included 441 participants with obesity or overweight (without diabetes) who received 60 weeks of open-label Zepbound, titrated to their Maximum Tolerated Dose (MTD), either 10 mg or 15 mg. Those who achieved a weight plateau (losing ≥5% of body weight) were re-randomized for 52 additional weeks into three arms:

  • Continuation of MTD: Remained on 10 mg or 15 mg Zepbound.

  • Dose Reduction: Stepped down to a 5 mg maintenance dose of Zepbound.

  • Placebo: Switched to a weekly placebo injection.

• Data (press release, Lancet paper): The trial demonstrated a clear dose-response relationship for maintaining weight loss (see graph below). Discontinuation due to adverse events during the maintenance phase was extremely low: 0% for MTD and 0.7% for the 5 mg dose. Nausea and vomiting were significantly lower in the 5 mg group compared to those staying on the higher MTD.

• Impact:

  • “Step-Down” Strategy: The “placebo rebound” (regaining over half of the lost weight) confirms that obesity is a chronic condition requiring long-term pharmacotherapy. For the first time, clinicians have high-quality data showing that 5 mg is a viable “maintenance pill” (or injection). While it may result in a small amount of regain, it drastically improves tolerability and remains far superior to stopping treatment entirely.

  • Economic Benefit: Using a lower dose for maintenance could potentially reduce the long-term cost of treatment and improve supply chain availability for the higher-dose pens.

• Next steps: Eli Lilly is expected to use this data to update the Zepbound prescribing information to include specific maintenance dosing guidelines. Next-stage trials are monitoring Morbidity and Mortality in Obesity (SURMOUNT-MMO) to see if the 5 mg dose provides the same long-term cardiovascular and renal protection as the higher doses.

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Generic / Metformin (mechanism opaque) / Nature Metabolism paper revealing its mechanism (T2D)

• Indication: Type 2 diabetes (T2D) is characterized by a dual failure of glucose regulation: peripheral insulin resistance, where cells (muscle, liver, and fat) stop responding effectively to insulin, and a compensatory beta-cell dysfunction where the pancreas can no longer produce enough insulin to overcome that resistance. This results in chronic hyperglycemia, which can damage blood vessels and organs over time. Metformin remains the first-line gold standard of care, despite our limited understanding of its mechanism of action, because it addresses this pathology without causing weight gain or hypoglycemia.

• Mechanism: The mechanism of metformin has been considered clinically opaque for approximately 70 years, dating back to its first use for diabetes in the mid-1950s. While metformin is the most widely prescribed drug for Type 2 Diabetes (T2D), it was discovered before the era of target-based drug design. For decades, the medical community accepted that it worked, even as they debated exactly how. Here is a brief timeline describing the opacity:

  • 1922–1957 (The Origins): Metformin was first synthesized in 1922 but sat in obscurity for decades. It was finally introduced as a diabetes treatment in 1957 by Jean Sterne.

  • 1994–2000 (The Mitochondrial Theory): Researchers began to suspect the liver was the primary target. In 2000, two independent groups proposed that it works by inhibiting Complex I of the mitochondrial electron transport chain.

  • 2001–2020 (The AMPK Debate): For nearly 20 years, the leading theory was that it worked through the AMPK pathway. However, this was later challenged by “loss-of-function” studies showing the drug still worked even without AMPK, throwing the mechanism back into uncertainty.

  • 2025 (The “Brain Pathway” Breakthrough): In July 2025, researchers have identified a “hidden” neural mechanism. Studies published in Science Advances revealed that metformin suppresses a protein called Rap1 in the hypothalamus, activating specific neurons to lower blood sugar.

• Summary of the old theory for how metformin worked: For more than three decades, the medical community has operated under a comfortable consensus: Metformin, the world’s most widely prescribed diabetes medication, works by targeting the liver. The narrative was simple and elegant. The drug enters the body, travels to the liver, and shuts down the production of excess glucose (gluconeogenesis). However, a persistent molecular mystery remained beneath the surface. Clinical data increasingly showed that standard doses of metformin rarely reach the liver in concentrations high enough to actually inhibit its molecular targets. Even more puzzling, recent studies noted that metformin fails to reduce glucose production in patients with well-controlled or recent-onset type II diabetes—yet the drug remains remarkably effective. If the liver isn’t the primary battlefield, where is the war against high blood sugar actually being won?

• New Data (Nature Metabolism paper): The key finding in the new research involves how metformin tricks the body into disposing of sugar. Using FDG-PET imaging, the researchers observed that metformin causes the small and large intestines to light up with activity. This happens because metformin inhibits mitochondrial complex I specifically within the intestinal epithelium (the gut lining). When these mitochondria are suppressed, the gut cells face an immediate energy crisis. To compensate, they stop relying on efficient oxygen-based energy production and switch to a high-speed, glucose-burning mode called glycolysis. Essentially, the drug turns the gut into a “glucose sink.” Instead of sugar passing through the intestinal wall and into the bloodstream, the gut cells pull massive amounts of glucose out of circulation to fuel their own survival.

• Impact:

  • Potential for “Better Metformin”: The study suggests that the future of biguanide therapy may lie in gut-restricted formulations that keep the drug’s concentration high in the intestines while minimizing systemic absorption. By combining gut-targeted drugs with P-glycoprotein inhibitors (like encequidar), researchers achieved a “far more dramatic” glucose-lowering effect with a similar drug (berberine). This approach could be used to develop new, more powerful metformin-like therapies that act exclusively in the “glucose sink” of the gut without causing toxicity in other organs.

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Dr. David Liu Lab / ABE8e-V106W-VRQR (base editor) / Preclinical (Dravet syndrome with SCN1A-p.R613X mutation)

In a study published in Science Translational Medicine on May 13, 2026, researchers from the David Liu Lab at the Broad Institute of MIT and Harvard, in collaboration with The Jackson Laboratory, demonstrated a potentially transformative approach to treating Dravet syndrome in genetic mouse models and human cells lines that mimic the disease.

• Indication: Dravet Syndrome (DS) is a catastrophic neurodevelopmental channelopathy characterized by treatment-resistant epilepsy, temperature-sensitive seizures, and a high incidence of sudden unexpected death in epilepsy (SUDEP). Approximately 80% to 90% of cases arise from de novo loss-of-function variants in SCN1A, the gene encoding the voltage-gated sodium channel α subunit Nav1.1. While current pharmacological management addresses symptomatic seizure burden, it fails to remediate the underlying genetic haploinsufficiency. In humans, DS symptoms typically manifest between 3 and 6 months of age, coinciding with the developmental surge in SCN1A expression. This temporal window defines a critical opportunity for disease prevention. The molecular pathology of the SCN1A-p.R613X variant centers on the impairment of parvalbumin-expressing (PV) inhibitory interneurons, where Nav1.1 is preferentially expressed. The introduction of a premature stop codon triggers nonsense-mediated decay (NMD) of the mutant transcript, leading to a profound reduction in Nav1.1 protein levels. This deficiency causes PV-interneuron hypoexcitability, disrupting the cortical inhibitory-excitatory balance and precipitating the DS phenotype.

• Mechanism: The ABE8e-V106W-VRQR is a precision genome editing tool designed to correct genetic mutations by converting A·T base pairs to G·C at specific locations without requiring double-stranded DNA breaks or donor DNA templates. Its mechanism is defined by the synergy of its three primary components: a highly active deaminase (ABE8e), a precision-enhancing mutation (V106W), and a flexible DNA-binding Cas9 domain (VRQR). To treat Dravet syndrome, the ABE8e-V106W-VRQR was used to target a specific Arg-to-STOP mutation (CGA > TGA). The editor binds to the target site using the VRQR domain guided by an sgRNA, and the V106W-modified ABE8e deaminase converted the stop codon (TGA) back into the functional arginine codon (CGA). This direct correction is designed to restore the production of functional Nav1.1 sodium channels, addressing the root cause of the disease. The system achieved 97% mRNA editing efficiency in the mouse neocortex when administered via one intracerebroventricular (ICV) injection, successfully targeting Parvalbumin-positive inhibitory neurons (PVINs).

• Data (Science Translational Medicine paper):

  • Outcomes of treated Dravet mice: In the 42.5°C heat lamp test (simulating a high fever), 100% of ABE-treated mice remained seizure-free, whereas vehicle-treated controls suffered seizures at an average of 40°C. 24-hour video monitoring showed that treatment entirely eliminated spontaneous seizures in treated animals, while 50–60% of untreated mice experienced frequent events. Treated Dravet mice achieved a 90% survival rate at Day 45 versus 27% survival in untreated mice.

  • Whole-cell patch-clamp recordings of Dravet mouse neurons: The team demonstrated that ABE treatment successfully rebalanced the brain’s circuitry. By correcting the sodium current and firing kinetics of these interneurons, the treatment successfully reversed the “electrical storms” of the Dravet brain, restoring the inhibitory brakes needed to prevent paroxysmal activity.

• Impact: Note that this approach is neither approved for use in human patients, nor is there any indication that it will enter clinical trials (as of May 2026). Before this can be applied to human patients, several areas require further optimization.

  • Optimization for Other SCN1A Variants: Because base editing is a precision tool, different strategies must be optimized for each specific genetic variant found in DS patients. . However, over 1,400 pathogenic SCN1A variants are currently identified that could potentially be targeted by precision genome editing like base or prime editing.

  • Advanced Delivery Methods: While this study used AAV9, future human applications may benefit from more transient delivery modalities, such as lipid nanoparticles (LNPs) or engineered virus-like particles (eVLPs), which could further reduce the risk of long-term off-target editing. Optimization for in human pharmacokinetics and safety would require Phase 1 clinical trials at least.

  • Early Genetic Screening: The researchers emphasize that early genetic screening and the use of pathogenicity-scoring tools (like AlphaMissense) will be essential to identify candidates for intervention before severe symptoms manifest.

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Inhibrx / INBRX-106 (hexavalent OX40 agonist) / Phase 2 (HNSCC)

The Phase 2/3 HexAgon-HN trial results represent a potential breakthrough for INBRX-106, a first-in-class hexavalent OX40 agonist, particularly in a landscape where previous bivalent OX40 candidates have historically failed to show clinical efficacy.

• Indication: Head and Neck Squamous Cell Carcinoma (HNSCC) primarily arises from the mucosal epithelium of the oral cavity, pharynx, and larynx, driven by genomic instability from chronic carcinogen exposure (tobacco and alcohol) or high-risk Human Papillomavirus (HPV) infection. Pathophysiologically, these insults lead to the loss of tumor suppressors like p53 and p16, alongside the upregulation of growth factor receptors such as EGFR, creating an immunosuppressive microenvironment that facilitates local invasion and lymphatic spread. The standard of care is risk-stratified: early-stage disease is typically managed with single-modality surgery or radiation, while locally advanced cases require a multidisciplinary approach involving surgery followed by adjuvant chemoradiotherapy or definitive cisplatin-based radiation. For recurrent or metastatic disease, the paradigm has shifted toward immune checkpoint inhibitors (e.g., pembrolizumab) with or without platinum-based chemotherapy, depending on PD-L1 expression levels.

• Mechanism: Unlike traditional bivalent antibodies that typically require Fc-receptor cross-linking to activate their targets, INBRX-106 is engineered as a hexavalent molecule. It induces higher-order clustering of the OX40 (CD134) receptor, which is critical for potent downstream signaling. OX40 is a tumor necrosis factor receptor (TNFR) family member expressed on activated CD4+ and CD8+ T cells. Agonism leads to enhanced T-cell survival, proliferation, and effector function. Combining INBRX-106 with Keytruda (pembrolizumab) addresses checkpoint resistance by providing a positive costimulatory “gas pedal” (OX40) while simultaneously removing the “brakes” (PD-1).

• Trial design: The data stems from the randomized, open-label Phase 2/3 HexAgon-HN study evaluating INBRX-106 in combination with Keytruda versus Keytruda alone in first-line (1L) patients with recurrent or metastatic (R/M) Head and Neck Squamous Cell Carcinoma (HNSCC). Patients were required to have a PD-L1 Combined Positive Score (CPS) ≥20.

• Data (press release): The reported readout shows a significant doubling of the objective response rate (ORR) compared to the current standard of care (44% for INBRX-106 + Keytruda versus 21.4% for Keytruda monotherapy). Early signals suggest the combination is generally well-tolerated, with most adverse events being Grade 1 or 2, avoiding the severe toxicity often seen with high-dose cytokine or early-generation co-stimulatory agents.

• Impact:

  • Overcoming “Cold” Tumors: HNSCC is highly immunosuppressive; the 44% ORR suggests that hexavalent OX40 agonism can successfully prime the immune system in patients who would otherwise have a limited response to PD-1 inhibitors alone.

  • Potentially Best-in-Indication: This data places INBRX-106 at the forefront of the “next generation” of HNSCC therapies, potentially challenging the current 1L standard of care for high PD-L1 expressing patients.

• Next steps: Following the success of the Phase 2 portion, the trial is designed to transition into a Phase 3 registrational study to confirm these ORR results and evaluate long-term endpoints like Progression-Free Survival (PFS) and Overall Survival (OS). If the Phase 3 data remains consistent, Inhibrx (under Sanofi, following their acquisition) will likely seek FDA approval for INBRX-106 as a 1L combination therapy for HNSCC.

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AstraZeneca / Eneboparatide (PTH analog) / Phase 3 (hypoparathyroidism)

AstraZeneca recently reported positive topline results for the Phase 3 CALYPSO trial evaluating eneboparatide (AZP-3601) in adults with chronic hypoparathyroidism. The data, presented at the European Congress of Endocrinology (ECE) 2026 in Prague, marks a significant step forward for AstraZeneca’s rare disease division, Alexion.

• Indication: The pathophysiology of hypoparathyroidism is defined by the absolute or relative deficiency of parathyroid hormone (PTH), which disrupts systemic mineral homeostasis. Under normal conditions, PTH stimulates bone resorption, distal renal calcium reabsorption, and the conversion of vitamin D to its active form (1,25(OH)₂D) to increase intestinal calcium absorption; its absence lead to the biochemical triad of hypocalcemia, hyperphosphatemia, and hypercalciuria. While most cases are acquired (post-surgical damage during neck surgery), others are autoimmune or genetic (e.g., CaSR or GATA3 mutations). The standard of care has historically relied on “conventional therapy” with high-dose oral calcium and active vitamin D (calcitriol), but this approach often fails to address long-term complications such as nephrocalcinosis and chronic kidney disease. Consequently, recent 2025-2026 clinical guidelines have shifted toward PTH replacement therapy, specifically with the FDA-approved Yorvipath (palopegteriparatide), which provides a more physiologic replacement that stabilizes serum calcium while reducing the risk of renal damage and improving patient quality of life.

• Mechanism: Eneboparatide is a novel, synthetic peptide designed as a selective PTH1 receptor agonist. It binds with high affinity to the R⁰ conformation of the PTH1 receptor. This specific binding triggers a sustained cyclic AMP (cAMP) signal, which more closely mimics physiological PTH activity compared to earlier analogs.conformation of the PTH1 receptor. This specific binding triggers a sustained cyclic AMP (cAMP) signal, which more closely mimics physiological PTH activity compared to earlier analogs.onformation of the PTH1 receptor. This specific binding triggers a sustained cyclic AMP (cAMP) signal, which more closely mimics physiological PTH activity compared to earlier analogs. It is engineered to maintain serum calcium (sCa) within the normal range while simultaneously increasing renal calcium reabsorption (reducing urinary calcium) and maintaining a balanced resumption of bone turnover without causing excessive bone resorption.

• Trial design: CALYPSO is the largest global Phase 3 trial conducted in 202 adults with chronic hypoparathyroidism receiving standard of care (oral calcium and active vitamin D). Patients were randomized 2:1 (eneboparatide vs. placebo) for a 24-week double-blind treatment period. Patients in the treatment arm were dosed with once-daily subcutaneous injections of eneboparatide starting at 20 µg, with titration up to 100 µg. The trial’s composite endpoint was achievement of normal albumin-adjusted serum calcium (8.3–10.6 mg/dL) AND independence from conventional therapy (elimination of active vitamin D and ≤600 mg/day of oral calcium).

• Data (press release): The trial met its primary and all key secondary endpoints with high statistical significance (p = 0.0001).

  • Primary Endpoint (Normalization + Independence): 31.1% of eneboparatide patients met the composite goal at Week 24 vs. 5.9% in the placebo group.

  • Secondary Endpoint (Hypercalciuria): Among patients with high urinary calcium at baseline, 56.6% normalized their levels on eneboparatide vs. 20% on placebo.

  • Bone Health: Biomarkers (P1NP and CTX) remained within normal ranges, and there was no clinically significant decline in bone mineral density (BMD) through 52 weeks.

  • Safety: Generally well-tolerated. While immunogenicity (anti-drug antibodies) was observed in a majority of patients, the company noted that calcium control could still be maintained through dose titration.

• Impact:

  • Renal Protection: By specifically reducing urinary calcium excretion (hypercalciuria), eneboparatide addresses one of the most significant long-term risks of hypoparathyroidism, chronic kidney disease and nephrocalcinosis.

  • Quality of Life: Significant improvements were reported in disease-specific physical symptoms and physical functioning scores (SF-36).

  • Physiologic Balance: Its design aims to avoid the bone-stripping effect sometimes seen with continuous high-dose PTH exposure, making it a potentially safer long-term option for skeletal integrity.

• Next steps: Detailed results from the 52-week open-label extension (which showed sustained benefits) were presented alongside the primary data. AstraZeneca plans to move forward with global regulatory submissions. Eneboparatide will likely compete with Ascendis Pharma’s Yorvipath (palopegteriparatide), which was approved a couple of years ago on August 12, 2024.

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Regenxbio / RGX-202 (AAV8-microdystrophin) / Phase 3 (DMD)

On May 14, 2026, REGENXBIO announced pivotal topline results for RGX-202 in Duchenne Muscular Dystrophy (DMD). While the trial hit its primary biomarker endpoint with high statistical significance, the market’s reaction has been tempered by a reported case of myocarditis and broader skepticism regarding single-arm gene therapy approvals.

• Indication: Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disorder characterized by the absence or functional deficiency of dystrophin, a critical protein that anchors the cytoskeleton of muscle fibers to the surrounding extracellular matrix. Pathophysiologically, the lack of dystrophin renders the sarcolemma fragile, leading to membrane rupture during muscle contraction, chronic calcium influx, and a cascade of inflammation and oxidative stress that results in the progressive replacement of muscle tissue with fibrosis and adipose tissue. The standard of care focuses on multidisciplinary management, primarily utilizing long-term corticosteroid therapy (e.g., prednisone or deflazacort) to delay the loss of ambulation and preserve respiratory and cardiac function. In recent years, the paradigm has expanded to include mutation-specific exon-skipping therapies and the first FDA-approved gene therapy, Elevydis (delandistrogene moxeparvovec-rokl), which aims to introduce a functional micro-dystrophin transgene to address the underlying genetic cause.

• Mechanism: RGX-202 uses an AAV8 vector to deliver a proprietary microdystrophin transgene. It is currently the only clinical-stage gene therapy that includes the C-Terminal (CT) domain. The CT domain is designed to recruit key proteins to the muscle cell membrane, potentially providing superior structural integrity and protection against contraction-induced damage compared to truncated versions like Sarepta’s Elevydis.

• Trial design: The data comes from the pivotal Phase 3 portion of a seamless Phase 1/2/3 multicenter, open-label (single-arm) AFFINITY DUCHENNE trial. It included 31 ambulatory boys (aged 1–12 years) received the pivotal dose of 2 × 10¹⁴ GC/kg. The primary endpoint was microdystrophin expression levels at 12 weeks. Secondary endpoints included functional changes measured by the North Star Ambulatory Assessment (NSAA) at 12 months.

• Data (press release, slide deck): Approximately 93% of patients (28/30) achieved microdystrophin expression >10% of normal at 12 weeks (p < 0.0001), meeting the primary endpoint. Mean expression was a robust 71.1%. In an interim cut of 9 patients at 12 months, there was a statistically significant correlation (p = 0.0002) between microdystrophin levels and functional improvement (NSAA). Regenxbio claims this correlation validates the biomarker as a surrogate for clinical benefit. One case of subacute myocarditis occurred in an 8-year-old participant. While the company noted the case resolved without changes to ejection fraction or permanent fibrosis, myocarditis is a known “class risk” for AAV gene therapies that often triggers intense regulatory scrutiny. Regenxbio reported that only one patient out of 31 (~3.2%) in the pivotal cohort developed a severe liver injury. The company highlighted this as a significant edge over Sarepta’s Elevydis, which has reported liver injury rates closer to 40%. Data through the two-year mark for earlier participants shows that mean gamma-glutamyl transferase (GGT) and total bilirubin levels, sensitive markers for liver inflammation, did not exceed the upper limit of normal.

• Mixed Impact:

  • Best-in-Class Potential: The high expression levels and the presence of the CT domain suggest RGX-202 could be more potent than first-generation therapies.

  • UniQure Precedent: Single-arm data failed to immediately convince the FDA of a clear functional “win” over natural history controls in the case of UniQure gene therapy for Huntington’s disease. Critics argue that without a placebo arm, it is difficult to prove the NSAA gains aren’t due to the intensive steroid regimens or patient selection.

• Next steps: Regenxbio expects to complete dosing for the full 60-patient pivotal and confirmatory cohorts by mid-2026. The company plans to request a pre-BLA meeting with the FDA in mid-2026, aiming for a Biologics License Application (BLA) submission for accelerated approval in 2027.

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Descriptive data releases without numerical data

• Alkermes / Lumryz (ER sodium oxybate) / Phase 3 (idiopathic hypersomnia): Idiopathic hypersomnia (IH) is a chronic neurological disorder characterized by debilitating excessive daytime sleepiness (EDS), prolonged nocturnal sleep, and severe “sleep inertia” (extreme difficulty awakening). Its pathophysiology remains largely unknown and is a diagnosis of exclusion. Alkermes recently announced positive topline results for the Phase 3 REVITALYZ study of Lumryz (extended-release sodium oxybate) in adults with Idiopathic Hypersomnia (IH). This readout is a significant milestone following Alkermes’ acquisition of Avadel Pharmaceuticals earlier this year. The trial met its primary and all key secondary endpoints with high statistical significance (p < 0.0001). Patients switched to placebo experienced a statistically significant worsening of excessive daytime sleepiness as measured by the Epworth Sleepiness Scale (ESS) compared to those who stayed on Lumryz. The safety profile was consistent with previous Lumryz trials in narcolepsy. Common adverse events (≥10%) included nausea, headache, anxiety, dizziness, and vomiting; no new safety signals were identified. Alkermes plans to present the detailed, granular data from the REVITALYZ study at a medical meeting later this year and submit a supplemental New Drug Application (sNDA) to the FDA by the end of 2026.

• Cabaletta / Rese-cel (CD19-CAR T) / Phase 1 (PV): Pemphigus vulgaris (PV) is a rare, life-threatening autoimmune blistering disease where the pathophysiology centers on the production of IgG autoantibodies (primarily against desmoglein 3 and/or desmoglein 1). These proteins are critical components of desmosomes, which provide the “glue” that holds keratinocytes together; the autoantibody binding triggers a process called acantholysis, leading to the separation of epidermal layers and the formation of fragile, flaccid bullae on the skin and mucous membranes. The standard of care in 2026 focuses on rapid disease control and long-term remission using a combination of systemic corticosteroids (prednisone) and the anti-CD20 monoclonal antibody rituximab, which is now firmly established as a first-line treatment for moderate-to-severe cases. Cabaletta Bio recently shared promising Phase 1 data for rese-cel (resecabtagene autoleucel) in Pemphigus Vulgaris (PV), specifically highlighting the success of their “preconditioning-free” (PC-free) approach at the ASGCT 2026 Annual Meeting (May 14, 2026). The current data focused on the first four refractory patients (mucosal or mucocutaneous PV) treated at the lowest dose (1.0 × 10⁶ cells/kg) without preconditioning: 2 out of 4 patients (50%) maintained a “compelling drug-free response” through 6 months of follow-up after stopping all immunomodulators; 3 of the 4 patients achieved complete peripheral B cell depletion, with CAR T expansion kinetics similar to those seen in patients with preconditioning. Rese-cel was generally well-tolerated. No Dose Limiting Toxicities (DLTs) or ICANS (neurotoxicity) were reported; one patient experienced Grade 1 Cytokine Release Syndrome (transient fever). Complete Phase 1/2 data across the RESET program, including further details on RESET-PV, will be presented at the EULAR 2026 Congress (June 3-6, 2026) in London.

• AstraZeneca / Imfinzi (anti-PDL1 mAb) / Phase 3 (MIBC): Muscle-Invasive Bladder Cancer (MIBC) occurs when malignant cells, primarily urothelial carcinomas, penetrate the basement membrane and invade the detrusor muscle layer (Stage T2–T4a) of the bladder wall. On May 14, 2026, AstraZeneca announced positive high-level results from the Phase 3 VOLGA trial. This marks the third successful Phase 3 readout for Imfinzi in bladder cancer (following NIAGARA and POTOMAC), solidifying its position in the curative-intent setting for patients who cannot receive standard platinum-based therapies. The interim analysis showed that the combination of Imfinzi + Padcev outperformed the current standard of care, having demonstrated statistically significant and clinically meaningful improvements in both event-free survival (EFS) and overall survival (OS) compared to the control group. The safety profile was consistent with the known profiles of each drug; no new safety signals were identified in the combination. Detailed data, including hazard ratios and secondary endpoints like Pathologic Complete Response (pCR), will be presented at an upcoming medical meeting (likely ESMO or ASCO GU).

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Introduction

On April 20, 2026, Eli Lilly and Company announced a definitive agreement to acquire Kelonia Therapeutics up to $7.00 billion in cash, inclusive of an upfront payment of $3.25 billion, and subsequent payments upon achievement of certain clinical, regulatory and commercial milestones. This acquisition centers on Kelonia’s iGPS platform, a specialized delivery system that modifies a patient’s T-cells directly inside the body to fight cancer (“in vivo CAR-T”). Unlike traditional CAR-T therapies that require complex external manufacturing and harsh chemotherapy, Kelonia’s approach is designed to offer a simpler, off-the-shelf alternative, pending further clinical validation and regulatory review. Initial clinical data for the lead candidate, KLN-1010, showed an overall response rate of 100% in a limited cohort of four patients with multiple myeloma. Jacob Van Naarden, executive vice president and president of Lilly Oncology and head of corporate business development, commented, “Autologous CAR-T therapies have meaningfully improved outcomes for patients with various cancers, but significant manufacturing, safety, and access hurdles mean that only a fraction of eligible patients actually receive them. Kelonia’s in vivo platform has the potential to change that by delivering rapid, durable responses in a far simpler, off-the-shelf format.”

Recent acquisitions of in vivo CAR-T companies have been unusual:

1. High Volume of Deals: There have been six acquisitions involving these technologies in past 13 months, which is an unusually high cadence.

2. Early Stage of Deals: Typically, pharmaceutical companies prefer to acquire FDA-approved or Phase 3 assets (~61% of acquisitions in our internal dataset) because they generate a better risk-adjusted return on investment, a must-have in order to compensate for impending patent cliffs. In contrast, most in vivo CAR-T acquisitions have been for preclinical-stage assets, with Kelonia being the only exception (Phase 1 data but only in four patients).

Here, we expand on how in vivo approaches advance the cutting edge and speculate on the factors driving acquirer conviction at the earliest stages of validation.

Optional Detour: The History of CAR-T

CAR-T Goes In Vivo

Our journey from the discovery of CAR-T, and discussion of the various challenges that limit access and adds treatment burden (ie. month-long manufacturing/cold chain and lymphodepleting chemotherapy) brings us back to the acquisition of Kelonia Therapeutics. How are is their technology different, and how do the advance the cutting edge of CAR-T therapy?

Kelonia’s iGPS platform (in vivo Gene Placement System) is designed to turn a patient’s own body into a factory for CAR-T cells. Instead of the complex process of removing a patient’s cells for laboratory modification, the iGPS therapy is administered as a single, direct intravenous infusion. The treatment uses specially engineered particles (modified lentiviruses) that are designed to selectively find and enter T-cells already circulating in the patient’s bloodstream. Once these particles enter the T-cells, they are designed to deliver genetic instructions that program those cells to become CAR-T cells. These newly created CAR-T cells then multiply and begin seeking out and destroying cancer cells throughout the body.

Eli Lilly’s stated rationale for the acquisition highlights the platform’s potential to democratize therapy by removing the vein-to-vein times and complex manufacturing cycles of traditional autologous CAR-T. By shifting the manufacturing site to the patient’s own body, the in vivo Gene Placement System (iGPS) platform provides an off-the-shelf solution that can be administered via standard intravenous infusion, with the intended goal of potentially enabling treatment in community-based settings, pending regulatory review of its safety profile in non-academic environments. The iGPS platform relies on three foundational technical pillars:

1. Vector Architecture: The platform utilizes an advanced, third-generation lentiviral vector (LVV). Critically, because T-cells are proliferating cells, the integrating nature of LVV provides a significant advantage over non-integrating RNA modalities; the genetic payload remains stable as the cells divide, ensuring superior therapeutic durability.

2. Targeting Mechanism: To avoid the liver accumulation common in systemic delivery, iGPS utilizes a modified vesicular stomatitis virus glycoprotein (VSV-G) fusogen co-expressed with an anti-CD3 antibody on the lentiviral envelope. This ensures viral entry is facilitated specifically through CD3 on T-cells, rather than the low-density lipoprotein receptor (LDLR) used by standard VSV-G. This mechanism is designed to mitigate non-specific liver uptake, a primary safety hurdle for competing lipid nanoparticle (LNP) technologies.

3. Therapeutic Delivery: The system facilitates the generation of CAR-T cells directly in the circulation through a single infusion, eliminating the need for apheresis and the toxic lymphodepleting chemotherapy regimens required for ex vivo engraftment. Unlike non-integrating technologies such as mRNA or circular RNA, iGPS’ integrating lentiviral vector ensures the CAR transgene is maintained through T-cell proliferation and differentiation, providing a stable genetic modification essential for long-term surveillance.

In the unproven and high-risk field of in vivo genetic medicine, early human data is the essential metric for de-risking multi-billion dollar capital outlays. Kelonia’s lead program, KLN-1010, has provided this validation through its Phase 1 inMMyCAR trial in relapsed/refractory multiple myeloma (r/r MM). Preliminary data presented at the America Society for Hematology (ASH) 2025 meeting for the initial four patients showed:

• Efficacy: A 100% minimal residual disease (MRD)-negative response rate across four patients (ie. undetectable cancer in all treated patients); MRD-negative responses were maintained through three months in the two patients with the longest follow up. Three of the four patients were treated at 2×10⁷ IU/kg. Deep responses and favorable safety profile compelled exploration of the therapeutic window to further reduce the cost of goods. The fourth patient was treated at a lower dose of 6×10⁶ IU/kg and achieved an MRD-negative response at month 1. All four patients remain in response, per International Myeloma Working Group’s (IMWG) criteria, with the longest follow-up of five months; complete response (CR) was the best overall response.

• Expansion and Durability: Robust CAR-T cell expansion similar to ex vivo therapies despite no lymphodepleting chemotherapy; reaching up to 85% of circulating T-cells. Persistent memory CAR-T in all patients observed through three months to date, which suggests KLN-1010 provides a reservoir for sustained anti-tumor surveillance. This integrates the rapid response of cellular therapy with the long-term control traditionally sought in vaccine or antibody-based approaches.

• Safety: Favorable toxicity profile with no cytokine release syndrome (CRS) of grade 3 or above, no Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), no delayed neurotoxicity, and markedly lower cytopenias compared to ex vivo CAR-T cell therapies.

In Vivo CAR-T Gold Rush Starts with the First Nugget

The Kelonia-Eli Lilly transaction highlights a remarkably efficient capital model. Originally incubated and seed funded by Venrock, Kelonia raised only $60 million in total private capital. For Venrock, the $20 million seed investment yields a $900 million return on the upfront payment alone (~45x), with the potential for a 100x return upon achievement of the $7 billion milestone total.

The story of Kelonia Therapeutics was a classic lab-to-launch biotech narrative. The scientific foundation of Kelonia was built at the Massachusetts Institute of Technology (MIT). The company’s technology is based on research from the laboratory of Dr. Michael Birnbaum, an Associate Professor of Biological Engineering. Dr. Birnbaum’s work focused on re-engineering viruses. While most gene therapy uses viral vectors to deliver genes, they are often clunky, they hit the wrong cells or aren’t efficient enough. Dr. Birnbaum and his team developed a way to create Lentiviral-like Particles (LVPs) that were essentially GPS-guided. By modifying the surface of these particles, they could ensure the genetic payload was only delivered to specific cells (like T-cells) while they were still inside the body.

Recognizing the commercial potential of an in vivo (inside the body) delivery system, the venture capital firm Venrock incubated the company. Kelonia officially launched in April 2022 with a $50 million Series A funding round. The company was led by Dr. Kevin Friedman, a veteran of the cell therapy space who had previously played a key role at bluebird bio and 2seventy bio. From day one, the company’s “North Star” was to eliminate the need for the multi-week, multi-hundred-thousand-dollar manufacturing process required for traditional CAR-T.

Kelonia branded its core technology as the iGPS (In Vivo Gene Placement System). To prove it worked, they focused on Multiple Myeloma, targeting a protein called BCMA. Big Pharma noticed early. In 2024, Kelonia signed major collaboration deals with Astellas and Johnson & Johnson, signaling that the industry viewed their off-the-shelf approach as a serious threat to the status quo. The turning point for the company came in December 2025 at the American Society of Hematology (ASH) Annual Meeting, which we covered in the previous section.

The surge of in vivo CAR-T acquisitions in the past 13 months confirms that Big Pharma is interested in moving away from the vein-to-vein logistics of the past. For the Eli Lilly team, the acquisition of Kelonia could be rooted in a diversification approach, recognizing that no single delivery vehicle will solve all in vivo CAR-T challenges. This puts the Kelonia acquisition at the forefront of an industry-wide spend exceeding $5 billion, alongside peers such as AbbVie, AstraZeneca, and Bristol-Myers Squibb.

While all such approaches are early-stage, the field is quickly becoming crowded. Kelonia serves as a complementary, rather than redundant, asset to Eli Lilly’s recent acquisition of Orna Therapeutics in three main ways:

• Modality & Maturity: Kelonia utilizes an integrating lentiviral approach, already validated in refractory patients (Phase 1). In contrast, Orna utilizes a non-integrating circular RNA (oRNA) delivered via LNPs, currently in Phase 1 with healthy volunteers.

• Targeting & Disease Scope: Kelonia’s KLN-1010 focuses on anti-BCMA (Multiple Myeloma), while Orna’s ORN-252 targets anti-CD19 (B-cell cancers and autoimmune diseases).

• Strategic Moat: Through this acquisition, Eli Lilly is positioned to assume Kelonia’s established strategic collaborations with Johnson & Johnson and Astellas. These agreements could provide Eli Lilly with oversight of partner-funded pipelines, subject to the terms and successful continuation of those specific development programs.

Owning both integrating (Kelonia) and non-integrating (Orna) platforms provides Eli Lilly with a diversified toolkit of genetic delivery mechanisms. They would be able to select the optimal modality based on whether a specific disease requires the permanent genetic modification afforded by LVV or the more transient effects of oRNA, helping to future-proof their oncology and immunology pipelines against competitive technological shifts.

Conclusion

The winner of the in vivo CAR-T race remains to be seen as pharmaceutical giants continue to place multi-billion dollar bets on these competing delivery mechanisms. Regardless of who leads the pack, the inevitable outcome is a more resilient and accessible arsenal for oncology. The ultimate victory will belong to the patients who finally gain access to these highly effective but once-elusive treatments.

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Introduction

On a wintry Friday evening in Stockholm, Ilya Mechnikov approached the podium at the Royal Academy of Music and delivered his Nobel Lecture before an audience of distinguished scientists and Swedish royalty. It was a speech that would end a decades-long civil war within the field of immunology, and would change the course of history forever.

“There is no need to be a doctor or a scientist to wonder why the human body is capable of resisting so many harmful agents in the course of everyday life. It is often seen that in households where all members are exposed to the same danger [whilst] disease does not strike everyone indifferently. For some individuals who go down at the attack, there are others who have immunity to a greater or lesser extent. […] A battle takes place between the two elements. […] Whenever the organism enjoys immunity, the introduction of infectious microbes is followed by the accumulation of mobile cells, of white corpuscles of the blood in particular which absorb the microbes and destroy them.”

Ilya Mechnikov’s Nobel Lecture (December 11, 1908)

Mechnikov, who was working at the Pasteur Institute in Paris at the time, had discovered that specific cells or, “white corpuscles of the blood” as he called them, moved toward and engulfed foreign particles. Before Mechnikov, inflammation (redness, heat, swelling) was viewed by the medical establishment as a purely destructive process, a symptom of disease. However, Mechnikov flipped this view. He argued that inflammation is a healing reaction. He demonstrated that the swelling and heat were actually signs of the body’s cellular army mobilizing to the site of injury.

Mechnikov saw the immune system as an ancient, inherited defense; a battle that had been raging since the first multicellular organisms appeared. However, the discovery of T-cells decades later revealed a complexity he could only imagine. By merging Mechnikov’s cellular army with the pinpoint targeting of laboratory engineering, we have moved beyond simply observing the battle to actively directing it.

Cells fighting cells. Cells fighting bacteria. Cells fighting cancer.

In Part 1 of this three-part Frontiers in Medicine series on CAR-T, we dive into the Immunology Civil War, discovery of T-cells, and their rebirth as medicines.

Immunotherapy’s Humble Beginnings

The history of Chimeric Antigen Receptor T-cell therapy (CAR-T) is a long and winding journey from early 19th-century observations to the cutting-edge techniques being developed today. The story begins with in the 1890s with Dr. William B. Coley, a bone surgeon at New York Memorial Hospital (now called Memorial Sloan Kettering Cancer Center).

In 1891, Dr. Coley was deeply affected by a young patient who had died due to bone cancer. While searching through hospital records to look for patients who had better outcomes, he found a case from seven years prior: a patient with an inoperable tumor in the neck had made a full recovery after contracting Erysipelas (a skin infection caused by Streptococcus pyogenes). Dr. Coley tracked the man down and found him healthy and cancer-free. He hypothesized that the severe immune response triggered by the infection had incidentally destroyed the cancer cells. Dr. Coley began experimenting by intentionally infecting cancer patients with live bacteria. While he saw some success, this was dangerous; at least two patients died from the infections. To make the treatment safer and more predictable, he switched to a mixture of heat-killed bacteria consisting of Streptococcus pyogenes (Gram-positive) and Serratia marcescens (Gram-negative). This cocktail became known as Coley’s Toxins. It was designed to provoke a high fever and a massive systemic immune response without causing a full-blown infection.

At the time, Coley didn’t know the molecular biology behind his treatment. Today, we understand that Coley’s Toxins worked through several immunological pathways:

1. Cytokine Storm: The bacterial components (specifically Lipopolysaccharides or LPS) triggered the release of Tumor Necrosis Factor (TNF), Interleukins, and Interferons.

2. Dendritic Cell Activation: The toxins acted as adjuvants, activating the innate immune system to recognize tumor antigens that it had previously ignored.

3. Fever Therapy: The sustained high fever (often reaching 103–105°F) induced by the toxins is thought to have a direct inhibitory effect on some tumor types and further stimulate immune cell activity.

During his career, Coley treated nearly 1,000 patients. Many cases of inoperable sarcomas (bone and soft tissue cancers) went into complete remission. However, the therapy faced significant criticism and was ultimately abandoned by the medical establishment due to several critical flaws:

• Inconsistency: Coley frequently changed the formula and dosage, making it difficult for other doctors to replicate his results.

• The Rise of Radiation: At the turn of the 20th century, X-rays and radium were discovered. Radiation was more modern, easier to standardize, and yielded more immediate results, leading the medical community to favor it over unpredictable toxins.

• The AMA Critique: The American Medical Association was skeptical of the treatment due to its lack of controlled trials, and the therapy was eventually labeled as “unproven”.

While Dr. William Coley was on the right track in identifying a connection between cancer and the immune system, he lacked a understanding of why Coley’s Toxins sometimes worked and how it could be optimized. In the 1970s, Dr. Lloyd Old provided another piece to the puzzle by utilizing a weakened strain of Mycobacterium bovis (the BCG vaccine) to train the immune system to attack non-muscle invasive bladder cancer (NMIBC). The success of the BCG vaccine in bladder cancer was not due to the vaccine attacking the cancer directly. Instead, it functioned as a biological adjuvant. When BCG is instilled directly into the bladder, it infects the urothelial cells and the tumor cells. This infection triggers a massive local release of cytokines (like IL-2, IL-12, and IFN-gamma). These signals act as a beacon, recruiting T-cells, Natural Killer (NK) cells, and macrophages to the bladder wall. The immune system, now highly activated to fight the bacterial infection, recognizes and destroys the tumor cells in the process.

Dr. Old’s work was pivotal for three reasons that paved the way for CAR-T therapies:

1. Validation of Non-Self Recognition: It proved that if you could make a tumor visible to the immune system, the body had the inherent machinery to eliminate it.

2. The Birth of “Active” Immunotherapy: Unlike non-living therapies like chemotherapy or later monoclonal antibodies, BCG required the patient’s own T-cells to do the heavy lifting, a fundamental requirement for CAR-T.

3. FDA Precedent: In 1990, BCG became the first immunotherapy to receive FDA approval for cancer, transforming it from an experimental theory into a standard of care that remains the frontline treatment for non-muscle invasive bladder cancer (NMIBC) today.

Yet, the discovery of Coley’s Toxins and the BCG vaccine begs the question: what is the mechanism of immunity? This very question set off a decades-long civil war, a bitter rivalry between two schools of thought in the field of immunology.

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Immunology Civil War: Cellularists versus Humoralists

The “Immunology Civil War” was a decades-long intellectual battle at the end of the 19th century that fractured the scientific world into two hostile camps. It was a disagreement that transcended science alone and spilled over into clashing cultures, nationalities, and philosophies about how life defends itself. The conflict pitted two camps against each other and was sharpened by the borders of 19th-century Europe:

• Humoralists: They were led by giants like 1905 Nobel Laureate Robert Koch, 1901 Nobel Laureate Emil von Behring, and soon-to-be 1908 Nobel Laureate Paul Ehrlich. Humoralists belonged to the German school of thought, which was rooted in chemistry. They saw the body as a sophisticated laboratory. To them, immunity was a series of precise, predictable chemical reactions: neutralization, precipitation, and side-chain interactions.

• Cellularists: They were led by the Russian zoologist and Paul Ehrlich’s soon-to-be 1908 Nobel co-Laureate Ilya Mechnikov. He belonged to the French school of thought, which was rooted in biology and followed in the footsteps of Louis Pasteur, who first published on the Germ Theory of Disease in 1857 and whose passing in 1895 predated the establishment of the Nobel Prize in 1901 by a mere six years. Cellularists saw the body as a living, breathing ecosystem. To them, immunity was an active, Darwinian struggle where cells decided to attack invaders.

In the 1890s, the Humoralists held the political upper hand. Emil von Behring had discovered antitoxins for diphtheria and tetanus. They showed that the liquid part of the blood (the serum) could neutralize toxins even without any cells present. The Germans ridiculed Mechnikov’s “wandering cells.” They argued that “phagocytes” (immune cells that engulfed and destroyed foreign particles, bacteria, and dead/dying cells) were merely scavengers that cleaned up the mess after the chemical serum had already killed the bacteria. In some cases, they believed white blood cells actually spread disease by eating bacteria and carrying them alive to other parts of the body.

Mechnikov, working out of the Pasteur Institute in Paris, countered with a radical idea: the cell was the instigator. He spent years performing meticulous microscopy to show that white blood cells actively hunted bacteria (chemotaxis) rather than simply stumbling upon them. The “humors” (serum) only seemed effective because the cells had produced the protective substances in the first place or were aided by them.

The war finally began to de-escalate in the early 1900s through the work of British scientist Almroth Wright. He discovered substances he called opsonins (from the Greek “to prepare food for”). Wright demonstrated that the serum (Humoral) contained so-called “opsonins” that coated the bacteria. This coating made the bacteria “tasty” and easier for the white blood cells (Cellular) to grab and eat. This unified theory suggested that that both sides were right.

This Immunology Civil War was tense but essential because it forced both sides to engage in an arms race that clarified each theory independently, until they were ultimately bought together into one harmonious model.

• For the Cellularists, it led to the discovery of the Innate Immune System, the rapid, non-specific response we are born with. Dendritic Cells or Macrophages use general sensors to detect detect non-self invaders, but they are blind to specific invaders. They eat a non-self invader and, importantly, show pieces of it (“antigens”) to the rest of the army.

• For the Humoralists, it led to the discovery of the Adaptive Immune System, the slower but more specific response that identifies invaders and remembers them. Triggered by the innate cells, B-cells/plasma cells churn out antibodies and T-cells that destroy the invaders.

The 1908 Nobel Prize was a deliberate “peace prize,” awarded jointly to Mechnikov (Cells) and Ehrlich (Humors), formally acknowledging that the human body requires both its chemical weapons and its cellular soldiers to survive. By awarding the prize to both Ilya Mechnikov and Paul Ehrlich, the Nobel Committee was forcing a reconciliation between two seemingly irreconcilable worldviews. It served as a formal declaration that the immune system was integrated and transitioned the field from “either/or” to “both/and.” This détente taught scientists valuable lessons that led to the intellectual maturity of immunology:

• Complexity is the rule: Evolution rarely relies on a single defense mechanism.

• Redundancy is a feature: The body has chemical weapons and cellular soldiers because if one fails, the other can often compensate.

• Cross-Disciplinary Discovery: The most powerful breakthroughs happen at the intersection of different fields (in this case, Zoology and Organic Chemistry). Immunology transitioned from a field of competing silos to one of integrated systems.

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Uncovering Immunity’s Cellular & Molecular Roots

As we have seen, until the mid-20th century, scientists believed the immune system was a single, monolithic entity. However, the discovery that it was actually composed of specialized cell types changed medicine forever. But how did we identify those cell types, and how do they differentiate between friend and foe? It starts with a forgotten organ.

For decades, the thymus (a small organ in the upper chest) was considered a vestigial organ, essentially a useless evolutionary leftover. The breakthrough came in 1961 with Dr. Jacques Miller, a French-Australian research scientist whose pivotal work occurred early in his career as a Ph.D. student at the University of London. He was studying leukemia in mice and began removing the thymus of newborn mice in a procedure known as a neonatal thymectomy. He observed something startling: the mice without a thymus were unable to reject foreign skin grafts, had almost no lymphocytes (white blood cells) in certain areas of their lymph nodes, and died prematurely from common infections. This provided evidence that the thymus was the “schoolhouse” where a specific type of immune cell learned how to function. As an aside, Jacques Miller is often cited as the only person still living who discovered the function of a major human organ. It is widely considered one of the greatest snubs in Nobel Prize history that he hasn’t received the award for medicine yet, though he did receive the Lasker Award in 2019.

Around the same time, Dr. Max Cooper and Dr. Robert Good were studying the Bursa of Fabricius in chickens (an organ humans don’t have, but which serves as the school for B-cells). They realized that the immune system had two distinct branches:

• B-cells (Bursa-derived): These cells produced antibodies to attack invaders in the blood (humoral immunity).

• T-cells (Thymus-derived): These cells did not make antibodies. Instead, they attacked infected or non-healthy cells directly (cell-mediated immunity).

While the work of Drs. Jacques Miller and Max Cooper in the 1960s successfully identified the T-cell as the footsoldier of the immune system, it simultaneously birthed one of the greatest mysteries in modern biology: how did the T-cell see its target? Unlike B-cells, which secrete antibodies that circulate like free-floating heat-seeking missiles, T-cells require physical, cell-to-cell contact to strike. Scientists hypothesized that this implied a physical receptor on their surface. Yet for two decades, this receptor remained unknown. The hunt moved from the gross anatomy of the thymus to the microscopic realm of the cell membrane and the hypothesized T-cell Receptor (TCR).

Before scientists had identified the receptor, they witnessed its peculiar behavior. In 1974, Peter Doherty and Rolf Zinkernagel discovered MHC Restriction. They found that T-cells were “double-locked”: they didn’t just recognize a virus; they recognized a virus only when it was presented by the body’s own self-identity markers (MHC). This was a massive hurdle for early researchers because it suggested the TCR wasn’t a simple key and lock like an antibody, but a complex sensor capable of a “dual handshake”. This work was so foundational it eventually earned the Nobel Prize in 1996.

By the early 1980s, the race became a sprint to physically isolate the receptor protein. Since the human genome hadn’t yet been sequenced, researchers used monoclonal antibodies as hooks to see if they could grab a protein on the T-cell surface that differed from one cell to the next. The breakthrough came in 1982, when Dr. James Allison (who later won the Nobel Prize for discovering immune checkpoint inhibitors) identified a protein that was “clonotypic”, meaning it was unique to a specific line of T-cells. Shortly after, teams led by Ellis Reinherz, and the duo of Philippa Marrack and John Kappler, confirmed the TCR was a heterodimer composed of two chains (alpha and beta) linked together.

The climax of this history occurred in 1984, when the genetic blueprints for the TCR were finally cloned. Two labs working independently on opposite sides of the world crossed the finish line almost simultaneously: Dr. Mark Davis (Stanford) and Dr. Tak Wah Mak (University of Toronto). They used a brilliant technique called subtractive hybridization to compare the mRNA of T-cells to that of B-cells. Since the cells are nearly identical except for their receptors, they subtracted the common genes. What remained was the code for the TCR.

So, what is our most up-to-date understanding of how T-cells find and eliminate infected cells or tumor cells? T-cells circulate through the body, constantly feeling the surface of other cells. They aren’t looking for the virus/tumor itself, but for a specific signal called the MHC-peptide complex. Every cell in your body regularly chops up its internal proteins into tiny pieces (peptides) and holds them out on a tray called the MHC (Major Histocompatibility Complex). If the cell is healthy, the T-cell’s TCR recognizes the peptide as “self” and moves on. When a cell is infected or cancerous, it inadvertently puts a piece of the viral or mutated protein on that MHC tray. If a T-cell has a TCR that perfectly fits that specific viral or mutated peptide, it latches on. This is the MHC Restriction mentioned earlier, the TCR must recognize both the foreign peptide and the body’s own MHC tray simultaneously. This ensures the T-cell only attacks infected body cells, not free-floating viruses (which are the B-cell’s job). Once the TCR is locked in, the T-cell undergoes a physical transformation to become a Cytotoxic T-Lymphocyte (CTL). The T-cell pulls the infected cell close, forming an immunological synapse, a tight seal between the two. The T-cell sprays toxic proteins into the gap, primarily perforins (pokes holes in the infected cell’s membrane) and granzymes (enters through perforin holes and triggers programmed cell death or apoptosis). The infected cell implodes, preventing the virus or cancer from replicating further. The T-cell then detaches, completely unharmed, and moves on to find the next target.

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Programming T-cells to Hunt Cancer

The discovery of the T-cell and the subsequent mapping of its receptor (TCR) unveiled a biological assassin designed to eliminate threats while sparing the host. However, cancers deploy strategies to hide from, shield themselves from, and sabotage T-cells that are actively hunting them:

• Hiding (avoiding detection): T-cells can only see cancer if the tumor displays its mutated proteins on an MHC tray. Many tumors evolve to stop producing MHC molecules entirely or mutate the proteins (B2M) that stabilize them. Without the tray, the T-cell simply walks past the tumor, unaware it is dangerous. Tumors may also stop expressing the specific mutated proteins (antigens) that the immune system was originally trained to recognize, a phenomenon known as antigen escape.

• Shielding (protect itself from harm): Healthy cells have “off switches” called immune checkpoints (like PD-L1 or CD80/CD86) that are displayed on the cell surface and prevent T-cells from attacking. This is useful for preventing the immune system from damaging healthy organs. However, cancer cells frequently over-produce immune checkpoints, forcing hostile T-cells into a state of exhaustion or paralysis. Cancer often utilizes another shielding tactic: the recruitment of immunosuppressive cells that similarly serve to wind down an immune response. These cells include regulatory T-cells (T_regs), which are attracted to tumor-derived TGF-beta and IL-10, and myeloid-derived suppressor cells (MDSCs), which neutralize the toxic proteins T-cells use to kill their target cells (perforin/granzymes).

• Sabotaging (actively shutting down the immune system): The area surrounding a tumor, the Tumor Microenvironment (TME), is often transformed into a hostile no-go zone for immune cells. Tumors can recruit cells called fibroblasts to create a dense wall of collagen that physically prevents T-cells from entering the tumor core. Tumors consume vast amounts of glucose and pump out lactic acid, creating an acidic, low-oxygen environment. This toxic soup inhibits T-cell metabolism, making them too weak to mount an attack.

By the late 1980s, the realization was clear: to defeat an opponent as adaptive as cancer, the T-cell’s natural hardware (the MHC-restricted TCR) required a fundamental update. This realization birthed a new era of synthetic immunology. Scientists sought to bypass the tumor’s cloaking devices by creating a hybrid molecule that never existed in nature. By fusing the relentless killing power of the T-cell with the pinpoint targeting precision of a laboratory-engineered antibody, researchers created the first living drug. This was no longer a therapy that merely nudged the immune system to target cancer; it was a genetically fortified army designed to execute its mission with mechanical precision.

In 1987, Dr. Yoshikazu Kurosawa and his team at the Institute for Comprehensive Medical Science in Japan achieved the world’s first successful fusion of antibody and T-cell receptor components, although it targeted bacteria instead of cancer. Dr. Kurosawa’s team was the first to address the “MHC problem” by asking if a T-cell could be forced to use an antibody’s search function. Unlike modern CAR-Ts, which use a single, simplified chain (scFv), Dr. Kurosawa’s team created a double-chain chimeric receptor (DCCR). They took the Variable (V) regions of an antibody (which recognize specific targets) and fused them to the Constant (C) regions of a T-cell receptor’s Alpha and Beta chains. They chose a target called phosphorylcholine, a molecule found on the surface of certain bacteria (S. pneumoniae). They inserted these chimeric genes into a line of T-cells and exposed them to the bacteria. Using a technique called fluorometry, they watched the cells’ internal chemistry. When the antibody grabbed the bacteria, the T-cells responded with a massive calcium influx, the biological alarm that tells a T-cell it has found a target. This was the first demonstration that a T-cell could be programmed to recognize a target of interest.

Separately, Dr. Zelig Eshhar was working at the Weizmann Institute of Science in Israel. He was frustrated by the fact that T-cells were fussy, they could only see cancer if it was presented on an MHC tray. He knew that antibodies, on the other hand, were expert hunters that could find targets anywhere. To solve this problem, he created a so-called T-Body by fusing the “searching” part of an antibody (known as the single-chain variable fragment or scFv) and the “killing” part of a T-cell (the cytoplasmic domain of the CD3ζ chain that triggers a signaling cascade within a T-cell leading to the release of cell-killing perforin and granzymes). In 1989, Dr. Eshhar published a landmark paper showing that these T-bodies could kill cancer cells in a petri dish. He had effectively bypassed the cloak of invisibility that tumors used to hide from the natural immune system.

Despite the success in the lab, this 1st generation of CAR-T was a clinical failure when tested in patients throughout the 1990s and early 2000s. Why? Eshhar’s CAR-Ts provided a signal to attack target cells, but they would immediately exhaust themselves and die within hours or days. They couldn’t multiply, and they couldn’t survive long enough to fully eliminate tumors. To get around this, doctors had to give patients extra doses of IL-2, but they caused massive, toxic side effects for the patients, making the treatment both ineffective and dangerous. To kill a large tumor, a few million CAR-T cells would have to turn into billions of CAR-T cells inside the patient.

As a result of these failures, many in the scientific community wrote off CAR-T as a dead end for nearly a decade. Dr. Eshhar himself faced skepticism and struggled to find funding, at one point even pitching an antibody-based opium sensor to a Swedish company just to keep his lab’s lights on. However, this early experiment was essential. It proved that programmed recognition and killing of cancer cells was possible.

It wasn’t until the early 2000s that Dr. Michel Sadelain at Memorial Sloan Kettering and Dr. Carl June at the University of Pennsylvania added the proliferation signals to create 2nd generation CAR-Ts. The breakthrough was the realization that researchers could engineer these signals directly into the synthetic receptor by adding a costimulatory domain between the scFv (targeting) and the CD3ζ chain (killing trigger) domains. In 2002, Dr. Sadelain’s team was the first to demonstrate that adding a CD28 costimulatory domain allowed T-cells to multiply and survive in the presence of cancer. CD28-based CARs are characterized by rapid, powerful metabolic activity. They rely heavily on glycolysis (burning sugar quickly) to mount a massive, immediate attack on the tumor. This design became the foundation for Yescarta (axicabtagene ciloleucel), the first CAR-T approved for lymphoma.

A few years later, Dr. Carl June’s team utilized a different domain called 4-1BB (also known as CD137). 4-1BB is a member of the TNF-receptor family. It sends a different survival signal that promotes oxidative phosphorylation, a slower and more efficient mechanism for burning energy. 4-1BB CARs don’t strike as hard or as fast as CD28 cells, but they have much higher persistence. In some of June’s early patients, these cells were still circulating and patrolling the body ten years after the initial treatment. This design became the foundation for Kymriah (tisagenlecleucel), the first-ever FDA-approved CAR-T therapy (2017).

Cell-ebrating Clinical Success

The 2010 Landmark Trial (published in the New England Journal of Medicine in 2011) was the watershed moment that shifted CAR-T therapy from a theoretical promise to a clinical breakthrough. While the trial was small, enrolling only three patients with advanced Chronic Lymphocytic Leukemia (CLL), the results were so explosive that they fundamentally changed the trajectory of oncology.

By 2010, the three patients in the trial had exhausted every available treatment, including multiple rounds of chemotherapy and monoclonal antibodies. They had several pounds of tumor mass in their bodies and were essentially in end-of-life care. Dr. Carl June’s team utilized their 2nd generation CAR-T design, which featured the 4-1BB costimulatory domain. This was the critical difference; previous trials by other groups using 1st generation CARs had failed to show any significant cell persistence or clinical benefit. After the patients were infused with their own engineered T-cells, the researchers observed a phenomena never before seen in human medicine:

• Massive T-cell Expansion: In the patient known as “Patient 1” (Bill Ludwig), the CAR-T cells multiplied by a factor of 1,000 to 10,000 times inside his body.

• Serial Killing Effect: Calculations suggested that each single CAR-T cell successfully destroyed approximately 1,000 to 1,500 leukemia cells.

• Systemic Eradication: Within weeks, the pounds of tumor mass residing in the blood, bone marrow, and lymph nodes became undetectable.

When the results were published in August 2011, the headlines were staggering. The paper reported Complete Remissions in two of the three patients. Following this trial, Novartis partnered with UPenn in a landmark deal, signaling the first major Big Pharma entry into the space. The 4-1BB domain worked as intended. The CAR-T cells didn’t just kill the cancer and disappear; they remained in the patients’ blood as sentinel cells.

The trial also provided the first clinical description of Cytokine Release Syndrome (CRS). As the CAR-T cells engaged in a massive war with the leukemia, the patients developed high fevers, dangerously low blood pressure, and organ stress. This was a terrifying moment for the researchers, but they soon realized it was paradoxically a biomarker of success: the sicker the patient got, the more effectively the living drug was working.

In a follow-up more than a decade later in 2022, these same patients were still cancer-free, and the original CAR-T cells were still detectable in their blood, proving that a single infusion could potentially provide a lifetime of protection. The study focused on Doug Olson and Bill Ludwig, the two survivors from the 2010 trial. At the 10-year mark, both were still in complete remission (Bill Ludwig remained cancer-free but unfortunately passed away in January 2021 due to complications from COVID-19). Researchers found that the CAR-T cells had evolved inside the patients’ bodies. While killer CD8+ T-cells did the initial work of destroying the tumor in 2010, the long-term patrolling was carried out by a highly activated population of CD4+ CAR T-cells. Following this paper, Dr. Carl June made headlines by stating, “We can now conclude that CAR-T cells can actually cure patients with leukemia,” a rare and bold claim in oncology.

The story of Emily Whitehead is another critical milestone in the development of CAR-T therapy. If the 2011 NEJM paper demonstrated that CAR-T could work in adults, Emily demonstrated that it could work in children, and in doing so, she inadvertently taught the medical world how to manage the therapy’s most dangerous side effect: Cytokine Release Syndrome (CRS).

Emily was diagnosed with acute lymphoblastic leukemia (ALL) in 2010 at age five. Despite 16 months of aggressive chemotherapy, her cancer relapsed twice. By early 2012, her doctors told her parents, Tom and Kari Whitehead, that she had run out of options and should enter hospice. Refusing to give up, they enrolled her in a Phase 1 clinical trial at Children’s Hospital of Philadelphia (CHOP) led by Dr. Stephan Grupp. On April 17, 2012, Emily became the first pediatric patient in the world to receive CAR-T cells (the same 4-1BB construct developed by Carl June’s team).

A few days after the infusion, Emily became critically ill. This was the first time pediatricians had witnessed a full-scale Cytokine Release Syndrome (CRS). She experienced 105°F fevers, a massive drop in blood pressure, and respiratory failure. She was placed on a ventilator in the PICU and given a 1-in-1,000 chance of surviving the night. Dr. Grupp’s team ran an emergency blood test and found that her levels of Interleukin-6 (IL-6), a signaling protein for inflammation, were 1,000 times higher than normal. In one of the most famous happy accidents in medical history, Dr. Carl June’s own daughter had juvenile arthritis and took a drug called Actemra, which happens to block IL-6. Actemra had never been used for cancer-related inflammation, but with Emily near death, the team administered it as a desperate measure. Within hours, her fevers vanished. She woke up on May 2, 2012, her 7th birthday. If Emily had died, it is widely believed the FDA would have shut down the CAR-T program. Instead, her survival solidified Actemra as the gold standard of managing CRS, though the condition remains a significant and potentially life-threatening risk of CAR-T therapy.

Three weeks after Emily woke up, a bone marrow biopsy showed no signs of cancer. Emily famously stood by her father’s side when he testified before the FDA in a 2017 hearing, leading to the unanimous approval of Kymriah, the first approved CAR-T therapy. Like the adult patients in the 2022 Nature study, Emily still has patrolling CAR-T cells in her blood today. They have functioned as a permanent, living immune system against her leukemia for over a decade.

As of April 2026, the FDA has approved several CAR-T therapies that have transformed the treatment landscape for hematologic malignancies. These therapies are generally categorized by their target antigen: CD19 (for B-cell leukemias and lymphomas) and BCMA (for multiple myeloma).

CD19 is a protein found on the surface of nearly all B-cells, both healthy and cancerous. This makes it an ideal target for B-cell related cancers. These are the FDA-approved CAR-T therapies targeting CD19:

• Kymriah (Tisagenlecleucel): The “pioneer.” Approved in 2017, it uses a 4-1BB costimulatory domain (the design from Carl June’s team). It is primarily used for pediatric and young adult ALL and certain large B-cell lymphomas.

• Yescarta (Axicabtagene ciloleucel): Also approved in 2017, it uses a CD28 costimulatory domain (the Sadelain design). It is a standard of care for aggressive Large B-cell Lymphoma (LBCL) and Follicular Lymphoma (FL).

• Tecartus (Brexucabtagene autoleucel): Developed specifically for Mantle Cell Lymphoma (MCL) and adult ALL. It involves a specialized manufacturing process that removes circulating tumor cells to prevent them from interfering with the T-cell engineering.

• Breyanzi (Lisocabtagene maraleucel): Notable for its defined composition. Unlike other CAR-Ts where the ratio of CD4+ to CD8+ cells is random, Breyanzi is administered in a specific 1:1 ratio. This is intended to make the side-effect profile (like CRS) more predictable and manageable.

For decades, Multiple Myeloma was considered incurable. The discovery of B-cell Maturation Antigen (BCMA) as a target allowed CAR-T to enter this space. These are the FDA-approved CAR-T therapies targeting BCMA:

• Abecma (Idecabtagene vicleucel): The first BCMA-directed CAR-T approved (2021). It is used for patients with relapsed or refractory multiple myeloma who have already tried four or more lines of therapy.

• Carvykti (Ciltacabtagene autoleucel): A highly potent dual-target therapy. It features two different BCMA-binding domains that attach to the cancer cell in two different spots. Carvykti has shown some of the highest response rates in clinical history for myeloma, with a recent trend moving it into earlier lines of treatment (meaning patients get it sooner in their journey, rather than as a last resort).

Scientists continue to innovate in the space with novel targets for hematological malignancies (CD79a, PRC5D, CMA, CD33) and solid tumors (CLDN6, CLDN18.1, MUC16, GPC3, PSMA) that are currently being tested in clinical trials.

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CAR-T’s Challenge #1: Access Gap

Emily Whitehead’s father often speaks about the lottery they won by being near Children’s Hospital of Philadelphia (CHOP) and having access to the Kymriah clinical trial. Therein lies the biggest challenge for CAR-T therapy. While CAR-T is a medical breakthrough, it is currently a logistical nightmare. The biotech industry refers to this as the Access Gap: a chasm between the number of patients who need the therapy and the number of doses that can actually be manufactured.

At the heart of this problem is the autologous nature of current therapies: every single dose is a bespoke, one-off product created from the patient’s own living cells. The most critical metric in the CAR-T industry is Vein-to-Vein (V2V) time. This is the total number of days between the moment a patient’s cells are collected and the moment they are infused back into the patient as a living drug. The typical vein-to-vein time averages 21 to 35 days and involves:

1. Leukapheresis: The patient travels to a specialized center where their blood is filtered to collect T-cells.

2. Cold Chain Logistics: The cells are cryopreserved and shipped via specialized medical couriers to a centralized manufacturing facility (often across the country).

3. Genetic Re-coding: In a clean Room (ISO 5 environment), technicians use viral vectors to insert the CAR gene into the T-cells.

4. Expansion: The cells are grown in bioreactors until they reach a therapeutic dose (often hundreds of millions of cells).

5. Quality Control (QC): The final product undergoes rigorous testing for purity, potency, and sterility.

6. Return Flight: The cells are frozen again, shipped back, and thawed at the patient’s bedside for infusion.

The “vein-to-vein” process is fraught with several points of failure:

• Manufacturing Constraints: High-tech manufacturing facilities have limited capacity. A patient might be ready for treatment but, if there is no slot available at the factory, they must wait, often while their cancer continues to progress.

• Manufacturing Failure: Since the starting material is a sick patient’s T-cells (which have often been decimated by years of chemotherapy), the cells sometimes fail to grow in the lab. This results in a manufacturing failure, meaning the patient loses weeks of time and may no longer be healthy enough for a second attempt.

• The Cold Chain: Maintaining a chain of custody at temperatures below -150°C is incredibly expensive and risky. A single power failure or shipping delay can destroy a half-million-dollar treatment.

• Bridging Chemotherapy: Since the process takes a month, many patients require bridging chemotherapy just to keep them alive until their CAR-T cells are ready. This adds further toxicity and cost to the treatment.

Due to the complexity of leukapheresis and CRS management, CAR-T is largely restricted to elite academic medical centers. Patients in rural areas or developing nations are effectively locked out of the therapy. The labor-intensive, one-patient-one-batch model is the primary driver of the astronomical cost of these therapies, which can exceed $400,000. Despite the clinical triumphs of Drs. June and Sadelain, the ‘vein-to-vein’ reality of autologous CAR-T remains present significant challenges to global health equity for the average patient.

CAR-T’s Challenge #2: Lymphodepleting Chemotherapy

The next biggest challenge for CAR-T therapy after the access gap is the requirement for lymphodepleting chemotherapy. If you infuse CAR-T cells into a normal immune system, the new cells often fail to expand because they are competing with the existing resident cells. Conditioning serves three primary functions:

1. Creating a Niche: It physically eliminates existing lymphocytes to make room for the CAR-T cells to multiply.

2. Cytokine Sink Elimination: It removes cells that soak up vital growth factors like IL-7 and IL-15. By removing the competition, these homeostatic cytokines surge, providing a nutrient-rich environment for the CAR-T cells to feast on.

3. Suppression of Suppressors: It temporarily wipes out Regulatory T-cells (T_regs) and Myeloid-Derived Suppressor Cells (MDSCs) that the tumor has recruited to protect itself.

While various protocols exist, the gold standard for CAR-T conditioning is the combination of Fludarabine and Cyclophosphamide (often abbreviated as Flu/Cy). Flu/Cy is typically administered over three consecutive days, ending 2 to 7 days before the CAR-T infusion. Unlike myeloablative chemotherapy used for bone marrow transplants, which completely wipes out the bone marrow, lymphodepletion is generally non-myeloablative. It is designed to be intense enough to clear the T-cells but gentle enough that the patient’s blood counts can eventually recover.

However, lymphodepleting chemotherapy adds a significant layer of treatment burden to an already frail patient:

• Cytopenias: Patients often experience prolonged periods of low white blood cell counts (neutropenia), leaving them extremely vulnerable to life-threatening infections during the window when the CAR-T cells are starting their work.

• Gut Toxicity: Chemotherapy can damage the lining of the gut, which some researchers believe may actually contribute to the severity of Cytokine Release Syndrome (CRS) by allowing bacterial products to leak into the bloodstream.

The convergence of these two challenges, the grueling logistics of the vein-to-vein cycle and the physiological toll of lymphodepleting chemotherapy, creates a formidable ceiling for the current generation of CAR-T therapies. While autologous manufacturing has undoubtedly turned the tide for thousands of patients, it remains a bespoke, resource-intensive model that tethers a revolutionary medicine to high-cost academic centers and toxic pre-conditioning regimens. The future of the field, therefore, hinges on a fundamental decoupling of the therapy from the lab.

Conclusion

The journey from Ilya Mechnikov’s observation of cellular immunity to the precise genetic re-coding of a patient’s own T-cells represents a century of medical progress and a fundamental shift in our relationship with biology. We have moved from being passive observers of the “Immunology Civil War” to the architects of its most advanced weaponry.

However, as we have seen, the intellectual maturity of the field has brought us to a new kind of crossroads. The clinical triumphs of pioneers like Carl June and Michel Sadelain have proved that we can achieve remissions that last years, but the logistical hurdles of the access gap and the physiological toll of lymphodepletion remind us that our work is unfinished. We have created a compelling treatment, but it is currently a bespoke treatment, tethered to elite labs and high-cost academic centers. The next era of CAR-T will not be defined by whether we can kill cancer, but by whether we can decouple the therapy from the laboratory.

If the 20th century was about understanding the “battle” Mechnikov described, the 21st century is about democratizing the victory. Stay tuned for Part 2, where we discuss the evolution of therapies that extend the legacy of CAR-T, and Part 3, where we discuss the re-tooling of CAR-T against autoimmune diseases.

To contact us, please send us an email at biotechreadout@gmail.com

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Table of Contents

This week, we discuss…

…landmark events:

• First ever FDA-approved PROTAC, ushering in a brand new therapeutic modality; Arvinas & Pfizer / Veppanu (SERD) / FDA approval (2L ER+ HER2- ESR1m mBC) ⬇️

• First randomized controlled trial testing obesity drug semaglutide in Alcohol Use Disorder; Investigator-sponsored / Semaglutide (GLP1 agonist) / Phase 2 (AUD) ⬇️

…potentially first-in-disease medicines:

• In non-obstructive hypertrophic cardiomyopathy (nHCM); Cytokinetics / Aficamten (cardiac myosin inhibitor) / Phase 3 (nHCM) ⬇️

• In a rare but devastating liver disease called primary sclerosing cholangitis (PSC); Mirum / Volixibat (iBAT inhibitor) / Phase 2b (PSC) ⬇️

…potentially best-in-disease medicines:

• In second-line HR+ HER2- metastatic breast cancer regardless of PIK3CA mutation status; Celcuity / Gedatolisib (pan-PI3K/mTOR inhibitor) / P3 success (2L PIK3CAm HR+ HER2- mBC) ⬇️

• In hidradenitis huppurativa (HS); Avalo / AVTX-009 (anti-IL1b mAb) / Phase 2 (HS) ⬇️

• In inactive thyroid eye disease (TED); Viridian / Elegrobart (IGF-1R inhibitor) / Phase 3 (chronic/inactive TED) ⬇️

Arvinas & Pfizer / Veppanu (SERD) / FDA approval (2L ER+ HER2- ESR1m mBC)

On May 1, 2026, the FDA granted approval for Veppanu (vepdegestrant) for adults with ESR1-mutated, ER+/HER2- advanced or metastatic breast cancer who have progressed following at least one line of endocrine therapy. This is a landmark approval, as it represents the first-ever FDA-approved PROTAC (proteolysis-targeting chimera) therapy.

• Indication: The pathophysiology of ESR1-mutated (ESR1m) metastatic breast cancer is driven by acquired ligand-independent activation of the estrogen receptor. While initial ER+ disease depends on circulating estrogen, chronic exposure to aromatase inhibitors (AIs) often triggers mutations in the ESR1 gene (most commonly in the Y537 or D538 residues of the ligand-binding domain). These mutations lock the estrogen receptor in a constitutively “on” conformation, allowing tumor cells to proliferate even when systemic estrogen levels are depleted. In the second-line (2L) setting, the standard of care has pivoted toward precision endocrine therapy following progression on a 1L CDK4/6 inhibitor plus an AI.

• Mechanism: Veppanu is a heterobifunctional protein degrader that utilizes PROTAC technology to eliminate the estrogen receptor (ER) rather than just blocking it. It binds simultaneously to the ER and an E3 ubiquitin ligase. This tags the ER for destruction by the cell’s natural waste disposal system, the proteasome. Unlike traditional selective estrogen receptor degrader (SERDs) or aromatase inhibitors, Veppanu effectively degrades ESR1 mutations, which are common drivers of resistance (found in 40-50% of patients) after exposure to initial endocrine therapies.

• Trial design: The approval centered on the Phase 3 VERITAC-2 study in which 624 patients with ER+/HER2- advanced breast cancer (270 patients had confirmed ESR1 mutations; the group for which the drug was approved) who had progressed on 1–2 lines of endocrine therapy (including at least one line with a CDK4/6 inhibitor) were randomized 1:1 to receive either oral Veppanu (200 mg daily) or intramuscular Faslodex (current standard of care). The major efficacy outcome was progression-free survival (PFS) as assessed by blinded independent central review (BICR) in the population of patients whose tumors had an ESR1 mutation and in the overall population evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Additional efficacy outcomes were overall survival (OS) and objective response rate (ORR) as assessed by BICR.

• Data (press release, label): A statistically significant difference in PFS by BICR was observed for the patients whose tumors had ESR1 mutations for Veppanu compared with Faslodex/fulvestrant (see table and graph below). Overall survival was immature with 16% of deaths in this population at the time of the PFS analysis. Most common (≥10%) adverse reactions with Veppanu, includinglaboratory abnormalities, were decreased white blood cells, increased AST, musculoskeletal pain, fatigue, decreased hemoglobin, decreased neutrophils, increased ALT, increased alkaline phosphatase, nausea, decreased bloodpotassium, increased bilirubin, decreased appetite, electrocardiogram QT-prolonged, decreased platelets, and constipation. The label includes warnings for QTc interval prolongation and embryo-fetal toxicity.

• Impact:

  • First-in-Modality: Validates PROTAC technology as a viable modality for cancer treatment.

  • Oral Convenience: Provides an oral alternative to the intramuscular injections required for fulvestrant.

  • Precision Medicine: The FDA simultaneously approved the Guardant360 CDx as a companion diagnostic to identify ESR1 mutations via ctDNA (blood test), cementing molecular profiling as a standard step in treatment selection.

• Next steps: The trial sponsors (Arvinas and Pfizer) intend to jointly identify and select a third-party partner with the capabilities and expertise to maximize the commercial potential of Veppanu. The companies are on track to announce selection of a third party. Ongoing studies are evaluating vepdegestrant in combination with other agents (e.g., CDK4/6 inhibitors) to see if earlier lines of therapy can benefit. This success paves the way for the trial sponsor’s other PROTAC candidates targeting neurodegenerative and neuromuscular diseases.

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Investigator-initiated / Semaglutide (GLP1 agonist) / Phase 2 (AUD)

On May 2, 2026, the Lancet published the first large-scale, double-blind, randomized controlled trial (RCT) specifically using semaglutide (the 2.4 mg Wegovy dose approved for obesity) to treat Alcohol Use Disorder (AUD). The study was led by Professor Anders Fink-Jensen and Dr. Mette Kruse Klausen at the Mental Health Center Copenhagen in Copenhagen, Denmark (Rigshospitalet). The trial was funded by the Novo Nordisk Foundation, which is the controlling shareholder of Novo Nordisk, the manufacturer of Wegovy (semaglutide). However, the study was truly “investigator-initiated,” meaning the foundation provided the funding as a grant, but the company (Novo Nordisk) was not involved in the study’s design, execution, or data analysis.

Note that semaglutide is not FDA-approved to treat alcohol use disorder and Novo Nordisk is “not currently conducting any dedicated clinical studies to evaluate marketed semaglutide products … in patients with substance use disorders or addiction-related illnesses”, according to the company. As of May 2026, semaglutide remains only FDA-approved for Type 2 Diabetes (Ozempic/Rybelsus) and Chronic Weight Management (Wegovy). Neither the author nor this publication encourages or condones the off-label use of semaglutide.

• Indication: Alcohol Use Disorder (AUD) is characterized by a dysregulation of the brain’s reward and executive control systems, primarily involving the chronic adaptation of GABAergic (inhibitory) and glutamatergic (excitatory) neurotransmission. Prolonged alcohol consumption downregulates GABA receptors and upregulates NMDA receptors, leading to a state of hyperexcitability during withdrawal that drives compulsive seeking behavior through the mesolimbic dopamine pathway. The current standard of care employs a multimodal approach, combining psychosocial interventions—such as Cognitive Behavioral Therapy (CBT), Motivational Enhancement Therapy (MET), and 12-step programs with FDA-approved pharmacotherapies. These can include naltrexone (an opioid antagonist to reduce cravings), acamprosate (to stabilize glutamate signaling), and disulfiram (an aversive agent that induces illness upon alcohol ingestion), though clinical uptake of these medications remains low despite their efficacy.

• Mechanism: Semaglutide is a GLP-1 receptor agonist (GLP-1RA). While its primary metabolic function is increasing insulin secretion and slowing gastric emptying (we covered this in our “Frontiers in Medicine” piece on Obesity, Part 2), its effect on addiction is centered in the central nervous system. It is believed to modulate the brain’s reward system, specifically the mesolimbic dopamine pathway (the ventral striatum). By interacting with these receptors, semaglutide reduces the dopamine rush associated with alcohol consumption, effectively dampening the reinforcing pleasure of drinking and reducing the psychological urge or craving. Nevertheless, this mechanism is largely theoretical.

• Trial design: The Phase 2 was a randomized, double-blind, placebo-controlled trial evaluating once-weekly subcutaneous semaglutide (escalated to 2.4 mg) versus placebo over 26 weeks in 108 adults with comorbid obesity (BMI ≥30) and Alcohol Use Disorder (AUD) seeking treatment. The primary endpoint was the change in the number of heavy drinking days (HDD) from baseline to week 26.

• Data (paper): The trial demonstrated a significant effect in reducing alcohol consumption. Semaglutide recipients saw a -41.1% reduction in heavy drinking days compared to -26.4% in the placebo group at week 26. he semaglutide group reduced their monthly intake by ~1,550g (compared to ~1,026g for placebo). As the investigators expected, the semaglutide group lost significantly more weight (~11.2 kg vs ~2.2 kg). The profile was consistent with other GLP-1 trials; gastrointestinal issues (nausea, vomiting) were the most common adverse events.

• Impact:

  • Magnitude of Effect: The reduction in WHO drinking-risk levels was notably higher than standard-of-care AUD medications like naltrexone or acamprosate. The publication specifically highlights a massive potential benefit for the estimated 8 million Americans who suffer from both obesity and AUD. However, semaglutide would have to be investigated in manufacture-sponsored trials and reviewed by regulators for this to come to fruition.

  • Validation of Anecdotes: This trial provides the first high-quality clinical evidence to back up years of anecdotal reports from Wegovy users claiming they lost interest in alcohol.

• Next steps: Despite the clinical success of this investigator-initiated trial, the path to formal FDA approval for semaglutide in AUD is currently stagnant. The company has explicitly stated they are not currently conducting dedicated studies for AUD. Their focus remains on diabetes, obesity, and cardiovascular/kidney outcomes. Since this trial focused on patients with obesity, more research is needed to determine if the same effect occurs in lean patients with AUD. The academic researchers who conducted this trial called for larger, multi-center Phase 3 trials and longer follow-up periods to see if the “sobriety” effect persists after the drug is discontinued. Notably, Eli Lilly is evaluating a GLP1/GIP dual agonist called brenipatide for alcohol use disorder (AUD) in two Phase 3 clinical trials with estimated completion dates in April 2028.

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Cytokinetics / Aficamten (cardiac myosin inhibitor) / Phase 3 (nHCM)

The Phase 3 ACACIA-HCM trial results for aficamten in non-obstructive hypertrophic cardiomyopathy (nHCM) represent a major milestone, as this is the first cardiac myosin inhibitor to succeed in this specific, hard-to-treat patient population. Last year, aficamten was approved under the trade name Myqorzo by the FDA to treat adults with symptomatic obstructive hypertrophic cardiomyopathy (oHCM). This Phase 3 data could support a future FDA approval, pending further regulatory review, roughly doubling the number of patients that Myqorzo could treat, according to Cytokinetics’ estimates (see the figure below).

• Indication: The pathophysiology of non-obstructive hypertrophic cardiomyopathy (nHCM) is characterized by genetic mutations in the cardiac sarcomere that lead to excessive heart muscle thickening (hypertrophy) without a physical blockage in the left ventricular outflow tract. This results in diastolic dysfunction, where the thickened ventricle becomes stiff and fails to fill properly, alongside hyperdynamic contractility that increases myocardial oxygen demand. Over time, this cellular stress leads to interstitial fibrosis and elevated filling pressures, causing symptoms like exertional dyspnea, fatigue, and chest pain. Historically, the standard of care has been limited to symptom management using non-specific medications such as beta-blockers or calcium channel blockers to slow the heart rate and improve diastolic filling; however, these do not address the underlying disease mechanism, leaving a significant unmet need for targeted therapies. A retrospective study led by Dr. Milind Desai at the the Cleveland Clinic following 3,393 patients (Jadam et al. JACC (2025)) found that 20-year survival was as low as 57% for nHCM and 50% for oHCM. While nHCM carries a slightly better survival profile than oHCM, the high rate of arrhythmic risk and the lack of targeted therapies have made it a particularly challenging disease for cardiologists to manage.

• Mechanism: Aficamten is a next-generation cardiac myosin inhibitor. It binds selectively to cardiac myosin, reducing the number of active myosin heads that can bind to actin. By dampening hypercontractility (a hallmark of HCM), it reduces the excessive force of heart muscle contraction. In nHCM, where there is no physical blockage (outflow tract obstruction), the drug works by improving diastolic relaxation and lowering the metabolic stress on the heart muscle.

• Trial design: The Phase 3 ACACIA-HCM trial was a double-blind, randomized, placebo-controlled trial comparing aficamten versus placebo for 36 weeks with a dose-titration period guided by echocardiography (ECG) in adults with symptomatic non-obstructive HCM (nHCM). The trial had a dual primary endpoint, meaning that it needed to show a statistically significant improvement in at least one of these endpoints to be deemed a “success”. They included:

  • Change in KCCQ-CSS (Kansas City Cardiomyopathy Questionnaire - Clinical Summary Score) at Week 36.

  • Change in pVO₂ (Peak Oxygen Consumption during exercise) at Week 36.

• Data (press release): The trial met both dual primary endpoints with statistical significance (see the graphs below). Additionally, key secondary endpoints were met with high significance (p < 0.001), including improvements in NYHA Functional Class and reduction in NT-proBNP (a marker of cardiac wall stress), although numerical values were not shared in this release. There were “no new safety signals” associated with aficamten, according to the trial sponsor. Left ventricular ejection fraction (LVEF) < 50% occurred in 10% of aficamten patients vs. 1% in placebo, with most cases being asymptomatic and reversible upon dose adjustment or interruption. This is important because if LVEF drops too low, it can lead to systolic heart failure. The label requires clinicians to pause or “ct” (continue/titrate) therapy if LVEF falls below 50%, as this indicates the heart is no longer pumping effectively enough to meet the body’s needs. The study data showed that most LVEF drops were asymptomatic and resolved once the drug was paused, suggesting that the “stop-start” guidance on the label is a potentially effective mechanism for managing the drug’s primary effect.

• Impact:

  • First-in-Indication Potential: While aficamten is already FDA-approved for obstructive HCM (oHCM), this Phase 3 data could support a future FDA approval in non-obstructive hypertrophic cardiomyopathy (nHCM), pending further regulatory review.

  • Patient Benefit: The data shows patients feel better (KCCQ) and can physically do more (pVO2), addressing the high unmet need for the roughly 30% of HCM patients who do not have an obstruction.

  • Competitive Edge: This readout is particularly significant because the competitor drug, mavacamten (approved for oHCM as Camzyos), previously failed to show significant benefit in its own Phase 3 nHCM trial. This cements aficamten as the leader in this segment.

• Next steps: Full data results will be presented at an upcoming major medical meeting (possibly ESC Heart Failure or similar). Cytokinetics has 10 presentations scheduled for the European Society of Cardiology (ESC) Heart Failure Congress in Barcelona (May 9–12, 2026). This includes a Late-Breaking Science presentation on the dose-dependent effects of aficamten (from the MAPLE-HCM study). The trial sponsor plans to “discussing [these results] with the U.S. FDA and other regulatory authorities” for the nHCM indication.

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Mirum / Volixibat (iBAT inhibitor) / Phase 2b (PSC)

Mirum Pharmaceuticals announced positive topline results from its VISTAS Phase 2b study of volixibat on May 4, 2026. This data de-risks the asset for Primary Sclerosing Cholangitis (PSC), a rare liver disease with no currently approved treatments for cholestatic pruritus (itch).

• Indication: Primary Sclerosing Cholangitis (PSC) is a chronic, progressive liver disease characterized by immune-mediated inflammation, thickening, and obliterative fibrosis of both intrahepatic and extrahepatic bile ducts. This beading of the ducts leads to cholestasis (impeded bile flow), which eventually causes biliary cirrhosis, portal hypertension, and an increased risk of cholangiocarcinoma. While the exact etiology remains unknown, the strong association with inflammatory bowel disease (IBD), present in roughly 70–80% of patients, suggests a complex interplay between genetics, gut microbiota, and immune dysregulation. Currently, there is no FDA-approved treatment that halts disease progression. Management focuses on symptom relief, such as using ursodeoxycholic acid (UDCA) for biochemical improvement (though its impact on survival is debated), endoscopic balloon dilation for dominant strictures, and ultimately, liver transplantation for end-stage disease. PSC patients have a three- to four-fold increased risk of all-cause mortality compared to the general population. The median time from diagnosis to either liver transplantation or death is approximately 15 to 21 years. This range varies significantly; for patients seen at major transplant centers (who often have more advanced disease), the median survival may be as low as 13 years. For those who undergo a liver transplant, the prognosis is generally good, with a 5-year survival rate of approximately 85%.

• Mechanism: Volixibat is an oral, minimally absorbed, potent ileal bile acid transporter (IBAT) inhibitor. It blocks the apical sodium-dependent bile acid transporter (ASBT/SLC10A2) in the terminal ileum. By preventing the reabsorption of bile acids (which are normally 95% recycled), it promotes their fecal excretion. Reducing the systemic and hepatic bile acid pool is thought to lower the concentration of pruritogens (itch-inducing substances) in the blood, thereby alleviating severe cholestatic pruritus.

• Trial design: The VISTAS Phase 2b trial evaluated volixibat 20 mg twice daily (BID) versus placebo in 158 patients with PSC and cholestatic pruritus (111 primary analysis cohort had moderate-to-severe itch, 47 secondary analysis cohort had mild itch). The primary endpoint was mean change in weekly averaged daily itch score (Adult ItchRO scale, 0–10) from baseline to the average of the last 12 weeks of a 28-week treatment period.

• Data (press release, slide deck): The study met its primary endpoint with high statistical significance. It also met key secondary endpoints, showing more patients with a ≥2 point reduction in Adult ItchRO (55.6% volixibat versus 26.3% placebo, p=0.0019) and a greater reduction in serum bile acids (-33 volixibat versus +2.1 placebo, p=0.0019; side-note: they didn’t include units in the press release). Statistically significant reductions in pruritus were observed as early as Week 2. The profile was “consistent with the IBAT inhibitor class” according to the trial sponsor, with higher incidence of diarrhea (40.3% volixibat versus 8.6% placebo) and numerically higher discontinuations due to AEs (9.1% volixibat versus 2.5% placebo).

• Impact:

  • Potentially first-in-indication: There are currently no FDA-approved therapies specifically for the treatment of pruritus in PSC. Volixibat is now positioned to potentially be the first.

  • Quality of Life: The ~2.7 point reduction is considered clinically meaningful, as itch in PSC is often debilitating, leading to sleep deprivation and significant psychological distress.

  • Class Validation: This success further validates Mirum’s IBAT platform, which already includes Livmarli (maralixibat) for Alagille syndrome and PFIC.

• Next steps: The trial sponsor plans to present this data as a late-breaking oral presentation at the EASL Congress on May 30, 2026. They also anticipate a pre-NDA meeting with the FDA, scheduled for Summer 2026, with an NDA submission in 2H 2026. The trial sponsor is also evaluating volixibat in the VANTAGE Phase 2b study for Primary Biliary Cholangitis (PBC), with topline data expected in Q1 2027.

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Celcuity / Gedatolisib (pan-PI3K/mTOR inhibitor) / P3 success (2L PIK3CAm HR+ HER2- mBC)

On May 1, 2026, Celcuity announced positive topline Phase 3 results for the PIK3CA-mutated cohort of the VIKTORIA-1 trial. This follows the company’s ongoing regulatory momentum, with a PDUFA date for the PIK3CA wild-type population set for July 17, 2026. This is a descriptive data release without numerical data, but it’s important enough that it merits its own section.

• Indication: The pathophysiology of PIK3CA-mutated (PIK3CAm) HR+/HER2- metastatic breast cancer is characterized by the hyperactivation of the PI3K/AKT/mTOR pathway, which serves as a critical escape mechanism for tumor cells to bypass estrogen receptor (ER) inhibition. Found in approximately 40% of cases, PIK3CA mutations (most commonly in the H1047R, E542K, or E545K domains) lead to constitutive signaling of the p110α catalytic subunit, driving cell proliferation and survival even under the pressure of endocrine therapy. In the second-line (2L) setting, the established standard of care for these patients is Piqray (alpelisib), a p110α-selective PI3K inhibitor, in combination with Faslodex (fulvestrant), which significantly improved progression-free survival (PFS) in the SOLAR-1 trial. Emerging therapies like gedatolisib (a pan-PI3K/mTOR inhibitor) are actively shifting the benchmark toward triplet combinations or more potent, selective inhibition to overcome the resistance mechanisms associated with first-generation PI3K inhibitors.

• Mechanism: Gedatolisib is a highly potent, pan-class I PI3K and mTORC1/C2 inhibitor. It targets the interconnected PI3K/AKT/mTOR (PAM) pathway at multiple points. Unlike single-target inhibitors (e.g., Piqray/alpelisib, which targets only PI3K-alpha, gedatolisib inhibits all four PI3K isoforms plus both mTOR complexes. By blocking both upstream and downstream components, gedatolisib prevents the adaptive resistance (cross-activation of PI3K isoforms) that typically occurs when a tumor is treated with an isoform-specific inhibitor. In the triplet regimen, it works alongside estrogen receptor degrader therapy (Faslodex/fulvestrant) and a CDK4/6 inhibitor (Ibrance/palbociclib) to simultaneously shut down the three primary drivers of ER+ breast cancer growth.

• Trial design: The Phase 3 VIKTORIA-1 evaluated HR+/HER2- advanced breast cancer who had progressed on a prior CDK4/6 inhibitor plus an aromatase inhibitor. The latest data release focuses on “Study 2”, a cohort of patients who have PIK3CA mutations. It tested three arms:

  • Arm 1 (Triplet): Gedatolisib + Faslodex + Ibrance

  • Arm 2 (Doublet): Gedatolisib + Faslodex

  • Arm 3 (Active Control): Piqray + Faslodex (The current standard of care for PIK3CA-mutated mBC)

• Data (press release): The topline results demonstrated that both gedatolisib-based regimens (Arm 1 Triplet and Arm 2 Doublet) were superior to the current SOC (Piqray/Faslodex) at improving progression free survival (PFS) with statistical significance. Detailed figures will be presented at 2026 ASCO Annual Meeting, which is scheduled to take place from May 29 to June 2, 2026.

• Impact:

  • Potentially New Standard-of-Care: By beating Piqray head-to-head, gedatolisib establishes itself as the potential new “best-in-class” PI3K-pathway inhibitor for 2L PIK3CAm HR+ HER2- mBC. According to the trial sponsor’s estimates, HR+/HER2- breast cancer is the most common subtype of breast cancer (70% of all breast cancers), of which approximately 40% have PIK3CA mutations.

  • Overcoming Resistance: The data suggests that gedatolisib can resensitize tumors to CDK4/6 inhibition (palbociclib) even after they have already progressed on that class of therapy.

  • Pan-Population Efficacy: Unlike many competitors that only work in mutated populations, gedatolisib has now shown Phase 3 success in both PIK3CA-mutated (this release) and PIK3CA-wild-type patients (earlier release, data shown in the graph below).

• Next steps: The trial sponsor plans to present full data, including specific median PFS months and Hazard Ratios (HR), will be shared during a late-breaking oral session at ASCO 2026. They also intend to file a Supplemental New Drug Application (sNDA) for the PIK3CA-mutated population based on these results. The FDA is currently reviewing the first NDA for gedatolisib in the PIK3CA wild-type population under Priority Review (July 17, 2026 PDUFA). The trial sponsor is already enrolling patients in a Phase 3 trial evaluating gedatolisib in the first-line setting (treatment-naïve) to move the therapy earlier in the treatment paradigm.

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Avalo / Abdakibart (anti-IL1b mAb) / Phase 2 (HS)

Avalo Therapeutics announced positive topline results for its Phase 2 LOTUS trial evaluating abdakibart (AVTX-009) in moderate to severe Hidradenitis Suppurativa (HS).

• Indication: Hidradenitis Suppurativa (HS) is a chronic inflammatory skin disease primarily driven by the occlusion of the hair follicle (infundibulum), leading to follicular rupture and the subsequent release of keratin and bacteria into the dermis. This triggers a potent immune response involving the overexpression of cytokines like TNF-α, IL-17, and IL-1β, resulting in painful abscesses, nodules, and the formation of extensive scarring and draining tunnels (sinus tracts). The standard of care follows a staged approach: mild cases are managed with topical antibiotics (clindamycin) or resorcinol, while moderate-to-severe disease requires systemic intervention. This typically begins with oral antibiotics (tetracyclines or clindamycin/rifampin) as first-line therapy, followed by biologics, most notably TNF-inhibitors like Humira (adalimumab) or IL-17A inhibitors like Cosentyx (secukinumab), with surgical debridement or “unroofing” reserved for treating persistent tunnels and refractory lesions.

• Mechanism: Abdakibart is a humanized monoclonal antibody (IgG4) that targets and inhibits interleukin-1 beta (IL-1β) signaling. IL-1β is a central driver of the inflammatory cascade in HS, contributing to the formation of painful nodules, abscesses, and draining tunnels. By neutralizing IL-1β, abdakibart aims to reduce systemic and local inflammation.

• Trial design: The Phase 2 LOTUS trial was a randomized, double-blind, placebo-controlled trial evaluating two dosing schemes of abdakibart (600mg loading then 300 mg every 4 weeks (Q4W); 300mg loading then 150 mg every 2 weeks (Q2W)) against placebo in 253 adults with moderate to severe HS. The primary endpoint was the proportion of subjects achieving HiSCR75 (75% reduction in total abscess and inflammatory nodule [AN] count) at Week 16.

• Data (press release, slide deck): The trial met its primary endpoint with statistical significance for both dose regimens (16-week HiSCR75 rates of 42.2% and 42.9% for Q2W and Q4W doses respectively versus 25.6% placebo, p=0.018 and 0.015 respectively). Based on the cross-trial comparison provided in the LOTUS study topline results, abdakibart demonstrates numerically competitive HiSCR75 rates compared to both approved therapies and other prominent pipeline candidates (see below). The caveat is that these data are derived from separate clinical trials with differences in design and patient populations. No head-to-head clinical trials have been conducted to date. All timepoints shown in the figure are at Week 16, with the exception of povorcitinib, which is at Week 12.

• Impact:

  • Potentially Best-in-Disease: The 42.9% HiSCR75 rate is among the highest observed in a trial of this size for HS. A caveat is that, on a placebo-adjusted basis, abdakibart’s HiSCR75 rate comes in numerically lower than competing anti-IL-1β antibody lutikizumab (~17% abda versus ~28% lutiki). Given very high placebo variability across trials (ranging from 13% to 26% in the abdakibart trial), the most precise statement that we can make at this point is that abdakibart is roughly “on par” with competitive molecules. Only a large head-to-head trial would be able to infer non-inferiority/superiority with high precision.

  • Dosing Convenience: The success of the 300 mg every-4-weeks (E4W) regimen provides a patient-friendly monthly dosing option, which is a competitive advantage over more frequent treatments.

  • Target Validation: Reinforces the critical role of IL-1β in HS pathology, potentially positioning it as a preferred pathway over IL-17 or TNF for certain patient subsets.

• Next steps: The trial sponsor plans to present detailed results at an upcoming medical conference (likely a major dermatology congress). They have also confirmed plans to advance abdakibart into a registrational Phase 3 program for HS. The company is exploring abdakibart in other immune-mediated inflammatory diseases.

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Viridian / Elegrobart (IGF-1R inhibitor) / Phase 3 (chronic/inactive TED)

Viridian Therapeutics recently announced positive topline results for elegrobart (VRDN-003) from its Phase 3 REVEAL-2 trial in patients with chronic/inactive Thyroid Eye Disease (TED). This readout follows the REVEAL-1 success in active TED, positioning elegrobart as a potential best-in-class subcutaneous (SC) treatment.

• Indication: Chronic (inactive) Thyroid Eye Disease (TED) is a late-stage autoimmune condition where the initial inflammatory “hot” phase has subsided, but the underlying tissue remodeling has left permanent structural damage. The pathophysiology centers on the activation of orbital fibroblasts via the IGF-1R and TSHR signaling complexes; in the chronic phase, this leads to significant fibrosis (scarring) and adipogenesis (fat expansion) within the confined orbital space. This volume increase results in persistent proptosis (bulging eyes), restricted extraocular muscle movement (leading to double vision), and potential optic nerve compression. Because inflammation is no longer the driver, the standard of care traditionally shifts from immunosuppression to mechanical intervention. Management typically involves rehabilitative surgeries performed in a specific sequence: orbital decompression to reduce pressure, followed by strabismus surgery to align the eyes, and finally eyelid retraction repair. However, the recent emergence of IGF-1R inhibitors like Tepezza (teprotumumab), and potentially elegrobart, has begun to shift the paradigm by offering a non-surgical medical option to reduce proptosis even in this inactive, fibrotic stage.

• Mechanism: Elegrobart is an anti-Insulin-like Growth Factor-1 Receptor (IGF-1R) monoclonal antibody delivered subcutaneously via a low-volume autoinjector. It is a half-life extended version of veligrotug (VRDN-001). This allows for less frequent dosing (Q4W or Q8W) and home administration, compared to the intravenous (IV) infusions required for the current market leader, Tepezza.

• Trial design: The Phase 3 REVEAL-2 evaluated two dose schedules of elegrobart (Q4W/once every 4 weeks and Q8W/once every 8 weeks) against placebo in 204 patients with chronic/inactive TED (characterized by lower inflammation/CAS but persistent proptosis). The primary endpoint was the proptosis responder rate (reduction of ≥2mm) at Week 24.

• Data (press release, slide deck): Both doses met the primary endpoint with high statistical significance (see graphs below). Elegrobart also became the first subcutaneous (SC) treatment to demonstrate a statistically significant diplopia (double vision) response in patients with chronic/inactive TED (24w diplopia responder rate 61% for Q4W elegro [p=0.0118] versus 55% for Q8W elegro [p=0.0419] versus 38% placebo).

• Impact:

  • Potentially Best-in-class IGF-1R Inhibitor for TED: The data suggests that the Q8W (every 2 months) regimen is just as effective as the Q4W regimen, which would drastically reduce the treatment burden for patients. Nearly half (44%) of the patients in the Q4W arm achieved complete resolution of their diplopia (p = 0.0295), meaning they no longer experienced double vision in any direction of gaze. This is a potentially life-altering outcome for patients who previously relied on prisms or surgery.

  • Potentially Better Convenience: By offering an at-home autoinjector with “IV-like” efficacy, the trial sponsor aims to capture chronic patients who typically avoid the logistics of IV infusion centers.

  • Potentially Restores Confidence in Elegrobart’s Potency After Previous Mixed Phase 3: The successful Phase 3 REVEAL-2 data in chronic TED could revitalize enthusiasm elegrobart following the a mixed reaction to the Phase 3 REVEAL-1 active TED data on March 30, 2026. In the REVEAL-1 (active TED) readout, the proptosis responder rate (70.7% for the Q8W dose) was seen as slightly trailing the historical performance of IV Tepezza (~83% in its pivotal trial). This led to fears that the move from intravenous to subcutaneous (SC) delivery came with an “efficacy haircut.” REVEAL-2’s 54% responder rate in chronic TED is relatively strong, potentially allaying fears that the SC version is significantly weaker.

• Next steps: The trial sponsor stated that they “remain on track to submit a Biologics License Application (BLA) to the U.S. FDA for elegrobart in Q1 2027”, with Phase 3 data for both inactive TED (REVEAL-2 trial) and active TED (REVEAL-1 trial) in hand. Their IV candidate, veligrotug (VRDN-001), has a PDUFA date of June 30, 2026. If approved, veligrotug’s launch could serve as the commercial foundation for a subsequent elegrobart launch, pending regulatory review.

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To contact us, please send us an email at biotechreadout@gmail.com

Disclaimers

Investigational Status Disclaimer

The therapeutic candidates discussed in this newsletter are currently in clinical development and have not been approved for commercial sale by the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or other global regulatory authorities. Their safety and efficacy have not been established. References to pipeline products and ongoing clinical trials involve significant risks and uncertainties. Statements regarding the potential safety, potency, or efficacy of investigational drugs reflect current hypotheses and are not a guarantee of future performance or regulatory clearance. The outcome of clinical trials is inherently unpredictable, and clinical results from earlier stages may not be predictive of results in later, larger-scale trials.

No Medical Advice Disclaimer

This newsletter is for informational and educational purposes only. The content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or another qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read in this publication.

No Patient-Provider Relationship Disclaimer

The information provided in this newsletter is for educational and analytical purposes only. Receipt of this information, or any interaction with this content, does not create a physician-patient, pharmacist-patient, or any other professional-provider relationship between you and the authors or publishers. This newsletter should not be used as a substitute for a personal consultation with a qualified healthcare professional.

Forward-Looking Statements Disclaimer

This newsletter contains “forward-looking statements” regarding future events, including clinical trial timing, regulatory milestones, and projected market performance. These statements are based on current expectations and assumptions that are subject to significant risks and uncertainties. Actual results may differ materially from those expressed or implied. We undertake no obligation to update these statements as a result of new information or future developments.

Third-Party Links & Content Disclaimer

This newsletter contains links to third-party websites, including clinical trial registries and corporate presentations. Biotech Readout does not endorse, guarantee, or assume responsibility for the accuracy or reliability of any information offered by third-party providers.

Errors and Omissions Disclaimer

While we strive for technical accuracy, the information in this newsletter is provided on an “as is” basis with no guarantees of completeness, accuracy, or timeliness. Biotech Readout assumes no liability for any errors or omissions in the content of this publication.

Non-Endorsement Disclaimer

Any reference to specific commercial products, processes, or services by trade name, trademark, or manufacturer does not constitute or imply an endorsement or recommendation by the author. All trademarks are the property of their respective owners.

No Investment Advice Disclaimer

This newsletter is for informational purposes only and does not constitute financial, investment, or legal advice. The author is not a registered investment advisor. You should consult with a professional financial advisor before making any investment decisions. The biotechnology sector is highly volatile; past performance is not indicative of future results.

Conflict of Interest Disclaimer

The author of this newsletter maintains a position of independence. At the time of publication, the author holds no direct financial interest, equity, or options in any of the companies mentioned in this report. No compensation has been received from any third party to feature or analyze specific therapeutic candidates or corporate entities.

Introduction

On May 6, 2026, Bayer announced an agreement to acquire Perfuse Therapeutics Inc. for a total potential value of up to $2.45 billion, comprising a $300 million upfront payment and additional development, regulatory, and commercial milestone payments based on success criteria (Bayer press release, Perfuse press release). The centerpiece of the acquisition is PER-001, a small molecule endothelin receptor antagonist currently in Phase 2 clinical development for the treatment of Glaucoma and Diabetic Retinopathy (DR). These diseases fall under a broader clinical umbrella of Diabetic Eye Disease (DED).

Diabetic Eye Disease (DED) constitutes a blockbuster indication space, representing an aggregate revenue run rate of almost $11 billon as of 4Q 2025 according to quarterly press releases associated with Vabysmo, Eylea, Eylea HD, Pavblu, Lucentis, and Ozurdex*. There are about 14 in clinical development, making the field relatively sparse.

Acquisitions in the Diabetic Eye Disease space are just as sparse. Perfuse is among the rare DED-focused acquisition, with the another that comes to mind being Merck’s purchase of EyeBio in May 2024 for $1.3 billion in cash and up to $1.7 billion in potential future payments tied to specific developmental, regulatory, and commercial achievements (lead program was EYE103 now called MK-3000 was a Phase 2 ready tri-specific Wnt agonist for diabetic macular edema).

Most acquired DED-related drugs were reeled in through mega-mergers, in which the DED drug(s) constituted one of many pipeline candidates. This includes Novartis’ 2010 acquisition of Alcon for $12.9 billion (included Lucentis, Rhopressa, Simbrinza, and Triesence) and AbbVie’s 2020 acquisition of Allergan for $63 billion (included Ozurdex).

Here, we dive into the story of Perfuse Therapeutics, unpack Diabetic Retinopathy (DR) and glaucoma, describe how PER-001 could advance the standard of care.

All Eyes on Perfuse

The history of Perfuse Therapeutics is a classic stealth-to-success biotech narrative, beginning with a focus on a specific unmet need, retinal ischemia (blocked blood flow), and culminating in one of the most significant ophthalmology acquisitions of 2026.

Perfuse Therapeutics was founded in South San Francisco, California, by Dr. Sevgi Gurkan, a physician-scientist and biotech executive whose career bridges high-level academic research, clinical practice, and venture-backed drug development. She received her medical degree from Hacettepe University and completed her residency in Pediatrics at the University of Southern California (USC). She later earned degrees in Nephrology and a Master of Science in Clinical Research from the Mount Sinai School of Medicine. Afterwards, she served as an Associate Professor at Rutgers University and was the Director of the Pediatric Kidney Transplant Program at Robert Wood Johnson University Hospital. Dr. Gurkan was also one of the founding scientists of the Child Health Institute of New Jersey, where she conducted NIH-funded basic science research, balancing a full-time clinical load with laboratory work. Dr. Gurkan then transitioned into the corporate sector by taking on leadership roles at major pharmaceutical and venture firms:

• Merck Research Laboratories (MRL): Dr. Gurkan was a founding member of the Merck Research Laboratories South San Francisco discovery site, where she served as a Director of Research. At Merck, she was responsible for launching new therapeutic areas and building a portfolio of novel mechanisms through both internal development and M&A. She originally joined Merck as a Medical Director in Early Clinical and Translational Development for Cardiometabolic Diseases.

• OrbiMed: Dr. Gurkan joined OrbiMed in 2018 as a Venture Partner, where she focused on identifying and building companies around novel therapeutic mechanisms.

Dr. Sevgi Gurkan founded Perfuse in 2018, the exact same year she joined OrbiMed as a Venture Partner. This suggests that the company was incubated within the OrbiMed ecosystem. There, she served as CEO and a member of the Board of Directors. The company’s core mission was to pivot away from the industry’s singular focus on lowering intraocular pressure (IOP) and instead target ischemia-induced ocular diseases. The team believed that many vision-threatening conditions, particularly glaucoma and diabetic retinopathy, were driven by poor blood flow (hypoperfusion) caused by an overabundance of Endothelin-1, the body’s most potent vasoconstrictor. The company established its headquarters in the Bay Area but maintained critical R&D facilities in Durham, North Carolina, tapping into the regional expertise in ocular drug delivery.

In July 2020, Perfuse closed a $9 million Series A round (though some reports suggest the total raised was closer to an undisclosed amount with participation from Access Industries and Catalio Capital Management). During this period, the company perfected its proprietary sustained-release drug delivery platform. Unlike standard drops, they developed a bio-erodible intravitreal implant that could be injected with a 25-gauge applicator, allowing for 6-month dosing of their lead asset, PER-001. By late 2022, Perfuse had successfully transitioned from a pre-clinical research outfit to a clinical-stage biotech.

The most critical chapter in the company’s history occurred during the clinical testing of PER-001. In August 2023, Perfuse initiated a major Phase 2 study for Diabetic Retinopathy (DR). The trial aimed to prove that an endothelin receptor antagonist could not only dry the retina but also improve contrast sensitivity and reduce ischemia. In April 2025, the company reported reported top-line Phase 2a data for both glaucoma and DR. Theresults were notable for observed numerical improvements in visual field sensitivity, a functional signal that has historically been difficult to achieve with pressure-lowering agents alone.

The history of Perfuse as an independent company effectively ended nearly a year later on May 6, 2026, with the announcement of its acquisition by Bayer. For Bayer, the acquisition secured a product that complements their blockbuster ophthalmology drug, Eylea. For Perfuse, the deal provides the “scale and global resources” to take PER-001 through Phase 3, regulatory review, and (if approved) into the hands of millions of patients globally.

Diabetic Retinopathy (DR), Blindness by Blood Vessel

As I alluded to earlier, Diabetic Eye Disease (DED) is a broad family of specific conditions that share the same root cause (chronically high blood sugar), but impact the eye in very different ways.

Retinal vascular disorders are the most common subfamily of DED and are driven by the breakdown of the blood-retinal barrier at the back of the eye that disrupts the retina, the light-sensitive layer inside the eye that detects light and converts it into signals your brain can use for vision. Diabetic Retinopathy (DR) is the most common cause of vision loss among working-age adults. It is characterized by the death of blood-vessel-molding pericytes due to oxidative stress (secondary to Polyol pathway overstimulation), followed by vascular leakage (“microaneurysms”) and blockage (“ischemia”), and ultimately excessive vascular growth as the eye desperately attempts to restore blood and oxygen to the retina. These new vessels can be very problematic by blocking light from hitting the retina/optic nerve or even detaching the retina from the back of the eye. According to Bayer’s market research, DR “affects about 146 million people globally today and is projected to increase to 160 million people by 2045.” Furthermore, “25 million people [currently] have vision‑threatening DR and 1.3 million people are blind.”

The standard of care for Diabetic Retinopathy (DR) has shifted significantly in 2025–2026. The clinical focus has moved from watchful waiting to early intervention and long-term vascular stabilization. This new paradigm is led by anti-VEGF (vascular endothelial growth factor) agents. These drugs prevent vision loss by inhibiting the formation of abnormal, leaky blood vessels in the retina.

• Aflibercept (Eylea / Eylea HD): The recently launched 8 mg high-dose formulation (Eylea HD) has seen rapid adoption because it allows for extended dosing intervals (up to 4 months), reducing the injection burden for patients.

• Faricimab (Vabysmo): Since its approval, Vabysmo has been the fastest-growing competitor to Eylea. It is a bispecific antibody that targets both VEGF and Ang-2, which may provide better vascular stability and longer durability than traditional anti-VEGFs.

• Ranibizumab (Lucentis / Susvimo): While Lucentis sales have declined due to biosimilar competition, the Susvimo continuous delivery system (a refillable implant) is a high-value product for DR patients needing long-term suppression with fewer visits.

How does Perfuse Therapeutics fit in? Their lead program, PER-001, is a potent Endothelin-1 (ET-1) receptor antagonist. Since ET-1 is the body’s most powerful vasoconstrictor, blocking it allows constricted vessels to dilate and restores blood flow to ischemic areas of the retina. By improving perfusion, PER-001 could potentially prevent the death of retinal cells rather than just drying up the fluid they leak.

Data presented at American Society of Retina Specialists (ASRS) 2025 medical meeting suggests that PER-001 could provide functional vision improvements that anti-VEGFs often miss. Their Phase 2a trial demonstrated that functional visual gains can be achieved even while the Diabetic Retinopathy Severity Scale (DRSS) remains stable. Treatment with PER-001 delivered superior outcomes across all primary functional metrics:

• Low Luminance Contrast Sensitivity: The High Dose group showed a mean improvement of +0.9 dB, while the Low Dose group improved by +0.65 dB. Compared to the -2.1 dB worsening in the sham control, this represents a delta of ~3 dB. Clinically, a 3 dB gain is equivalent to three lines of vision (15 ETDRS letters), a major regulatory benchmark.

• Visual Acuity: Patients treated with PER-001 avoided the decline observed in the control group, showing a mean difference of +5.07 to +5.47 letters compared to control.

• Peripheral Vision: Patients with baseline deficits showed an improvement of +1.8 dB/year (Low Dose) compared to negligible change (+0.01 dB) in the control.

While anti-VEGF helps patients read letters on a bright chart (BCVA), PER-001 appears to help patients see better in dimly lit environments or distinguish subtle textures, which are major complaints for diabetic patients.

One of the most disruptive aspects of PER-001 is its delivery system. It is a bio-erodible intravitreal implant (utilizing PLGA polymer technology similar to Ozurdex) designed for 6-month sustained release. This could catalyze the shift from injections every 4–8 weeks (Standard Eylea) to a twice-yearly implant, which could address the compliance gap that leads to real-world vision loss in DR patients.

Glaucoma, Blindness by Pressure in the Eye

Glaucoma another disease that Perfuse’s PER-001 was designed to treat and is often described as the “silent thief of sight” because it typically progresses without pain or noticeable symptoms until significant permanent damage has occurred. Bayer defines glaucoma as a “progressive optic neuropathy that causes the loss of retinal ganglion cells, resulting in loss of visual fields.” While most forms of glaucoma are chronic and progressive, certain types are considered medical emergencies. If left untreated, chronic glaucoma can lead to irreversible blindness. As Bayer puts it:

Glaucoma […] is the leading cause of irreversible vision loss affecting ~76-80 million people worldwide (2020) and is projected to affect ~112 million people by 2040 due to population aging.

Unlike DR, the glaucoma market is heavily genericized, but fixed-dose combinations and novel delivery platforms can improve patient compliance. The medical standard of care for glaucoma focuses on a stepped approach to lowering intraocular pressure (IOP) to a target level that prevents optic nerve damage, primarily through the use of prostaglandin analogues (PGAs) like latanoprost or bimatoprost as first-line therapy due to their high efficacy and once-daily dosing. If PGAs are insufficient, clinicians typically introduce adjunctive therapies such as beta-blockers (e.g., timolol) or carbonic anhydrase inhibitors to decrease fluid production, or alpha-agonists and Rho kinase (ROCK) inhibitors (e.g., Rhopressa) to further enhance aqueous outflow. To improve adherence and reduce the washout effect of multiple drops, fixed-dose combinations like Combigan or Simbrinza are frequently utilized, while the most recent advancements in the pharmaceutical standard of care include sustained-release implants like iDose TR, which provide continuous medication for months to eliminate the patient’s daily burden of self-administration.

While traditional standard of care targets intraocular pressure (IOP), Perfuse’ PER-001 addresses the 50% of patients who continue to progress toward blindness despite having normal or controlled pressure. PER-001, a small-molecule endothelin-1 (ET-1) receptor antagonist, targets the blood flow of the eye. ET-1 is the most potent vasoconstrictor in the body and is upregulated in glaucoma patients, starving the optic nerve of oxygen. PER-001 blocks ET-1 receptors to dilate constricted vessels, directly increasing Optic Nerve Head Blood Flow (ONH-BF). The Phase 2a clinical trial for PER-001 in 33 patients with progressive mild-to-moderate glaucoma demonstrated significant improvements across functional, structural, and physiological metrics over a 24-week period. The data was presented on May 6, 2025 by Steven Mansberger, MD, MPH, in an oral presentation at the Association for Research in Vision and Ophthalmology (ARVO) 2025 Annual Meeting titled “PER-001, an endothelin antagonist, increased optic nerve head blood flow with structural and functional improvements in patients with glaucoma”. In this specific Phase 2a cohort (n=33), investigators observed numerical improvements in annualized Visual Field (VF) deviation (see summary table below). Further large-scale pivotal trials are required to confirm these preliminary findings.

PER-001 was found to be “safe and well-tolerated”, according to Perfuse. The only drug-related adverse events were two cases of vitreous floaters, which were mild, intermittent, and resolved on their own. There were no reports of serious adverse events (SAEs), intraocular inflammation, or changes in IOP therapy.

Conclusion

Ultimately, the Perfuse Therapeutics story could offer a new hope for the millions of patients currently slipping through the cracks of the standard of care. Whether it’s the glaucoma patient whose vision fades despite “normal” pressure, or the diabetic patient struggling with low-light contrast, PER-001 targets the ischemia that current blockbusters ignore. By combining Dr. Gurkan’s vasculature-first vision with Bayer’s global infrastructure, the path to a twice-yearly, disease-modifying implant could be on the horizon. As PER-001 transitions into its pivotal trial program later this year, all eyes will be on its ability to maintain early efficacy signals and clear regulatory review.

To contact us, please send us an email at biotechreadout@gmail.com

Disclaimers

*Revenue run rates are estimates based on the author’s synthesis of publicly available 10-K/10-Q filings and may not reflect GAAP-certified annual totals.

Investigational Status Disclaimer

The therapeutic candidates discussed in this newsletter are currently in clinical development and have not been approved for commercial sale by the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or other global regulatory authorities. Their safety and efficacy have not been established. References to pipeline products and ongoing clinical trials involve significant risks and uncertainties. Statements regarding the potential safety, potency, or efficacy of investigational drugs reflect current hypotheses and are not a guarantee of future performance or regulatory clearance. The outcome of clinical trials is inherently unpredictable, and clinical results from earlier stages may not be predictive of results in later, larger-scale trials.

No Medical Advice Disclaimer

This newsletter is for informational and educational purposes only. The content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or another qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read in this publication.

No Patient-Provider Relationship Disclaimer

The information provided in this newsletter is for educational and analytical purposes only. Receipt of this information, or any interaction with this content, does not create a physician-patient, pharmacist-patient, or any other professional-provider relationship between you and the authors or publishers. This newsletter should not be used as a substitute for a personal consultation with a qualified healthcare professional.

Forward-Looking Statements Disclaimer

This newsletter contains “forward-looking statements” regarding future events, including clinical trial timing, regulatory milestones, and projected market performance. These statements are based on current expectations and assumptions that are subject to significant risks and uncertainties. Actual results may differ materially from those expressed or implied. We undertake no obligation to update these statements as a result of new information or future developments.

Third-Party Links & Content Disclaimer

This newsletter contains links to third-party websites, including clinical trial registries and corporate presentations. Biotech Readout does not endorse, guarantee, or assume responsibility for the accuracy or reliability of any information offered by third-party providers.

Errors and Omissions Disclaimer

While we strive for technical accuracy, the information in this newsletter is provided on an “as is” basis with no guarantees of completeness, accuracy, or timeliness. Biotech Readout assumes no liability for any errors or omissions in the content of this publication.

Non-Endorsement Disclaimer

Any reference to specific commercial products, processes, or services by trade name, trademark, or manufacturer does not constitute or imply an endorsement or recommendation by the author. All trademarks are the property of their respective owners.

No Investment Advice Disclaimer

This newsletter is for informational purposes only and does not constitute financial, investment, or legal advice. The author is not a registered investment advisor. You should consult with a professional financial advisor before making any investment decisions. The biotechnology sector is highly volatile; past performance is not indicative of future results.

Conflict of Interest Disclaimer

The author of this newsletter maintains a position of independence. At the time of publication, the author holds no direct financial interest, equity, or options in any of the companies mentioned in this report. No compensation has been received from any third party to feature or analyze specific therapeutic candidates or corporate entities.

Introduction

On May 3, 2026, UCB announced a definitive agreement to acquire Candid Therapeutics for $2 billion upfront payments and up to $200 million in potential future milestone payments ($2.2 billion total) (UCB press release, Candid press release). The acquisition centers on four T-cell engagers (TCE) for autoimmune diseases:

• Cizutamig (BMCA x CD3 TCE) / Phase 2 ready for generalized myasthenia gravis (gMG), two autoimmune disease caused by auto-antibodies that mistakenly attack the patient’s own body

• CND261 (CD20 x CD3 TCE) / Phase 1

• CND319 (CD19 x CD20 x CD3) / IND-enabling

• CND460 (BMCA x CD19 x CD3) / IND-enabling

T-cell engagers (TCE) constitute a blockbuster indication space, representing an aggregate revenue run rate of almost $3.8 billion as of 4Q 2025 according to quarterly press releases associated with Blincyto, Imdelltra, Talvey, Elrexfio, and Lunsumio* (see graph below). There are only 6 approved TCE’s (recently-approved Lynozyfic doesn’t have any reported sales and isn’t pictured below), but the space is quickly becoming crowded with at least 86 clinical/preclinical programs in development.

If executed, the proposed Candid acquisition would constitute the largest acquisition in the TCE space to date (see graph below).

Here, we will define how the T-cell engagers (TCE) drug modality can treat autoimmune diseases and dive into the history of Candid Therapeutics.

What is a T-cell Engager (TCE)?

T-cell engagers (TCEs) are specialized types of immunotherapies, typically bispecific antibodies, designed to bridge the gap between a patient’s immune system and a target cell (usually a cancer cell or a pathogenic B-cell). Unlike traditional antibodies that simply flag a target for destruction, a TCE act as a molecular matchmaker: it physically grabs a T-cell and pulls it into direct contact with the target cell to force an immune attack.

A T-cell engager has two distinct binding arms:

• The Effector Arm (anti-CD3): This arm binds to the CD3 receptor on the surface of a T-cell. This binding bypasses the normal, complex “recognition” process of the immune system and essentially “hot-wires” the T-cell into an active state.

• The Target Arm (BCMA, CD19, and PSMA are the most common): This arm binds to a specific protein found on the surface of the cell you want to kill.

By bringing these two cells into close proximity, the TCE creates an artificial synapse. The T-cell then releases toxic enzymes (perforins and granzymes) that punch holes in the target cell, causing it to die.

Normally, T-cells only attack targets that are presented to them in a very specific way (via MHC). TCEs bypass this requirement, meaning they can kill cells that have evolved to hide from the natural immune system. Because they directly activate T-cells, they are incredibly powerful. However, this power can lead to Cytokine Release Syndrome (CRS), a firestorm of immune activity that can be dangerous if not managed. Unlike CAR-T cell therapy, which requires a bespoke, month-long manufacturing process using a patient’s own cells, TCEs are off-the-shelf drugs that can be administered immediately to any patient.

T-cell engagers (TCEs) potentially offer a potent immune reset strategy for autoimmune diseases like generalized myasthenia gravis (gMG) by mimicking the profound B-cell and plasma cell depletion observed in early CAR-T clinical trials. While traditional biologics often only partially reduce circulating B-cells, data from CAR-T therapies, such as those targeting CD19, have shown that near-complete elimination of the B-cell lineage can lead to drug-free remission for up to 2 years in lupus patients by clearing the autoantibodies at their source (see graphic below). TCEs achieve a similar depth of depletion by physically bridging endogenous T-cells to these pathogenic B-cells and long-lived plasma cells, inducing a rapid, systemic purge of the autoantibody-producing machinery. This reset allows the immune system to eventually repopulate with a naive, non-autoreactive B-cell repertoire, offering the potential for long-term clinical durability without the complex manufacturing and intensive lymphodepletion required for CAR-T. The strategic emphasis on BCMA in Candid’s cizutamig provides a unique competitive edge. Unlike CD20, which is absent on long-lived plasma cells, BCMA is highly expressed on these antibody factories. By targeting BCMA, cizutamig is designed to deplete the source of autoantibody production that remains untouched by rituximab and other CD20-targeted therapies.

Keeping it Candid

The history of Candid Therapeutics is a masterclass in the Asset Aggregator business model, comprised of a pipeline of in-licensed fast-followers drugs, moving from inception to a multi-billion dollar exit in roughly two years. Founded in September 2024, the company was built on the thesis that T-cell engagers (TCEs), which have revolutionized blood cancer treatment, could be repurposed to reset the immune system in autoimmune diseases.

Candid did not start with a single in-house discovery. Instead, it was formed through a sophisticated three-way merger and licensing strategy designed to consolidate the best available TCE assets. Candid was launched in San Diego in 2024 by proven operators:

• Chief Executive Officer (CEO) Dr. Ken Song was the former CEO of RayzeBio (lead program was an actinium radiopharm targeting SSTR2 to treat GEP-NETs) and had sold it to Bristol-Myers Squibb for $4.1 billion earlier that year in February 2024

• Chief Financial Officer (CFO) Arvind Kush was also CFO of RayzeBio through its IPO and sale.

• Chief Medical Officer (CMO) Tim Lu, MD, PhD was previously CMO of a separate acquisition; DICE Therapeutics (oral IL-17 inhibitors for plaque psoriasis) was sold to Eli Lilly for approximately $2.4 billion in an all-cash deal in August 2023.

The company debuted with a massive $370 million capital raise led by Venrock, Fairmount, TCGX, venBio Partners. Candid simultaneously acquired Vignette Bio and TRC 2004. Through these deals, they secured the rights to their lead assets:

• From Vignette: This in-housed cizutamig (BMCA x CD3 TCE), which was originally licensed from EpimAb Biotherapeutics.

• From TRC 2004: This brought in CND261 (CD20 x CD3 TCE), which was originally licenced from Ab Studio.

Trispecific TCEs CND319 (CD19 x CD20 x CD3) and CND460 (BMCA x CD19 x CD3) were later in-licensed from WuXi Biologics on January 6, 2025 for up to $925 million in upfront payments, and development and sales milestones.

By January 2026, Candid delivered initial descriptive analysis of Phase 1 clinical data for Cizutamig and CND261 suggesting that potentially competitive profiles. While sparse, their press release described “on-target efficacy” (“B-cell/plasma cell depletion”) and “favorable safety profiles” (CRS rates with no ICANS). These molecules were optimized for an improved safety profile from the start. Cizutamig was purposely designed to prioritize T-cell mediated cytotoxicity against target cells while strictly limiting systemic cytokine production, and CND261 was developed with an engineered low CD3 affinity to prevent the over-activation of T-cells that typically drives high-grade CRS.

Importantly, Candid outlined plans to initiate Phase 2 proof-of-concept trials in two autoimmune indications (revealed to be gMG and ILD in a subsequent press release), and reported “ongoing clinical evaluation in ten [additional] indications [to] inform additional Phase 2 clinical development plans”, thereby providing additional strategic opportunities for value creation.

In early 2026, Candid attempted a rapid entry into the public markets, announcing a definitive merger agreement with the struggling public company Rallybio. The primary catalyst for Rallybio’s decline was the failure of RLYB212, its most advanced clinical candidate. It was being developed to prevent FNAIT (fetal and neonatal alloimmune thrombocytopenia), a rare bleeding disorder in newborns. In a Phase 2 trial, the drug failed to reach target concentration levels required for efficacy. The pharmacokinetic (PK) performance, and the company was forced to discontinue the entire program. With a dwindling cash runway and no late-stage clinical catalyst to attract new investors, the reverse merger with Candid, which had a high-demand pipeline and fresh capital, was a financial survival mechanism for Rallybio’s remaining shareholders.

In tandem with the reverse merger with Rallybio, Candid secured an additional $505 million in private investment (PIPE) from a syndicate including Viking Global and other investors, which would have given the combined company nearly $1 billion in cash. However, that reverse merger will never take place. In a dramatic turn of events it was superseded by a direct acquisition from a global pharmaceutical giant, UCB. UCB was already a leader in immunology and moved to preempt the IPO/merger to gain full control of cizutamig, which they believe is a “potential best in class BCMA TCE for autoimmune diseases”.

Conclusion

The acquisition of Candid Therapeutics by UCB marks a definitive end to the company’s brief but high-octane independent run, but it’s just the beginning for the TCE-in-autoimmune story. By scooping the reverse merger, UCB has just bought a pipeline that buys them time in a race where first- or best-in-class immune reset could define the next century of immunology.

To contact us, please send us an email at biotechreadout@gmail.com

Disclaimers

*Revenue run rates are estimates based on the author’s synthesis of publicly available 10-K/10-Q filings and may not reflect GAAP-certified annual totals.

Investigational Status Disclaimer

The therapeutic candidates discussed in this newsletter are currently in clinical development and have not been approved for commercial sale by the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or other global regulatory authorities. Their safety and efficacy have not been established. References to pipeline products and ongoing clinical trials involve significant risks and uncertainties. Statements regarding the potential safety, potency, or efficacy of investigational drugs reflect current hypotheses and are not a guarantee of future performance or regulatory clearance. The outcome of clinical trials is inherently unpredictable, and clinical results from earlier stages may not be predictive of results in later, larger-scale trials.

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This newsletter is for informational purposes only and does not constitute financial, investment, or legal advice. The author is not a registered investment advisor. You should consult with a professional financial advisor before making any investment decisions. The biotechnology sector is highly volatile; past performance is not indicative of future results.

Conflict of Interest Disclaimer

The author of this newsletter maintains a position of independence. At the time of publication, the author holds no direct financial interest, equity, or options in any of the companies mentioned in this report. No compensation has been received from any third party to feature or analyze specific therapeutic candidates or corporate entities.

Introduction

In Part 1 of this series on obesity, we traced the evolution of obesity from a perceived moral failing to a recognized chronic disease, explored the hormones like leptin and ghrelin that govern our weight, and shared the genetic breakthroughs that are finally rewriting the willpower myth. In Part 2, we explore the evolution of obesity treatments and how the field climbed out of a century-long dark age and into its current golden age.

The Dark Ages of Obesity Medicines

The first described attempts at producing weight loss are those of Soranus of Ephesus, a Greek physician, in the second century AD. He believed that health depended on the tension of the body’s internal pores. Disease occurred if pores were too tight (strictum) or too loose (laxum). Obesity was viewed as a state of congestion and sluggishness. To fix it, the physician had to loosen and evacuate the system to restore flow. He prescribed elixirs of laxatives and purgatives, as well as heat, massage, and exercise. This remained the mainstay of treatment for well over a thousand years.

If you’re wondering why this specific protocol lasted over a millennium, the credit (or blame) goes to Caelius Aurelianus. In the 5th century, Aurelianus translated Soranus’s Greek works into Latin. His text, On Chronic Diseases, became the standard medical textbook for the Middle Ages. Because the Roman Empire’s medical infrastructure collapsed, the Church and later medieval scholars clung to these Latin translations as “absolute truth.” While the “pore” theory eventually died out, the core components Soranus identified (metabolic stimulation, physical exertion, and caloric restriction) formed the foundations of every wellness movement from the Renaissance until the discovery of the calorie in the 19th century.

Yet, these interventions appear quaint in contrast to the three-headed hydra of horrifying and now banned obesity medications that plagued the 20th Century:

• Thyroid Tablets (1920s–1938); banned as a weight loss treatment in 1938 due to potentially fatal cardiac and CNS/PNS toxicity.

• Uncoupling Agents (1933-1938) like dinitrophenol (DNP); banned as a weight loss treatment in 1938 due to drug-related cataracts and potentially fatal hyperthermia. DNP was, in fact, a volatile industrial chemical used in French munitions factories to sensitize artillery shells; its weight-loss potential was only discovered when factory workers began to unexpectedly lose weight.

• Amphetamines/“Rainbow Pills” (1930s-1997), banned as a weight loss treatment in late 1960s and 1997 due to cardiac and neuropsychiatric toxicity.

I won’t cover their history, and will simply note that they are all banned for very good reasons; they led to the death and disability of thousands and stopping them required the expansion of the FDA’s legal mandate. The fallout from these medical misfires harmed patients and created a safety trauma that dictated FDA policy and clinical skepticism for over half a century. In retrospect, it’s no wonder than it took until 2013 for the American Medical Association (AMA) to formally recognize obesity as a disease.

Since the banned drug classes listed above were often marketed to people seeking a slimmer figure rather than those with clinical illness, the medical community began to view obesity treatment as an elective, cosmetic pursuit. This led to a higher bar for safety; if a drug is for a lifestyle choice, even a 1% risk of a serious side effect (like blindness or heart failure) was considered unacceptable. After the high profile withdrawal of Fen-Phen in 1997, the FDA’s advisory committees became famously risk-averse. For nearly two decades, they rejected or delayed review of now approved medicines like Qsymia or Contrave if they showed even minor cardiovascular signals, fearing a repeat of the “Rainbow Pill” deaths. The perceived danger of pills drove the medical community toward Bariatric Surgery. For a long time, cutting into a healthy organ was seen as safer and more medically rigorous than prescribing a pill, largely because of the obesity’s checkered past of pharmaceutical toxicity.

A Surgical Approach to Obesity

The history of bariatric surgery is a story of serendipitous discovery, evolving from extreme malabsorptive procedures to modern metabolic interventions. It was born out of the observation that patients who underwent intestinal resections for cancer or trauma often suffered from significant, unintended weight loss.

The first intentional surgeries for obesity were designed to prevent the body from absorbing calories by bypassing large sections of the small intestine. In 1954, Dr. Viktor Henrikson performed the first surgery specifically designed to treat obesity in Gothenburg (Göteborg), Sweden. Henrikson’s operation in Gothenburg was an extensive small bowel resection (literally removing about 105 cm of the intestine) rather than a bypass. He theorized that physically shortening the gut would limit caloric absorption. The related Jejunoileal Bypass (JIB) procedure, where the intestine is rerouted rather than removed, was developed shortly after in the United States. Dr. Richard Varco performed the first JIB in 1953 at the University of Minnesota, followed by a famous published report by Kremen, Linner, and Nelson in 1954 at Mount Sinai Hospital in Minneapolis. While patients lost massive amounts of weight, the “blind loop” of bypassed intestine caused severe complications, including chronic diarrhea, electrolyte imbalances, and bypass enteritis (liver failure). By the late 1970s, the JIB was largely abandoned due to its high morbidity.

The surgical field turned away from the intestines and towards the stomach. In 1966, Dr. Edward Mason (often called the “Father of Bariatric Surgery”) at the University of Iowa noticed that women who had a partial gastrectomy for peptic ulcers remained thin. Mason developed a procedure that combined restriction (making the stomach smaller) with malabsorption (bypassing a portion of the small intestine), known as the Roux-en-Y Gastric Bypass (RYGB). The RYGB proved to be far safer than the JIB. It reduced the stomach to a small pouch, limiting how much a person could eat, while the bypass altered hunger hormones.

In the 1980s–1990s, surgeons began looking for ways to lose weight without rerouting the intestines, focusing solely on shrinking the stomach. The Vertical Banded Gastroplasty (VBG), also developed by Dr. Mason, involved stapling the stomach to create a small pouch and using a plastic band to slow the exit of food. It became popular but often failed long-term as patients circumvented the surgery with high-calorie liquids. Adjustable Gastric Banding (“Lap-Band”) was introduced in the 1990s. This was an inflatable silicone ring placed around the top of the stomach. It was popular because it was reversible and didn’t involve cutting the stomach, but it fell out of favor due to high rates of “band slippage” and inadequate long-term weight loss.

A big turning point in the history of bariatric surgery was the shift from open surgery (large incisions) to laparoscopy (keyhole surgery). In 1994, the first laparoscopic gastric bypass was performed. This reduced recovery time from weeks to days and significantly lowered the risk of infections and hernias, making the surgery accessible to a much wider population.

Today, the Sleeve Gastrectomy is the most common bariatric procedure performed worldwide. It is simpler than the bypass and has a lower risk of long-term vitamin deficiencies. It’s also a classic example of a serendipitous medical breakthrough. It wasn’t originally designed as a standalone surgery. Rather, it was a safety measure for high-risk patients that worked far better than anyone expected.

To understand the Sleeve Gastrectomy, you have to look at its predecessor, the Biliopancreatic Diversion with Duodenal Switch (BPD-DS). Developed in the late 1980s by Dr. Douglas Hess, this was a massive, high-risk operation that involved both a sleeve stomach and a significant intestinal bypass. While highly effective for weight loss, it was physically taxing and took many hours to perform. For patients with a BMI over 60 or those with severe heart disease, the long anesthesia time and complexity were often lethal.

In the late 1990s and early 2000s, surgeons including Dr. Michel Gagner at Mt. Sinai in New York began looking for a way to make the BPD-DS safer. They came up with a two-stage approach:

• Stage 1: Perform just the stomach reduction (the “Sleeve”) to induce initial weight loss and make the patient healthier.

• Stage 2: After 12–18 months, once the patient had lost 50–100 lbs, bring them back to perform the complex intestinal bypass part of the surgery.

The “Aha! moment” occurred when patients started failing to show up for their second-stage appointments. Surgeons realized that many of these Stage 1 patients were losing massive amounts of weight, and keeping it off, without ever having the intestinal bypass. It was originally thought the Sleeve worked solely through restriction (a smaller stomach). However, researchers discovered that removing the fundus (the upper curve of the stomach) also removed the primary production site of ghrelin, the hunger hormone. This meant the Sleeve Gastrectomy wasn’t merely a mechanical tool, but a neuroendocrine intervention.

By the mid-2000s, the data was undeniable. In 2006, the first International Consensus Summit on Sleeve Gastrectomy was held, and by 2010, major surgical societies officially recognized it as a primary, standalone procedure. By 2026, the Sleeve Gastrectomy accounted for over 60% of all bariatric surgeries globally. Its rise was driven by:

• Simplicity: It does not involve rerouting the intestines or placing foreign objects (like the Lap-Band).

• Pylorus Preservation: By keeping the stomach’s exit valve (the pylorus) intact, it avoids “Dumping Syndrome,” a common and unpleasant side effect of the Gastric Bypass.

• Safety Profile: It carries a significantly lower risk of the internal hernias and long-term vitamin deficiencies that plagued the JIB and BPD eras.

The discovery of the Sleeve Gastrectomy shifted the entire surgical philosophy from “how much can we bypass?” to “how can we best manipulate hunger hormones?”

The Golden Age of Obesity Medicines

The contrast between the 20th-century Dark Ages of Obesity Medicines and the current Golden Age of GLP-1/GIP receptor agonists represents a shift from systemic toxicity to molecular precision, as well as a return to hormone biology. While early interventions tried to brute force weight loss by overstimulating the heart or overheating the body, modern assets mimic the body’s natural signaling pathways to regulate appetite and metabolism.

Thyroid tablets and mitochondrial uncouplers worked by creating a state of artificial disease (hyperthyroidism or uncoupled cellular respiration). They forced the body to burn energy by damaging its efficiency. Amphetamines worked by triggering a fight-or-flight stress response to suppress hunger. In contrast, current Golden Age is defined by the FDA-approved incretin mimetics semaglutide (marketed as Wegovy for obesity and Ozempic for Type 2 diabetes) and tirzepatide (marketed as Zepbound for obesity and Mounjaro for Type 2 diabetes). They mimic hormones naturally secreted by the gut after a meal to promote satiety (GLP-1 and GIP). Instead of stressing the system, they signal the brain’s satiety centers (hypothalamus) to feel full and slow gastric emptying, working with the body’s regulatory hardware rather than against it.

As of 2026, the medical community has transitioned from cautious observation to broad, enthusiastic adoption of semaglutide and tirzepatide. These drugs are no longer viewed as short-term fixes but as foundational therapies for Adiposity-Based Chronic Disease (ABCD). Major medical organizations have officially shifted their treatment algorithms to prioritize these assets:

• American Diabetes Association (ADA) 2026 Standards: The ADA now recommends semaglutide and tirzepatide not just for glucose control, but specifically for comorbidity management. They are now first-line recommendations for patients with diabetes who also have obesity, heart failure (specifically HFpEF), or chronic kidney disease.

• American Association of Clinical Endocrinology (AACE) 2025/2026 Update: The AACE has reframed obesity as a “neuroendocrine disease.” Their latest guidelines prioritize “second-generation” anti-obesity medications (semaglutide/tirzepatide) over older stimulants due to their superior weight loss (20-22% average) and metabolic “reset” capabilities.

• NICE (UK) & Global Access: By April 2026, the UK’s NHS has begun a massive multi-year rollout of tirzepatide, acknowledging its cost-effectiveness in preventing long-term complications like stroke and heart attack.

As of April 2026, the combined annualized revenue run rate of semaglutide (marketed as Wegovy for obesity and Ozempic for Type 2 diabetes) and tirzepatide (marketed as Zepbound for obesity and Mounjaro for Type 2 diabetes) exceed $80 billion per year.

The obesity space has also seen a number of multi-billion dollar acquisitions, consisting mostly (but not exclusively) of incretin drugs.

The discovery of incretins, a family of hormones that GLP-1 and GIP belong to, took over a century. It involves a slow and steady progression from vague physiological observations to the precise molecular engineering of drugs like Wegovy and Zepbound.

Sugar Rush

In Part 1, we discussed two hormones that are linked to body weight and counterbalance each other: ghrelin (hunger signal) and leptin (satiety signal). However, they aren’t the only metabolic hormones on the block. We can’t discuss incretins before first taking a detour into the sugar handling hormones: insulin (sugar storage) and glucagon (sugar moblization). They are the breadcrumbs that ultimately led researchers to the discovery of incretins.

The story starts in the 1920s with Frederick Banting and Charles Best beginning their work at the University of Toronto. They were investigating treatments for Type 1 Diabetes, a disease in which the body fails to produce insulin a persistent autoimmune response kills the insulin-producing beta cells (different from Type 2 Diabetes where patients produce insulin but have become insensitive to it). At the time, Type 1 Diabetes was a death sentence. Banting and Best set out to isolate an internal secretion from the pancreas that could regulate blood sugar, a feat that had frustrated scientists for decades. Before Frederick Banting started, others had tried to isolate insulin from pancreatic extracts but would fail because the pancreas is a dual-purpose organ: it contained both insulin and digestive enzymes, which would chew up the insulin in crude extracts. To solve this, they tied off the pancreatic ducts of living dogs so that the acinar cells died (which produce digestive enzymes), then created extracts from the resulting tissue. To prove it worked, they had a second group of dogs whose entire pancreata had been removed, making them severely diabetic. When these dogs were near death from high blood sugar, Banting and Best injected their extract. Within hours, the dogs’ blood sugar plummeted, and their strength returned. One dog, famously known as Dog 92 (or Marjorie), was kept alive for 70 days using these extracts, a record at the time. They found insulin, but what about glucagon?

The discovery of glucagon occurred in the exact same experiment, but Banting and Best dismissed it as nothing more than a pesky impurity. They noticed that immediately after injecting the pancreatic extract, there was often a brief, sharp increase in blood glucose before the insulin took over and lowered it. In 1923, Charles Kimball and John Murlin at the University of Rochester realized this wasn’t a mistake or a side effect of the insulin. They isolated this “hyperglycemic factor” and named it glucagon, derived from “glucose agonist.” For the next 30 years, much of the scientific community remained skeptical. Many believed glucagon was just damaged insulin or a byproduct of the extraction process rather than a hormone in its own right. In 1953, glucagon believers were vindicated when researchers at Eli Lilly (led by Alfred Staub) successfully crystallized glucagon in its pure form, proving once and for all that it was a distinct protein.

In the 1970s, Dr. Roger Unger at the University of Texas Southwestern Medical Center proposed a revolutionary idea: diabetes isn’t just an insulin deficiency; it’s a bihormonal disease. His central argument was that high blood sugar is not caused by a lack of insulin alone, but by the combined effect of insulin deficiency and glucagon excess. Dr Unger showed that excess glucagon was present in both Type 1 and Type 2 diabetes patients. Despite the strong scientific logic behind Dr. Unger’s bihormonal hypothesis, pure Glucagon Receptor Antagonists (GRAs) are not currently used in standard clinical practice to treat diabetes. Several candidates reached Phase 2 and Phase 3 clinical trials over the last decade, but these programs faced recurring safety hurdles that have prevented FDA approval (liver enzyme elevation, LDL cholesterol increase, alpha-cell hyperplasia, dangerous blood sugar spike on withdrawal).

A Fishing Expedition

While Dr. Unger’s bihormonal hypothesis didn’t result in a major therapeutic win, it did elevate the profile of glucagon, leaving breadcrumbs for other researchers to follow. One of those researchers was Dr. Joel Habener, an endocrinologist at Massachusetts General Hospital. Like Dr. Unger, Dr. Habener believed that if he could understand how glucagon was made, scientists might be able to develop a way to block it, thereby helping diabetics keep their blood sugar from spiking.

By the 1970s, it was becoming clear that many small hormones don’t start out that way. They are originally part of a much larger precursor protein that gets snipped into smaller, active pieces by enzymes. Habener wanted to find the proglucagon gene to see exactly how the body cuts the protein to create glucagon. He suspected that by mapping the gene, he might find other hidden peptides that also played a role in metabolism and could treat diabetes.

Since of the NIH moratorium on cloning mammalian DNA, Dr. Habener turned to the cold-blooded anglerfish (Lophius americanus), a creature that offered a unique anatomical advantage for a molecular biologist. Anglerfish has uniquely large clusters of endocrine tissue called Brockmann bodies. These organs are essentially glucagon factories, making it much easier to isolate the mRNA he needed compared to traditional lab animals. Dr. Habener’s team (including researchers like Graeme Bell and Lund) created a cDNA library from the Brockmann bodies and, since the partial amino acid sequence of glucagon was already known, they fashioned an radioactive probe to find colonies of transformed bacteria that contained the proglucagon gene. Once the correct cDNA was isolated, they used the Sanger sequencing method to determine its genetic code.

They expected a code long enough for the 29 amino acids of glucagon plus a small leader sequence, but instead they found a a massive open reading frame. By looking identifying coding regions for Lysine-Arginine pairs, Dr. Habener and his team could see exactly where cellular enzymes (prohormone convertases) were supposed to snip the long protein chain to release the individual hormones. To their surprise, the gene didn’t only code for glucagon. It also contained sequences for two additional, previously unknown peptides. These were named glucagon-like peptide 1 (GLP-1) and glucagon-like peptide 1 (GLP-2).

A Cut Above the Rest

The transition from identifying a gene sequence to finding a functional medicine was the most contentious period in GLP-1 history. After Dr. Joel Habener cloned the proglucagon gene, the scientific community was stuck: they had the code for GLP-1, but when they synthesized the full peptide (the 1–37 amino acid string), it did absolutely nothing. The breakthrough in the mid-1980s required a shift from genetics to protein chemistry to identify how the body actually cuts the protein to make it active.

Svetlana Mojsov, a chemist at Massachusetts General Hospital, played the pivotal role here. She noticed that the full 37-amino-acid sequence of GLP-1 contained internal dibasic sites, specific amino acid pairs Lysine and Arginine, that act as molecular “cut here” signs for cellular enzymes (prohormone convertases). Mojsov predicted that the first 6 amino acids were essentially a “spacer” and that the body clipped them off to create a shorter, active version: GLP-1 (7–37). She manually synthesized this truncated version, which was a massive technical feat at the time. Working with Habener and a young researcher named Daniel Drucker, they tested this shortened version on rat insulinoma cells. Unlike the full-length version, the 7–37 version triggered a massive release of insulin.

While the Boston team was looking at the gene, Dr. Jens Juul Holst in Copenhagen was coming from the clinical side. He was fascinated by the “Incretin Effect”, the fact that sugar consumed orally triggers a much larger insulin response than sugar injected directly into the blood. Dr. Holst was studying “dumping syndrome” patients (who had parts of their stomachs removed) and found a substance in their gut that stimulated insulin. He independently isolated the truncated GLP-1 from human intestinal tissue. His work proved that GLP-1 was a real hormone produced by the L-cells of the human gut in response to food.

Research from these two groups culminated in a series of landmark papers in 1987. The PNAS paper, led by Daniel Drucker, Svetlana Mojsov, and Joel Habener, was the first to show that GLP-1 (7–37) stimulates insulin gene expression and increases cAMP levels in pancreatic cells, while the full-length version (1-37) was inert. Months later, Dr. Jens Juul Holst published in FEBS Letters, confirming that the gut actually secretes this specific 7-37 version into the bloodstream after we eat and identifying it as a natural human incretin. These researchers jointly received the Lasker Award in 2024 for their contributions to GLP-1 based therapy for obesity.

Most importantly from a therapeutic standpoint, these studies showed that GLP-1 (7–37) was the most potent insulin-stimulating hormone ever discovered and that it only stimulated insulin when blood sugar was high. This was considered a “Holy Grail” of diabetes research. Unlike the older diabetes drugs (sulfonylureas) that forced insulin out and caused dangerous crashes (hypoglycemia), GLP-1 was smart; it stopped working as soon as blood sugar returned to normal.

Unfortunately, there was a major roadblock that accounted for the almost 20-year delay between the 1987 discovery of GLP-1 to the first FDA-approved drug in 2005: its short half-life (roughly 1.5 to 2 minutes). In its natural state, human GLP-1 only lasts a few minutes in the bloodstream. This extreme instability is not a biological mistake, it is a precision-engineered safety feature of the body to prevent life-threatening drops in blood sugar (hypoglycemia) once a meal has been processed.

The perpetrator was DPP-4 (Dipeptidyl Peptidase-4), an enzyme known to immunologists for decades as CD26. Its role as the assassin of GLP-1 wasn’t realized until the 1990s. DPP-4 was ubiquitous, sitting on the surface of blood vessels, kidneys, and floating freely in the plasma and waiting for a substrate to pass by. In 1993, Rolf Mentlein and his team at Kiel University in Germany performed a definitive study. They incubated GLP-1 in human serum and observed that the enzyme DPP-4 was specifically snipping off the first two amino acids (Histidine-Alanine) from its front end. When they added a DPP-4 inhibitor to the test tube, the GLP-1 remained intact, suggesting that DPP-4 was indeed responsible for GLP-1 degradation.

Mentlein’s discovery created two competing paths for the biotech industry:

1. The Inhibitor Path: Create a pill that blocks the enzyme throughout the whole body to let your natural GLP-1 last longer. Nancy Thornberry and the team at Merck led the charge here, developing a DPP-4 inhibitor that could be taken as a once-daily pill. In 2006, Januvia became the first of its class approved by the FDA.

2. The Bypass Path: Create a version of GLP-1 that the enzyme couldn’t recognize. This path led to the development of long-acting GLP-1 agonists, but it was by no means a straight shot to success.

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False Start

In 1987, an assistant professor of medicine at Harvard Medical School (HMS) and chief of the Diabetes Unit at Harvard-affiliated Beth Israel Hospital by the name of Dr. Jeffrey S. Flier had a meeting that would set a chain of events in motion that could have changed the course of medicine forever but did not, due to hodgepodge of idiosyncrasies that often befall biotech startups. A fellow endocrinologist, Dr. John Baxter from UCSF, happened across Dr. Flier who pitched him on an idea he had been kicking around: a nasal spray formulation with insulin (no, not GLP-1). Unlike investors who had balked at Dr. Flier’s idea, Dr. Baxter was intrigued an invited Dr. Flier to kickstart a development company in his recently founded biotech startup CalBio.

Dr. Flier wasted no time at all. He called up former colleague Ron Kahn (director of research at the Joslin Diabetes Center) and Bruce Spiegelman (another HMS professor), and proceeded to have “several memorable weekend sessions in [his] living room discussing potential project areas”. In collaboration with Dr. Baxter, the trio decided to spin up Metabolic Biosystems (MetaBio), a wholly owned subsidiary of CalBio that was kickstarted by a $30 million cash infusion from Pfizer over five years in exchange for exclusive rights to any clinical-stage programs. Their programs fell into four categories: insulin analogues, enhancers of insulin action, adipocyte secreted factors, and gut factors regulating metabolism. They had lots of ideas, but didn’t yet have a lead program. That would soon change when, in May 1987, Dr. Flier attended the American Society of Clinical Investigation meeting in Atlantic City.

Scanning a “thick book of abstracts”, Dr. Flier identified a Saturday 8:00 AM talk by Joel Habener’s lab at the Chalfonte-Haddon Hall Hotel (that name sounds familiar). Dr. Habener revealed that a new gastrointestinal peptide, GLP-1, enhanced insulin secretion in a glucose-dependent manner. Recognizing the magnitude of the discovery, Dr. Flier approached Dr. Habener immediately. Within weeks, MetaBio secured exclusive worldwide licenses for the GLP-1 patents from MGH and the Howard Hughes Medical Institute (HHMI).

Between 1988 and 1990, the joint team’s human infusion studies in Type 2 diabetic subjects yielded three critical findings:

• Strong Glucose Control: Several days of GLP-1 infusion lowered blood sugar significantly in patients with type 2 diabetes.

• A “Smart” Mechanism: Unlike traditional insulin shots, it only boosted insulin when glucose was high, drastically reducing the risk of dangerous “lows.”

• Weight Loss Potential: Crucially, the team discovered that GLP-1 slowed gastric emptying and reduced hunger—the exact mechanism driving today’s obesity drug craze.

However, this data would never see the light of day. In the 2024 memoir from which this section is sourced, Dr. Flier remarks, “none of this definitive work was ever presented publicly or published, so its existence, until now, has been known only to those involved.” In the next couple of years, the program would shut down and the ownership share of the founding MetaBio trio would be bought out. There were a few reasons that lead to the untimely demise of what seems to be the first GLP-1 agonist program in biotech history:

• Pfizer’s lack of conviction in injectable diabetes drugs: Following a presentation of the first-in-human data to Pfizer collaborators Nancy Hutson (then Senior VP of Global R&D at Pfizer’s Groton site) and Gregory Gardiner (then the architect of Pfizer’s external biotechnology strategy), senior management “concluded that there would never be another injectable therapy for diabetes other than insulin”, although their rationale was never explained to Dr. Flier. They told the MetaBio team to come back to them when they had identified an alternative route of administration other than IV, such as trans-nasal or transcutaneous. This was not a viable path, given the short half-life of GLP-1 and the fact that DPP-4 hadn’t been discovered yet (it was discovered a mere 1-2 years after MetaBio was sunsetted). Pfizer ended the deal a year early, leaving the company unfunded.

• Cannibalization by their TopCo’s lead program: As a wholly owned subsidiary, MetaBio had to compete for resources against CalBio’s lead asset, Natrecor (Auriculin), a treatment for heart failure. When Pfizer ended its commitment after four years, CalBio CEO Rich Casey faced a choice: hunt for a new partner or prioritize the “safer” bet of Natrecor. Casey later recalled a “herd mentality” on the street. Lacking a powerful internal champion or an independent capital structure to weather the setback, MetaBio’s GLP-1 program was sacrificed to fund Natrecor. While Natrecor eventually led to CalBio’s (renamed to Scios) acquisition by Johnson and Johnson (J&J) for $2.4 billion, a mere rounding error compared to the +$80 billion GLP-1 empire they let slip away.

After MetaBio collapsed, the patents returned to the institutions and were eventually picked up by Novo Nordisk. It took nearly 20 years for Novo Nordisk to achieve what Pfizer deemed impossible, eventually launching liraglutide (approved for obesity in 2014). Today, Novo Nordisk sees almost $35 billion in annual revenue from this class, a significant missed opportunity as a result of Pfizer’s premature exit. While the CalBio/Scios-J&J acquisition appeared to be a success, it represents a staggering Opportunity Cost. They chose a $2 billion exit today over a potentially +$10 billion market tomorrow (Pfizer acquired Metsera’s GLP-1 pipeline for up to $10 billion in November 2025) because they didn’t trust their own data over the prevailing industry dogma.

Monster Mash

The secret success then quiet collapse of MetaBio might have delayed the development of long-acting GLP-1 agonists, but only for a year or so. In the early 1990s, Dr. John Eng, a physician-researcher at the Bronx VA Medical Center, was studying various animal venoms. He was looking for bioactive peptides that might have medical applications. Dr. Eng focused on the Gila monster (Heloderma suspectum), a venomous lizard native to the Southwestern US. He knew these lizards could survive for months on a single meal while maintaining stable blood sugar. In 1992, Dr. Eng isolated a peptide from the lizard’s salivary secretions that he named Exendin-4. He realized that Exendin-4 was roughly 50% identical to human GLP-1. Crucially, the lizard version replaced the vulnerable Alanine at position 8 with a Glycine. This tiny change made the peptide invisible to the DPP-4 scissors, allowing it to last for hours in the blood instead of minutes.

Surprisingly, the discovery was initially met with silence. The Department of Veterans Affairs formally waived its rights to patent Dr. Eng’s discovery, viewing the maintenance fees as an unjustifiable expense. Dr. Eng, convinced of the peptide’s potential, assumed the patent costs out of his own pocket, a rare instance of a government researcher owning a blockbuster molecule. Eventually, a small San Diego biotech startup called Amylin Pharmaceuticals saw the potential. They licensed the peptide from Dr. Eng and began the arduous process of clinical development.

Amylin lacked the resources to bring a major metabolic drug to market alone, so they partnered with Eli Lilly in 2002. The clinical trials (the AC2993 program) demonstrated that twice-daily injections of the synthetic version of Exendin-4, then named exenatide, significantly lowered HbA1c levels. During the trials, researchers noticed a consistent side effect: patients were losing weight. This was the first clinical proof that GLP-1s could be more than insulin secretagogues. They were also potent satiety signals. On April 28, 2005, the FDA approved Byetta (exenatide) as an adjunctive therapy for Type 2 diabetes. It was the first approved GLP-1 receptor agonist in history, but it wouldn’t be the last.

The Hitchhiker’s Guide to GLP-1s

Novo Nordisk scientists followed a different route to subvert DPP-4. Researchers like Knud Jensen and Lotte Bjerre Knudsen set out to modify human GLP-1 so that it stays in the blood longer without changing its shape so much that the body thinks it’s an invader (like the lizard-derived Byetta). In the mid-1990s, the Novo team made a breakthrough in acylation, the process of attaching a fatty acid chain to a peptide. They attached a 16-carbon fatty acid (palmitic acid) to the GLP-1 molecule. This fatty acid acted like a sticky tail that hitchhiked on albumin in the bloodstream.

To make this work, they had to make two specific tweaks to the human GLP-1 sequence:

1. Amino Acid Substitution: They swapped one amino acid (Lysine for Arginine at position 34) to ensure the fatty acid tail only attached to one specific spot (position 26).

2. Fatty Acid Tail Linker: They added the C-16 fatty acid chain via a spacer (glutamic acid).

This created a molecule that was 97% identical to human GLP-1 but had a half-life of 13 hours, allowing for a simple once-daily injection (more convenient than the twice-daily shot Byetta). Liraglutide entered clinical trials under the name NN2211. Novo launched a massive clinical program called LEAD (Liraglutide Effect and Action in Diabetes), which consisted of six Phase 3 trials comparing liraglutide to every major diabetes drug on the market including insulin and Byetta. Liraglutide was not only superior in lowering blood sugar but was much better tolerated by patients. On January 25, 2010, the FDA approved Victoza (liraglutide), the world’s first human-sequence GLP-1 analog. During these trials, the weight loss was so consistent that Novo Nordisk decided to study a higher dose specifically for obesity. This led to the approval of Saxenda in 2014, the exact same molecule as Victoza, just at a 3.0 mg dose.

Two is Company

After the success of the once-daily Victoza, Novo Nordisk’s goal was clear: reach once-weekly dosing. To do this, they needed to make the molecule stickier and even more resistant to degradation. They achieved this in two ways:

1. Fatty Acid Optimization: Scientists replaced the 16-carbon fatty acid used in Liraglutide with a 18-carbon diacid chain. This significantly increased the molecule’s affinity for Albumin, acting like a much stronger anchor.

2. Amino Acid Shield: They swapped the Alanine at position 8 for Alpha-aminoisobutyric acid (Aib). This change made the N-terminus, the part that DPP-4 usually attacks, completely unrecognizable to the enzyme.

The resulting drug, called semaglutide, had a half-life of approximately 165 hours (7 days). Starting in 2013, the SUSTAIN program (1 through 10) tested semaglutide against nearly every competitor. SUSTAIN-6 (2016) proved that semaglutide significantly reduced major adverse cardiovascular events (MACE) in T2D patients. Ozempic (semaglutide) was approved for Type 2 Diabetes in 2017. Similar to Victoza/Saxenda, Novo recognized profound weight loss in the SUSTAIN trials and launched the STEP trials, leading to the 2021 approval of Wegovy (higher dose of the same active peptide in Ozempic) specifically for chronic weight management in overweight/obesity. Importantly, the SELECT trial demonstrated that Wegovy reduced the risk of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (MACE-3) by 20% (HR 0.8, p<0.001) in adults with established cardiovascular disease and obesity or overweight compared to a placebo control. This provided the first proof that weight loss in non-diabeted obese patients could result in an improvement in cardiovascular outcomes, which physicians and insurance companies tend to take more seriously.

While Novo Nordisk optimized GLP-1, Eli Lilly returned to the bihormonal philosophies of Drs. Roger Unger and Joel Habener. They realized that GLP-1 alone might have a ceiling and decided to pair it with another hormone: GIP (Glucose-dependent Insulinotropic Polypeptide). For years, GIP was considered a forgotten hormone because, unlike GLP-1, it doesn’t work well on its own in diabetics. However, Lilly’s researchers (led by Tamer Coskun) discovered that when you combine GIP and GLP-1, the GIP component seems to prime the adipose (fat) tissue and reduce the nausea often caused by GLP-1. Tirzepatide is a single peptide chain that activates both GLP-1 and GIP receptors. It uses a 20-carbon fatty acid for once-weekly dosing, similar to Novo’s technology but with a more potent weight loss effect in an overweight/obese population (Phase 3b SURMOUNT-5 trial showed -20.2% weight loss in the tirzepatide arm versus -13.7% weight loss in the semaglutide arm after 72 weeks of treatment, p<0.001). Mounjaro was approved for Type 2 diabetes in 2022, and Zepbound for overweight/obesity followed in 2023.

There are a number of other clinical-stage GLP-1/GIP dual agonists including CT-388 by Roche, SYH2082 by AstraZeneca, MariTide by Amgen (actually an anti-GIP antibody fused to a GLP-1 agonist), VK2735 by Viking Therapeutics, PN-458 by Protagonist, and KAI-9531 by Kailera. Others are turning to amylin, another pancreas-derived satiety hormone, in place of GIP for their dual agonists. These include Novo’s CagriSema (GLP-1 and amylin FDC) and Amycretin (dual agonist), and Pfizer’s MET-233i + MET-097i (GLP-1 and amylin FDC).

Three is a Crowd, and Five is a Stampede

Multi-agonists that stack multiple targets on top of GLP-1 are currently making their way through clinical trials. Retatrutide is a single peptide that activates three different receptors: GLP-1, GIP, and Glucagon (GGG). It is the direct successor to the dual-agonist tirzepatide. As we discussed, glucagon was suspected as the enemy in diabetes because it raises blood sugar. However, Eli Lilly’s researchers realized that activating the glucagon receptor in the presence of GLP-1/GIP can increase energy expenditure (calories burned) and specifically reduce liver fat.

In March 2026, Eli Lilly announced positive Phase 3 results from the TRANSCEND-T2D-1 trial. At the 12 mg dose, patients with Type 2 diabetes achieved up to a 2.0% reduction in HbA1c and lost an average of -16.8% of their body weight in just 40 weeks. A prior Phase 2 trial in patients with non-diabetic obesity showed up to -24.2% after 48 weeks of treatment on retatrutide, the most weight loss for any drug to date, as well as normalization in liver fat for in 93% of patients, supporting its ongoing investigation as a potential therapeutic for MASH (Metabolic Dysfunction-Associated Steatohepatitis). Eli Lilly plans to present Phase 3 TRANSCEND data for retatrutide American Diabetes Association (ADA) 2026 meeting from June 5-8, 2026.

Others are developing GGG drugs including BI 3034701 by Boehringer Ingelheim, UBT251 by Novo Nordisk, PN-477 by Protagonist, and KAI-4729 by Kailera. Recently, Eli Lilly has disclosed a quintuple agonist (GLP-1, GIP, Glucagon, Amylin/Calcitonin), with rat data to be presented at the ADA 2026 meeting. As of writing this, a different quintuple agonist (GLP-1, GIP, PPARα/γ/δ) was reported in Nature claiming greater weight loss potency then GLP-1/GIP dual agonism in diabetic induced obese (DIO) mice. Note that results in animal models frequently do not translate to human clinical safety or efficacy, so the jury is out on whether these quintuple agents are competitive, pending data from randomized placebo-controlled clinical trials in human patients with overweight/obesity.

What’s on the Horizon?

While much of the field has been focused on enhancing GLP-1’s weight loss potency, others have sought out complimentary mechanisms that they can stack onto GLP-1 that which add new effects. These include myostatin inhibitors to preserve muscle during weight loss (bimagrumab, emugrobart, taldefgrobep alfa), INHBE knockdown to selectively shed visceral fat (ARO-INHBE, WVE-007, SGB-7342), of FGF21 to enhance the liver fat degradation (MWN105, HEC88473).

The field is also shifting to greater convenience with once-daily oral pills. On December 23, 2025, the Novo Nordisk’s Wegovy pill was approved by the FDA and became the first oral GLP-1 for obesity. It uses a SNAC (salcaprozate sodium) absorption enhancer to protect the semaglutide peptide from being chewed up by stomach acid and enzymes. Nevertheless, the protection that SNAC offers isn’t absolute so the Wegovy pill requires an 8-hour overnight fast with a >30 minute post-dose fast (participants who took the pill after eating had zero or limited measurable exposure to the drug) and it must be taken with no more than 4 ounces (120 mL) of plain, still water (to avoid diluting the SNAC). Approved on April 1, 2026, Eli Lilly’s Foundayo (orforglipron) became the first approved small molecule GLP-1 agonist for obesity, and the only GLP-1 pill for weight loss that can be taken any time of day without food or water restrictions.

Conclusion

The transition of obesity medicine from the Dark Ages of systemic toxicity to the Golden Age of molecular precision is a medical success story. We have moved from a century of trying to brute force weight loss through dangerous stimulants and malabsorptive surgeries to an era of elegant neuroendocrine mimicry.

As we move toward the late 2020s, the ceiling for medical weight loss continues to rise. With retatrutide pushing the boundaries of triple-agonism and CagriSema exploring the synergy between the gut and the hindbrain, the distinction between surgical and medical outcomes is blurring. The clinical conversation has shifted from weight loss induction toward the optimization of maximal precision, muscle preservation, organ fat reduction, and quieting the food noise that has long been mischaracterized as a lack of willpower.

However, the Golden Age brings its own set of challenges. As these assets become foundational therapies for a massive global population, the focus of the next decade will likely shift toward durability, accessibility, and personalization. The race is now on to determine which patients benefit most from GIP-heavy versus glucagon-heavy pathways, and how we can maintain these metabolic resets over a lifetime.

Obesity was once a field defined by its failures. Today, it is the vanguard of biotech innovation. By following the breadcrumbs left by the fishing expeditions of the 1980s (literally), we haven’t just found a way to manage weight, we’ve unlocked a deeper understanding of the sophisticated hormonal symphony that governs us all.

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Press ⬇️ to go down to a section and ⬆️ to go back up to the Table of Contents

Table of Contents

This week, we discuss:

• Intellia / Lonvo-z (KLKB1 KO) / Phase 3 (HAE) - the first-ever successful Phase 3 readout for an in vivo CRISPR gene-editing therapy ⬇️

• Oruka / ORKA-001 (IL-23p19 mAb HLE) / Phase 2a (plaque psoriasis) - potential best-in-indication therapy (once yearly injectable versus current standard of 4–6 injections per year) ⬇️

• Veradermics / VDPHL01 (ER oral minoxidil) / Phase 2/3 (androgenetic alopecia) - if approved, it would be the first FDA-sanctioned oral non-hormonal treatment for hair loss in nearly 30 years ⬇️

• Mirum / Brelovitug (anti-HBsAg mAb) / Phase 2b (Hepatitis D) ⬇️

• Incyte / Povorcitinib (JAK1 inhibitor) / Phase 3 (nonsegmental vitiligo) ⬇️

• Pfizer / Elrexfio (BCMA x CD3 TCE) / P3 success (2L MM) ⬇️

Intellia / Lonvo-z (KLKB1 KO) / Phase 3 (HAE)

On April 27, 2026, Intellia Therapeutics announced positive topline results for the Phase 3 HAELO trial of lonvoguran ziclumeran (lonvo-z), formerly NTLA-2002. This marks the first-ever successful Phase 3 readout for an in vivo CRISPR gene-editing therapy.

• Indication: I covered the causal mechanism and treatment landscape of hereditary angioedema (HAE) in my piece on the Chiesi-KalVista acquisition earlier this week. Standard of care is gradually transitioning from the injectable C1-INH replacement (Cinryze) and anti-kallikrein mAbs (Takhzyro) to oral plasma kallikrein inhibitors (Orladeyo, Ekterly).

• Mechanism: Lonvo-z is an in vivo CRISPR/Cas9 therapy delivered via lipid nanoparticles (LNPs) that target the liver. It permanently inactivates the KLKB1 gene in hepatocytes, preventing the production of prekallikrein, the precursor to plasma kallikrein. A prior analysis from a Phase 1/2 trial showed that patients dosed with lonvo-z experienced an -89% reduction in plasma kallikrein sustained out to 36 weeks.

• Trial design: The Phase 3 HAELO trial was a randomized, double-blind, placebo-controlled trial comparing 52 patients who received a one-time 50mg dose against 28 patients who received placebo. The trial recruited 80 adults and adolescents (16+) with Type I or II HAE. Patients were required to discontinue their baseline long-term prophylaxis (LTP) before dosing, forcing the therapy to demonstrate efficacy in a real-world state of vulnerability. The primary efficacy was measured between weeks 5 and 28 post-infusion.

• Data (press release, slide deck): The trial met its primary endpoint (lonvo-z reduced attacks by 87% versus placebo between weeks 5 to 28, p<0.0001) and all key secondary endpoints with high statistical significance (attack fre rate 62% Lonvo-z versus 11% placebo, p<0.0001). As of the data cutoff, all patients who received lonvo-z at baseline or in crossover after week 28 remained LTP free. Furthermore, placebo patients who were crossed over to lonvo-z at week 28 saw a rapid reduction of HAE attacks (teal line in graph below). The most common adverse events were transient infusion-related reactions, headache, and fatigue. No Grade 3 or higher treatment-emergent events were reported.

• Impact:

  • Reduced Treatment Burden: For the 62% who are attack-free, the need for bi-weekly subcutaneous injections (e.g., Takhzyro) or daily oral pills (e.g., Orladeyo) is eliminated.

  • Steady-State Control: Unlike traditional prophylaxis, which can have trough periods where breakthrough attacks occur, the genomic knockout provides a constant, non-fluctuating reduction in kallikrein.

• Next steps: The trial sponsor has already initiated a rolling Biologics License Application (BLA) submission with the FDA as of late April 2026. The company expects to finish the BLA submission in the second half of 2026. If approved, the trial sponsor anticipates a U.S. launch in the first half of 2027. Patients in the HAELO trial will be followed for several years to monitor the long-term durability of the edit and potential delayed genomic risks. Additional clinical data from HAELO will be presented at the 2026 European Academy of Allergy and Clinical Immunology Congress (EAACI), taking place June 12-15 in Istanbul, Türkiye (abstract #100217).

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Oruka / ORKA-001 (IL-23p19 mAb HLE) / Phase 2a (plaque psoriasis)

On April 27, 2026, Oruka Therapeutics announced positive interim Phase 2a results for ORKA-001, positioning it as a potential best-in-class therapy for moderate-to-severe plaque psoriasis due to its extreme durability and high efficacy.

• Indication: The pathophysiology of plaque psoriasis is driven by a hyperactive IL-23/IL-17 immune axis, where IL-23 triggers Th17 cells to release cytokines like IL-17A and IL-17F, causing keratinocytes to proliferate rapidly and form raised, scaly plaques. The standard of care follows a severity-based escalation, increasingly moving toward high-efficacy systemic options for patients with moderate-to-severe disease. Topical therapies, including high-potency corticosteroids, Vitamin D analogs, and non-steroidal options like Vtama or Daliresp, remain the first line for localized disease. For patients who fail topicals or have extensive body surface area (BSA) involvement, the paradigm has shifted toward biologic agents that offer targeted inhibition of IL-23 (Skyrizi, Tremfya) or IL-17 (Bimzelx, Cosentyx), which can achieve complete or near-complete skin clearance (PASI 90/100). Additionally, the landscape has recently expanded to include advanced oral therapies, such as the TYK2 inhibitor Sotyktu and the newly approved oral IL-23 receptor antagonist Icotyde, providing patients with biologic-like efficacy in a convenient pill format.

• Mechanism: ORKA-001 is a monoclonal antibody that targets the p19 subunit of interleukin-23 (IL-23), a key driver of the Th17 inflammatory pathway in psoriasis. It features proprietary Half-Life Extension (HLE) technology (YTE-like or similar Fc-engineering) designed to dramatically increase circulation time. A prior Phase 1 showed drug concentrations remained above effective trough levels for a full year after a single 600 mg dose, suggesting the potential for once- or twice-yearly maintenance dosing.

• Trial design: The Phase 2a EVERLAST-A trial was a randomized, double-blind, placebo-controlled trial conducted in 84 adults with moderate-to-severe plaque psoriasis comparing 600 mg ORKA-001 at Week 0 and Week 4 (n=63) versus placebo (n=21). The primary endpoint was the percentage of patients reaching PASI 100 (complete skin clearance) at Week 16.

• Data (press release, slide deck): The trial met its primary endpoint (16-week PASI 100 of 63.5% for ORKA-001 versus 4.8% placebo) and a key secondary endpoint (IGA 0/1 (Clear/Almost) 84.1% for ORKA-001 versus 4.8% for placebo). These results numerically outperformed historical benchmarks for currently approved therapies on a cross-trial basis (16-week PASI 100 of 63.5% for ORKA-001 versus 62% Bimzelx versus 43% Skyrizi versus 30% Icotyde; see graph below); however, cross-trial comparisons have inherent limitations and do not substitute for head-to-head studies.

• Impact:

  • Pushing the Efficacy Frontier: The 63.5% PASI 100 rate at 16 weeks is among the highest ever recorded for therapies in the plaque psoriasis space.

  • Convenient Dosing Paradigm: If once-yearly dosing is validated, it would represent a massive shift from the current standard of 4–6 injections per year, potentially improving patient adherence and quality of life.

• Next steps: In 2H 2026, the trial sponsor expects to release of full EVERLAST-A data, including 28-week efficacy and 52-week follow-up for a subset of patients to confirm durability. A larger Phase 2b dose-ranging study is currently recruiting to identify the optimal induction and maintenance regimens. The trial sponsor expects to release results in 2027. Based on the Phase 2a strength, the company is preparing for Phase 3 initiation, likely following the conclusion of the Phase 2b dose-finding work.

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Veradermics / VDPHL01 (ER oral minoxidil) / Phase 2/3 (androgenetic alopecia)

• Indication: Androgenetic alopecia (AGA) is characterized by a genetically predetermined sensitivity of hair follicles to dihydrotestosterone (DHT), an androgen converted from testosterone by the enzyme 5-alpha reductase. This sensitivity triggers a process of follicular miniaturization, where the growth (anagen) phase progressively shortens and the hair follicles shrink, eventually producing fine, non-pigmented vellus hairs instead of thick terminal hairs. The current standard of care primarily targets these hormonal and physiological pathways through a combination of minoxidil, a vasodilator that prolongs the anagen phase and increases blood flow to the follicle, and finasteride, an oral 5-alpha reductase inhibitor that lowers systemic DHT levels. While these remain the primary FDA-approved interventions, the field is shifting toward optimized delivery systems, such as the extended-release oral minoxidil seen in VDPHL01, which aims to maximize the follicular conversion of minoxidil to its active sulfate form while mitigating the cardiovascular side effects associated with standard oral formulations.

• Mechanism: VDPHL01 is an extended-release (ER) formulation of minoxidil, designed to solve the spike and crash problem of standard oral minoxidil (which was originally an antihypertensive). It uses a sustained-release matrix to maintain steady blood levels, avoiding the rapid plasma spikes that cause cardiac side effects like tachycardia. Minoxidil is a prodrug that must be converted to minoxidil sulfate by the enzyme SULT1A1 in the hair follicle. Standard oral tablets often saturate this enzyme’s capacity with a quick burst; the ER formulation provides a steady drip that optimizes this conversion, leading to better and more consistent hair growth.

• Trial design: The Phase 2/3 trial (Study ‘302’) randomized 519 men with mild-to-moderate pattern hair loss (Norwood stages II–V) to VDPHL01 8.5 mg Once-Daily (QD), VDPHL01 8.5 mg Twice-Daily (BID), or placebo for 6 months (primary endpoint) with a longer-term extension. The co-primary endpoints were Non-vellus Target Area Hair Count (TAHC) and patient-reported “improved” or “much improved” ratings on the AAIRS scale.

• Data (press release, slide deck): The trial met all primary and key secondary endpoints with high statistical significance (see graphs below; p < 0.0001). tatistical separation from placebo was observed as early as Month 2, significantly faster than traditional topicals or orals. VDPHL01 was generally well-tolerated with overall AE rates similar to placebo. Most importantly, there were zero treatment-related serious adverse events (SAEs) and no cardiac events of special interest.

• Impact:

  • The First Non-Hormonal Pill: If approved, it would be the first FDA-sanctioned oral non-hormonal treatment for hair loss in nearly 30 years, offering a potent alternative to finasteride (which carries sexual side-effect risks) and messy topicals.

  • Superior Potency: The growth of ~30–33 hairs/cm² numerically exceeds historical benchmarks for both topical minoxidil and oral finasteride on a cross-trial basis.

  • Potentially Improved Compliance: By eliminating the need for daily scalp applications and reducing the risk of heart palpitations, it targets a much higher patient adherence rate.

• Next steps: The trial sponsor is running a second pivotal Phase 3 trial in men (Study ‘304’) and guides to topline results in the second half of 2026. An ongoing Phase 3 trial is evaluating the drug specifically for female pattern hair loss (Study ‘306’). The trial sponsor plans to submit a New Drug Application (NDA) to the FDA in late 2026 or early 2027, following the ‘304’ readout, positioning the drug for a potential 2027 launch.

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Mirum / Brelovitug (anti-HBsAg mAb) / Phase 2b (Hepatitis D)

• Indication: Hepatitis D (HDV) is a unique satellite virus that is obligate upon a co-existing Hepatitis B (HBV) infection, as it requires the Hepatitis B surface antigen (HBsAg) to wrap its own RNA genome and successfully infect hepatocytes. The pathophysiology is characterized by a high degree of viral replication that is more cytopathic and inflammatory than HBV alone, leading to rapid liver damage, necroinflammation, and a significantly accelerated progression to cirrhosis or hepatocellular carcinoma. The current standard of care has historically been limited to off-label use of pegylated interferon-alpha, which has a low success rate and significant side effects; however, the treatment landscape is shifting toward targeted therapies like bulevirtide (an entry inhibitor approved in Europe) and monoclonal antibodies like brelovitug that aim to disrupt the virus’s reliance on HBsAg, offering a more tolerable and effective means of achieving virologic suppression.

• Mechanism: Brelovitug is a potent, pan-genotypic, fully human IgG1 monoclonal antibody targeting the Hepatitis B surface antigen (HBsAg). It binds to the antigenic loop of HBsAg, preventing HDV (which uses HBsAg as its envelope) from entering and infecting new hepatocytes. It facilitates the rapid removal of circulating HDV/HBV virions and subviral particles from the bloodstream. By depleting the HBsAg that typically exhausts the immune system, it may help restore antigen-specific T-cell function and anti-viral immunity.

• Trial design: The AZURE-1 Phase 2b trial randomized patients with chronic HDV, quantifiable HDV RNA, and elevated ALT to to 300 mg brelovitug once weekly (QW), 900 mg brelovitug once every 4 weeks (Q4W), or a delayed treatment (placebo) arm. The primary endpoint was A composite of virologic response (≥2log₁₀ reduction in HDV RNA or undetectable) and ALT normalization at Week 24.

• Data (press release): The study showed high statistical significance (p = 0.003 for the QW arm) compared to the control group. Brelovitug showed a “favorable profile” according to the trial sponsor with no serious treatment-related AEs or discontinuations. The most common events were mild injection-site reactions (14–20%) and musculoskeletal pain.

• Impact:

  • First Effective Single-Agent: Hepatitis D is the most severe form of viral hepatitis, often leading to cirrhosis. Brelovitug’s ability to achieve 100% viral suppression as a monotherapy is a major breakthrough.

  • Tolerability Advantage: Current standard of care (interferons) has poor tolerability and high relapse rates. Brelovitug offers a potentially safer alternative.

  • Convenience Improvement: The success of the 900 mg monthly (Q4W) arm suggests that a simple monthly injection could be viable for long-term maintenance.

• Next steps: The trial sponsor expects to present full results in a late-breaking poster session at the European Association for the Study of the Liver (EASL) congress in May 2026. The trial sponsor expects to report topline 24-week data from the pivotal Phase 3 studies, AZURE-1 and AZURE-4, by the end of 2026. If Phase 3 results confirm these findings, the trial sponsor plans to submit a BLA in 2027 under the FDA’s Breakthrough Therapy designation.

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Incyte / Povorcitinib (JAK1 inhibitor) / Phase 3 (nonsegmental vitiligo)

• Indication: Nonsegmental vitiligo is an autoimmune skin disorder characterized by the progressive destruction of melanocytes, primarily driven by a hyperactive IFN-γ / CXCL10 / CXCR3 signaling axis. In this pathway, CD8+ T cells infiltrate the skin and secrete interferon-gamma (IFN-γ), which triggers keratinocytes to produce chemokines that recruit even more autoreactive T cells, creating a self-sustaining feedback loop of pigment loss. The standard of care focuses on interrupting this immune attack and stimulating repigmentation, typically starting with topical corticosteroids or calcineurin inhibitors for localized disease. For patients with more extensive or recalcitrant involvement, treatment has been revolutionized by the approval of topical JAK inhibitors (such as ruxolitinib cream), which directly block the IFN-γ signaling loop, often used alongside narrowband UVB (NB-UVB) phototherapy to stabilize the disease and encourage the migration of melanocyte precursors from hair follicles to the skin’s surface.

• Mechanism: Povorcitinib works by selectively inhibiting Janus kinase 1 (JAK1), a key signaling node in the autoimmune destruction of melanocytes. It interrupts the IFN-gamma / CXCL9 / CXCL10 signaling loop. In vitiligo, CD8+ T cells secrete IFN-gamma, which activates the JAK/STAT pathway in keratinocytes to recruit more T cells. By blocking this signal, povorcitinib halts the immune attack, allowing melanocyte precursors (stem cells in the hair follicle) to migrate back into the skin and restore pigment.

• Trial design: The Phase 3 STOP-V1 & STOP-V2 trials randomized Over 900 adults with nonsegmental vitiligo involving ≥5% total body surface area (BSA) and ≥0.5% facial BSA to 300 mg povorcitinib once daily or placebo in the 52-week double-blind, placebo-controlled period. The primary endpoint was Facial Vitiligo Area Scoring Index 75 (F-VASI75) at Week 52.

• Data (press release): The program achieved high statistical significance (p < 0.001) across both pivotal studies. The trials also met key secondary endpoints, including T-VASI50 (50% or more total body repigmentation), showing that the oral systemic approach works beyond just facial areas. The tolerability profile was consistent with previous JAK1 studies; the most common adverse events were acne, nasopharyngitis, and upper respiratory infections. No new safety signals were identified.

• Impact:

  • Potentially Better Convenience: While Incyte’s Opzelura (ruxolitinib cream) is the standard for localized vitiligo, it is difficult to apply to large body areas. Povorcitinib offers a pill-once-daily solution for patients with extensive disease.

  • Efficacy Ceiling: Vitiligo repigmentation is a slow process. The 52-week data suggests that longer-term treatment leads to cumulative benefits, which is vital for a condition where patients often struggle with long-term adherence to topicals or phototherapy.

• Next steps: The trial sponsor plans to present more detailed data from the Phase 3 program at a major medical congress in the second half of 2026. The trial sponsor expects to file a supplemental New Drug Application (sNDA) for nonsegmental vitiligo in the first half of 2027. Povorcitinib is also in late-stage development for hidradenitis suppurativa (HS) and prurigo nodularis, with the HS application already under FDA review and a potential launch in early 2027, per the trial sponsor’s guidance.

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Descriptive data releases without numerical data

• Pfizer / Elrexfio (BCMA x CD3 TCE) / P3 success (2L MM): On April 29, 2026, Pfizer announced that the Phase 3 MagnetisMM-5 trial of Elrexfio (elranatamab) met its primary endpoint, demonstrating a statistically significant and clinically meaningful improvement in progression-free survival (PFS) as a monotherapy compared to the standard-of-care triplet (daratumumab, pomalidomide, and dexamethasone) in patients with relapsed or refractory multiple myeloma (RRMM) who have received at least one prior line of therapy. Elrexfio is a BCMA x CD3 bispecific T-cell engager (TCE) that functions by simultaneously binding to B-cell maturation antigen (BCMA) on myeloma cells and the CD3 receptor on T cells, thereby bridging them and inducing potent T-cell-mediated cytotoxicity. The trial’s interim results, which exceeded the pre-specified hazard ratio threshold for efficacy, support moving the therapy into second-line (2L) treatment—significantly earlier than its current fourth-line accelerated approval—and reinforce a manageable safety profile consistent with prior data, featuring no new safety signals. Following this success, the trial sponsor plans to present detailed findings at an upcoming medical congress and engage with global regulatory authorities for label expansion, while continuing to evaluate overall survival (OS) as a key secondary endpoint and progressing with other MagnetisMM trials exploring combination regimens in earlier settings.

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Table of Contents

This week, we discuss:

• Regeneron / Otarmeni (AAV1-OTOF) / FDA-approval (severe-to-profound/profound OTOF-related hearing loss); first FDA-approved gene therapy for genetic hearing loss ⬇️

• Monopar / ALXN1840 (bis-choline tetrathiomolybdate) / Phase 3 (Wilson disease) ⬇️

• GSK / Risvutatug rezetecan (B7-H3 ADC) / Phase 1 (non-squamous NSCLC) ⬇️

• Merck / MK-2010 (PD1 x VEGF bsAb) / Phase 1 (NSCLC) ⬇️

• Nektar / Rezpeg (IL-2 pathway agonist) / Phase 2b OL (alopecia areata) ⬇️

• Johnson & Johnson / Carvykti (BCMA CAR-T) / Phase 2 (smoldering MM) ⬇️

• Roche / Enspryng (anti-IL6 mAb) / Phase 3 (MOGAD) ⬇️

• AstraZeneca / Ultomiris (anti-C5 mAb) / Phase 3 (IgAN) ⬇️

• AstraZeneca / Tozorakimab (anti-IL33 mAb) / Phase 3 (COPD) ⬇️

Regeneron / Otarmeni (AAV1-OTOF) / FDA-approval (severe-to-profound/profound OTOF-related hearing loss)

On April 23, 2026, the FDA granted accelerated approval to Otarmeni (lunsotogene parvec-cwha) via CNPV, marking the first FDA-approved example of a gene therapy to restore a neurosensory function to normal levels. It is indicated for pediatric and adult patients with severe-to-profound hearing loss (any frequency >90 dB HL) associated with molecularly confirmed biallelic variants in the OTOF gene, preserved outer hair cell function, and no prior cochlear implant in the same ear. Importantly, the manufacturer (Regeneron) will provide Otarmeni for free to clinically eligible individuals in the U.S.

• Indication: The OTOF gene, which encodes the protein otoferlin. Otoferlin acts as a “calcium sensor” at the synapse between inner hair cells and the auditory nerve; without it, sound signals are never transmitted to the brain. The clinical standard of care has historically focused on bypassing the biological synaptic failure through cochlear implantation (CI). Because the auditory nerve is typically healthy in these patients, electrical stimulation from a CI can effectively transmit sound signals to the brain, and OTOF patients often demonstrate superior speech perception outcomes compared to those with other genetic forms of deafness.

• Mechanism: Otarmeni uses a dual-adeno-associated virus (AAV1) vector system. Because the OTOF gene is too large for a single AAV, it is split into two halves that recombine within the cell to form the full-length functional gene. Expression is driven by a proprietary Myo15 cell-specific promoter, ensuring otoferlin is only produced in the inner hair cells where it is naturally required. A single, one-time intracochlear infusion performed surgically under general anesthesia, similar to the approach used for cochlear implantation.

• Trial Design: Accelerated approval was based on the CHORD trial, an ongoing, registrational, multi-center, Phase 1/2 open-label study. The trial included 20 children and adolescents (aged 10 months to 16 years) with molecularly confirmed biallelic OTOF variants. Patients received either a unilateral (one ear, n=10) or bilateral (both ears, n=10) infusion. The primary efficacy endpoint was the achievement of a hearing sensitivity threshold 70 dB HL assessed by average pure tone audiometry (i.e., average of PTA thresholds at 0.5, 1.0, 2.0, and 4.0 kHz) at Week 24 after product administration.

• Data: At Week 24, a total of 9/20 (45%) patients achieved an average PTA threshold 45 dB HL (ability to hear soft conversational speech level) and 3/20 (15%) achieved 25 dB HL (normal hearing level i.e., ability to hear whispers). One patient received a cochlear implant as rescue treatment approximately 8 months after Otarmeni administration in the same ear following determination of treatment failure. Among the 20 patients, 12 patients were evaluated at Week 48 after product administration. Of these, all 9 patients who previously had a response at Week 24 and who were evaluated at Week 48 maintained their response. One additional patient who had not initially achieved response at Week 24, achieved an average PTA threshold 70 dB HL by Week 48, resulting in a total of 10/12 (83%) patients who achieved an average PTA threshold 70 dB HL by Week 48. Eight of the 12 (67%) patients achieved an average PTA threshold 45 dB HL and 5 of the 12 patients (42%) achieved 25 dB HL by Week 48. Additionally, 9 of the 12 patients (75%) demonstrated presence of auditory brainstem response (ABR) to a click (broadband sound) stimulus of 90 dB nHL by Week 48. The most common adverse events included otitis media (38%), vomiting (33%), nausea (29%), dizziness (21%), procedural pain (17%), gait disturbance (8%), and nystagmus (8%). No serious drug-related adverse events were reported.

  

• Impact:

  • Restoration vs. Amplification: Unlike cochlear implants, which bypass the hair cells to stimulate the nerve electrically, Otarmeni restores the natural biological pathway, potentially allowing for better sound quality, music appreciation, and speech development.

  • Economic Accessibility: Regeneron has committed to providing the drug at no cost to clinically eligible patients in the U.S. (though surgical/facility costs may still apply).

  • Regulatory Milestone: This was one of the fastest BLA approvals in FDA history (61 days) and the first under the National Priority Voucher program.

• Next Steps: As an accelerated approval, the trial sponsor must verify clinical benefit through the confirmatory portion of the CHORD trial, which will focus on long-term durability and speech perception outcomes. Participants will be followed for several years to ensure the AAV expression remains stable and to monitor for any delayed immune responses. The trial sponsor anticipates regulatory filings in the EU (EMA) and other major markets throughout 2026.

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Monopar / ALXN1840 (bis-choline tetrathiomolybdate) / Phase 3 (Wilson disease)

ALXN1840 (tiomolibdate choline), a late-stage therapy for Wilson disease, has shown significant potential in addressing the neurological symptoms that often persist or worsen with existing treatments. Following recent data presentations at the American Academy of Neurology (AAN) 2026, here is the summary of its current clinical standing.

• Indication: Wilson disease is a rare autosomal recessive disorder characterized by the body’s inability to eliminate copper, leading to toxic accumulation in the liver, brain, and other vital organs. The disease is caused by mutations in the ATP7B gene, which encodes a transmembrane protein responsible for transporting copper into the bile for excretion and incorporating it into ceruloplasmin. When ATP7B is defective, copper cannot be excreted into the bile. It builds up in hepatocytes (liver cells). Once the liver’s storage capacity is exceeded, copper enters the bloodstream as “free” (non-ceruloplasmin-bound) copper. This generates reactive oxygen species through the Fenton reaction, leading to lipid peroxidation and cell death. The excess copper deposits in secondary tissues including the CNS (causing tremors, dystonia, and psychiatric symptoms), eyes (causing rings in the cornea called Kayser-Fleischer rings), and blood (causing Coombs-negative hemolytic anemia). Standard of care involves lifelong treatment with copper chelators and zinc salts as well as dietary changes to reduce copper levels.

• Mechanism: ALXN1840 is a first-in-class selective copper-binding agent. It forms a highly stable tripartite complex with copper and albumin in the blood and liver. By sequestering excess copper into these complexes, it renders the copper redox-inactive (preventing oxidative damage) and promotes its excretion through the biliary tract, the body’s natural route, rather than the kidneys. Unlike standard chelators, it is designed to mobilize copper rapidly without causing the initial neurological spike often seen when traditional treatments mobilize copper into the bloodstream and brain.

• Trial design: The FoCus trial (NCT03403205) was a randomized, rater-blinded, multi-center study comparing ALXN1840 to Standard of Care (SoC) such as penicillamine, trientine, or zinc. Patients included both treatment-naïve and treatment-experienced (previously on SoC for at least 1 year) patients aged 12 and older.

• Data: The latest readout emphasized “clinically meaningful” benefits for patients including lower rates of Neurologic Worsening (9% vs 25% SOC, p=0.038) and higher rates of Neurologic Improvement (45% vs 32% SOC), CGI-S (61% vs 17% SOC, p=0.008), and CGI-I (47% vs 19% SOC, p=0.003). Benefits were sustained and continued to increase over approximately 3 years of long-term follow-up. The profile was favorable across 266 patients. Drug-related Serious Adverse Events (SAEs) occurred in only 4.9% of patients, with neurologic SAEs in < 1%. No treatment-related deaths were reported.

• Impact: Wilson disease management has historically been plagued by “iatrogenic worsening,” where starting treatment causes a sudden release of copper that permanently damages the brain. ALXN1840’s data suggests it could:

  • Reduce Permanent Disability: By significantly lowering the rate of worsening (9% vs 25%).

  • Simplify Dosing: Offers a potential once-daily oral option with better tolerability than traditional heavy-metal chelators.

• Next steps: The trial sponsor plans to submit a New Drug Application (NDA) to the FDA in mid-2026. The company recently appointed a Chief Commercial Officer to build the launch framework. Following the U.S. filing, regulatory submissions in other global markets (EMA/MHRA) are expected to follow.

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GSK / Risvutatug rezetecan (B7-H3 ADC) / Phase 1 (non-squamous NSCLC)

Data from the AACR 2026 annual meeting (presented April 2026) highlighted the potent activity of risvutatug rezetecan (formerly HS-20093/GSK5764227) in combination with the PD-L1 inhibitor adebrelimab. This combination is being investigated as a second-line (2L) treatment in patients with non-squamous non-small cell lung cancer (nsq-NSCLC).

• Indication: Non-squamous non-small cell lung cancer (nsq-NSCLC) is the most common subtype of lung cancer, primarily comprising adenocarcinomas. Unlike squamous cell carcinoma, it typically originates in the peripheral lung tissues and is frequently associated with specific genetic “driver” mutations. The development of nsq-NSCLC involves a complex interplay of genetic mutations and environmental factors (e.g., smoking, radon, asbestos). Most nsq-NSCLC arises from Type II alveolar cells, which are responsible for surfactant production and lung repair. Nsq-NSCLC is characterized by a high frequency of actionable mutations, including EGFR (approx. 15-20% in Western populations), KRAS (approx. 30%), ALK, ROS1, and MET. Tumors often express PD-L1, a protein that suppresses the immune response, allowing cancer cells to evade T-cell detection. Survival is heavily dependent on the stage at diagnosis (5-year survival 62-73% for localized Stage I/II, 35-47% for regional Stage III, and 8-12% for Stage IV with brain/bone/liver metastasis). While rates have improved significantly due to targeted therapies and immunotherapy, metastatic disease remains a challenge. The current standard of care for advanced non-squamous NSCLC is centered on a biomarker-first approach, where treatment is dictated by the presence of actionable genetic drivers or PD-L1 expression levels. For patients without specific mutations (like EGFR or ALK), the backbone of frontline therapy typically involves platinum-based chemotherapy combined with PD-(L)1 immunotherapy, such as the KEYNOTE-189 regimen of Keytruda, carboplatin, and pemetrexed. If a patient progresses on this frontline treatment, the historical standard has been docetaxel (with or without ramucirumab), though this second-line setting is where newer assets like risvutatug rezetecan are currently challenging the status quo due to the relatively limited efficacy and high toxicity of traditional taxane chemotherapy.

• Mechanism: Risvutatug rezetecan is a next-generation B7-H3-directed antibody-drug conjugate (ADC). B7-H3 (CD276) is an immune checkpoint molecule overexpressed in various solid tumors, including NSCLC, and is associated with poor prognosis and immune evasion. Risvutatug rezetecan utilizes a topoisomerase I inhibitor (exatecan derivative) payload. The combination with adebrelimab (a PD-L1 monoclonal antibody) aims to leverage the “immunogenic cell death” induced by the ADC’s cytotoxic payload, which can sensitize the tumor microenvironment to checkpoint inhibition, even in patients who previously progressed on immunotherapy.

• Trial design: The data comes from a multi-center, open-label Phase 1 expansion cohort conducted in China (Hansoh Pharma). It enrolled patients with advanced non-squamous NSCLC without actionable genomic alterations (e.g., EGFR/ALK negative) who had failed at least one prior line of therapy (typically platinum-based chemo + IO).

• Data: The combination demonstrated encouraging efficacy signals in 2L NSCLC data to date including 47.1% ORR, 14 months mPFS, and 85% DCR in the efficacy-evaluable set (n=34) with a data cutoff of January 20, 2026.

• Impact:

  • Potentially redefining 2L Standard: If these results hold in larger trials, this combination could displace docetaxel as the preferred second-line treatment for nsq-NSCLC.

  • Overcoming IO Resistance: The high ORR in a post-PD-1/L1 population suggests that B7-H3 targeting effectively bypasses or reverses common mechanisms of resistance to traditional immunotherapy.

• Next steps: The trial sponsor is initiating/expanding global Phase 3 trials (e.g., the ARTEMIS program) to validate these China-specific results in a broader Western population. Based on the Breakthrough Therapy Designation already held for other indications (SCLC), the NSCLC data likely sets the stage for an expedited regulatory pathway. Parallel efforts are ongoing in Small-Cell Lung Cancer (SCLC), where risvutatug rezetecan recently received Orphan Drug Designation in Japan (March 2026).

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Merck / MK-2010 (PD1 x VEGF bsAb) / Phase 1 (NSCLC)

Data for MK-2010 (also known as LM-299), a PD-1 x VEGF bispecific antibody, was a key highlight at the AACR 2026 annual meeting (April 2026). Merck acquired this asset from LaNova Medicines (now a subsidiary of Sino Biopharm) in late 2024 to bolster its post-Keytruda strategy.

• Indication: Non-small cell lung cancer (NSCLC) arises from the malignant transformation of bronchial epithelial cells, driven by the accumulation of genetic alterations, such as mutations in KRAS, EGFR, or ALK, and environmental insults like tobacco smoke that disrupt normal cell signaling and apoptosis. These changes lead to uncontrolled cellular proliferation and the remodeling of the tumor microenvironment to support angiogenesis and immune evasion, often through the upregulation of the PD-1/PD-L1 pathway. The current standard of care is heavily dictated by molecular profiling and disease stage; early-stage tumors are primarily managed with surgical resection often followed by adjuvant chemotherapy or immunotherapy, while advanced or metastatic disease requires a biomarker-first strategy. For patients with actionable mutations, frontline therapy involves targeted tyrosine kinase inhibitors (TKIs), whereas those without such drivers typically receive a combination of platinum-doublet chemotherapy and immune checkpoint inhibitors (anti-PD-1/PD-L1). As the disease progresses, treatment shifts toward subsequent lines of therapy, such as docetaxel or increasingly prevalent antibody-drug conjugates (ADCs) and bispecific antibodies, to overcome acquired resistance.

• Mechanism: MK-2010 is a next-generation bispecific antibody (bsAb) designed to simultaneously hit two proven pathways. Dual Blockade: It inhibits the PD-1/PD-L1 checkpoint (releasing the “brakes” on T-cells) and the VEGF pathway (inhibiting tumor angiogenesis and normalizing the tumor vasculature). It utilizes a differentiated 2+1 or similar structure (an anti-VEGF antibody linked to two single-domain anti-PD-1 antibodies). This is intended to increase binding avidity in the presence of both targets, potentially improving selectivity for the tumor microenvironment over healthy tissue.

• Trial design: The data presented at AACR 2026 came from a Phase 1 study primarily conducted in China. The trial recruited patients with advanced solid tumors, with a heavy emphasis on a backfill cohort of 72 patients with NSCLC. NSCLC patients were required to have PD-L1 expression (TPS ≥1%) and no actionable genomic alterations (EGFR/ALK negative). The study explored doses of 20 mg/kg (low dose) and 30 mg/kg (high dose) administered intravenously every three weeks (Q3W).

• Data: The readout provided a competitive first look at MK-2010’s activity compared to rivals like ivonescimab. In the initial low-dose expansion, 6 out of 11 patients responded; in the high-dose expansion, 4 out of 9 patients responded. While the median follow-up was relatively short (~3.3 months), the responses in the frontline (1L) setting were particularly notable. The 1L ORR of 55% was specifically for the 20 mg/kg dose; the 30 mg/kg dose showed a slightly lower 44% ORR in the same setting. Safety was generally consistent with the PD-1 and VEGF classes. Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) occurred in 17% (low dose) and 27% (high dose). Common VEGF-related AEs included hypertension (~9%) and proteinuria (~5%).

  

• Impact:

  • The “Ivonescimab” Challenger: Following the HARMONi-2 data showing ivonescimab’s superiority over Keytruda, MK-2010 is a countermeasure by Merck to maintain their competitive advantage in the lung cancer market.

  • Frontline Potential: The 55% ORR in the 1L setting suggests that combining these two mechanisms into a single molecule may be superior to the historical attempts at combining two separate monoclonal antibodies.

• Next steps: The trial sponsor is finalizing the Recommended Phase 2 Dose (RP2D), likely settling on the 20 mg/kg or 30 mg/kg Q3W schedule. They are focused on transitioning from the China-based Phase 1 to global Phase 2/3 trials. Furthermore, Merck is exploring pairing MK-2010 with its own internal assets, such as the TROP2 ADC (sacituzumab tirumotecan), to further move the needle in PD-L1 low or refractory populations.

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Nektar / Rezpeg (IL-2 pathway agonist) / Phase 2b OL (alopecia areata)

Data from the REZOLVE-AA Phase 2b trial (presented April 20, 2026) highlights a unique “slow-burn” efficacy profile for rezpegaldesleukin (Rezpeg). While the trial initially missed its primary endpoint in the randomized controlled portion, the 52-week data suggests that its immune-modulating mechanism requires a longer induction period than traditional therapies.

• Indication: Alopecia areata is an autoimmune condition characterized by the sudden loss of immune privilege in the hair follicle, where a breakdown in self-tolerance leads CD8+ T cells to attack the hair bulb. This inflammatory process, primarily driven by the JAK-STAT signaling pathway and cytokines like IFN-gamma and IL-15, forces follicles into a premature telogen (resting) phase without permanently destroying the follicle’s regenerative potential. The standard of care is stratified by the extent of hair loss; localized patches are typically managed with intralesional corticosteroids (e.g., triamcinolone) or high-potency topical steroids to suppress regional inflammation. For patients with severe or extensive disease (alopecia totalis or universalis), treatment has shifted toward systemic therapy with JAK inhibitors, such as baricitinib or ritlecitinib, which provide broad suppression of the inflammatory signaling cascades. Other options include topical immunotherapy (e.g., DPCP) to induce a diversionary allergic contact dermatitis, though the field is increasingly moving toward targeted biologics, like the IL-2 pathway agonists you mentioned, to restore long-term immune homeostasis.

• Mechanism: Rezpeg is a first-in-class IL-2 receptor pathway agonist. It is designed to selectively stimulate and expand regulatory T cells (T_regs) by binding to the IL-2 receptor complex. In alopecia areata (AA), the loss of immune privilege at the hair follicle leads to T-cell-mediated destruction. Rezpeg aims to restore immune homeostasis, slowing down the autoimmune attack, rather than broadly suppressing the immune system like JAK inhibitors.

• Trial design: The Phase 2b REZOLVE-AA study was a randomized, double-blind, placebo-controlled trial. It included 92 adults with severe-to-very-severe alopecia areata (≥50% scalp loss). In the initial phase (36 weeks), patients were randomized to low-dose (18 µg/kg), high-dose (24 µg/kg), or placebo twice monthly. in the extension phase (Weeks 36–52), patients who demonstrated growth but still had a SALT >20 were allowed to continue on a blinded extension to evaluate the durability and deepening of response.

• Data: The trial presents a tale of two readouts. The trial technically missed its primary endpoint (mean change in SALT score) at Week 36 in the initial phase (grey box in figure below). The trial did not meet its primary endpoint in the intent-to-treat population, but a post-hoc, exploratory analysis excluding four patients suggested nominal significance, though such analyses are hypothesis-generating and require validation in future studies. The extended treatment showed that responses continued to mature significantly over time (green box in figure below). In the 52-week data, the SALT≤20 rates were 25.8% (low dose) and 27.6% (high dose). The 52-week data demonstrated a deepening of response, with 94% of patients completing the extension phase without any discontinuations due to adverse events. The safety profile remained favorable with no new signals or discontinuations during the 16-week extension period; the most common events were mild-to-moderate injection site reactions.

  

• Impact:

  • The First Biologic Alternative: If approved, Rezpeg would be the first biologic for AA, providing an alternative to JAK inhibitors (e.g., baricitinib, ritlecitinib) which carry boxed warnings for serious infections, malignancy, and MACE.

  • Homeostatic vs. Suppressive: Unlike JAKs, which require continuous suppression, Rezpeg’s Treg-mediated approach offers the potential for long-term disease control and possibly “treatment-free” intervals if immune tolerance is successfully re-established.

• Next steps: The trial sponsor has indicated that the 52-week data clarifies the need for a longer induction period (likely 52 weeks instead of 36) in registrational trials. The company plans to meet with the FDA in 2026 to finalize the Phase 3 design based on these results. Industry analysis are watching for off-treatment data to see if the hair growth is maintained after dosing stops, a key differentiator for the T_reg mechanism.

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Johnson & Johnson / Carvykti (BCMA CAR-T) / Phase 2 (smoldering MM)

Data presented at the AACR 2026 annual meeting (April 2026) by Dr. Omar Nadeem from the Dana-Farber Cancer Institute showcased the potential for early interception in smoldering multiple myeloma using Carvykti. The data were concurrently published in Nature Medicine.

• Indication: Smoldering Multiple Myeloma (SMM) is an intermediate, asymptomatic clinical stage of plasma cell dyscrasia characterized by a clonal proliferation of malignant plasma cells in the bone marrow. The pathophysiology involves a “two-hit” genetic model: the initial progression from monoclonal gammopathy of undetermined significance (MGUS) is often driven by primary translocations (e.g., involving the IGH locus on chromosome 14) or hyperdiploidy. This creates a stable but abnormal clone. The progression to symptomatic disease is then triggered by secondary genetic hits, such as mutations in KRAS, NRAS, or MYC, alongside a permissive bone marrow microenvironment that fails to suppress the malignant expansion, eventually leading to end-organ damage. The standard of care for SMM is currently transitioning from a “watchful waiting” approach to more proactive risk stratification. For low-to-intermediate risk patients, the consensus remains active observation with serial monitoring of laboratory markers every 3 to 6 months to detect early signs of progression. However, for high-risk SMM (defined by the “20/2-20” criteria: ≥20% bone marrow plasma cells, M-protein >2 g/dL, and an involved/uninvolved free light chain ratio >20), clinical guidelines and recent trial data increasingly support early intervention. Treatment in these cases typically involves lenalidomide, either alone or in combination with dexamethasone, to delay the onset of symptomatic multiple myeloma and improve progression-free survival.

• Mechanism: Carvykti is a BCMA-directed CAR-T cell therapy that utilizes a dual-epitope binding design to target B-cell maturation antigen (BCMA) on plasma cells. The rationale for using it in smoldering multiple myeloma (SMM) is that T cells in these patients are “fitter” and less exhausted than those in heavily pre-treated patients, potentially leading to more robust expansion and durability. It aims to eradicate the precursor malignant clones before they cause end-organ damage (CRAB criteria: calcium elevation, renal insufficiency, anemia, bone lesions).

• Trial design: The CAR-PRISM trial (NCT05767359) is an investigator-initiated Phase 2 study evaluating a single infusion of Carvykti without induction or bridging therapy. The trial involved 20 patients with high-risk SMM, defined by the 20/2/20 criteria (BM plasma cells >20%, M-protein >2 g/dL, and FLC ratio >20). Primary endpoints included safety and dose-limiting toxicities; secondary endpoints included Overall Response Rate (ORR) and Minimal Residual Disease (MRD) negativity.

• Data: The results demonstrated high rates of MRD negativity in this small study population; 100% of patients (20/20) achieved MRD negativity (10^-6 sensitivity) within 2 months. At a median follow-up of 15.3 months, all patients remained MRD-negative. Among 16 patients with ≥6 months follow-up, the Complete Response (CR) rate was 100%. No instances of disease progression or deaths were observed during the follow-up period. While low-grade cytokine release syndrome (CRS) was universal (100% Grade 1/2), classic ICANS was managed well. 7 cases of non-ICANS neurologic toxicities (NINTs) occurred, including facial nerve palsy, which is a known but manageable side effect for BCMA CAR-Ts. This included 4 cases of facial nerve palsy (all resolved) and 3 cases of mild motor symptoms that remained improved but present at last follow-up.

• Impact:

  • Potential Shift in Paradigm: Currently, SMM is managed with “watchful waiting” or mild intervention (Dara-Faspro). This trial suggests that Carvykti could offer the potential for long-term disease-free survival in high-risk patients.

  • Immune Robustness: The data confirmed that earlier intervention leads to rapid and deeper responses compared to later lines of therapy.

• Next steps: The primary focus of the Phase 2 trial is determining if these MRD-negative responses can be sustained for 5+ years, which would define a functional cure. Based on these pilot results, larger registrational trials or expansion cohorts in even earlier stages of plasma cell dyscrasias may be initiated. Investigators are looking at the 7 NINT cases to determine if specific biomarkers (like absolute lymphocyte count expansion) can predict and prevent these neurologic events.

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Roche / Enspryng (anti-IL6 mAb) / Phase 3 (MOGAD)

The recent data from the Phase 3 METEOROID trial for Enspryng represents a significant milestone in the treatment of Myelin Oligodendrocyte Glycoprotein Antibody-associated Disease (MOGAD). Presented at the 2026 American Academy of Neurology (AAN) Annual Meeting. If approved for the treatment of MOGAD, Enspryng would represent the first authorized treatment for this rare autoimmune condition.

• Indication: Myelin Oligodendrocyte Glycoprotein Antibody-associated Disease (MOGAD) is an inflammatory demyelinating condition of the central nervous system (CNS) characterized by the presence of serum antibodies (IgG) that target the MOG protein. Pathophysiologically, MOG is located on the outermost surface of the myelin sheath and oligodendrocyte membranes, making it highly accessible to circulating antibodies. When these autoantibodies bind to their target, they trigger a cascade of complement-mediated damage and cellular infiltration—predominantly by T-cells and macrophages—leading to myelin destruction. Unlike Multiple Sclerosis (MS), MOGAD is pathologically distinct, often showing floppy or large tumefactive lesions and a high predilection for the optic nerves and spinal cord, frequently sparing the brain in adult presentations. The standard of care for MOGAD focuses on the management of acute attacks followed by a risk-stratified approach to maintenance. Acute relapses are treated aggressively with high-dose intravenous methylprednisolone, with early transition to plasma exchange (PLEX) or intravenous immunoglobulin (IVIG) if a full clinical recovery is not achieved. Long-term management is nuanced; because some patients experience a monophasic course (a single lifetime event), maintenance immunosuppression is typically reserved for those with a relapsing phenotype or persistent MOG-IgG seropositivity. For these patients, off-label use of rituximab, mycophenolate mofetil, or monthly IVIG has been the historical mainstay, though the landscape is currently shifting toward targeted biologics, such as IL-6 receptor antagonists, following recent successful clinical trials.

• Mechanism: Enspryng is a humanized monoclonal antibody that targets the Interleukin-6 receptor (IL-6R). IL-6 is a key pro-inflammatory cytokine that drives the differentiation of B-cells into antibody-producing plasmablasts and promotes the survival of pathogenic T-cells. By blocking IL-6 signaling, Enspryng suppresses the inflammatory cascade, helps maintain blood-brain barrier integrity, and reduces the production of MOG antibodies that lead to optic neuritis, transverse myelitis, and acute disseminated encephalomyelitis (ADEM).

• Trial design: The Phase 3 METEOROID trial was a randomized, double-blind, placebo-controlled study involving adults and adolescents (≥12 years old) with MOGAD who had experienced at least one relapse in the prior year or two in the prior two years. Participants received either satralizumab (120 mg subcutaneous injection) or placebo, with or without background immunosuppressive therapy.

• Data: The trial met its primary and key secondary endpoints with high statistical significance. At 48 weeks, 87% of the Enspryng group remained relapse-free compared to 67% in the placebo group (p=0.0025). Enspryng reduced the risk of a new relapse by 68% compared to placebo and demonstrated a 66% reduction in ARR (p=0.0030). There was a 79% reduction in the annualized rate of active MRI lesions and a 73% lower proportion of patients requiring rescue therapies (e.g., steroids or plasma exchange). The safety profile was consistent with Enspryng’s established record in NMOSD. Common adverse events (>5%) included injection-related reactions, influenza, and arthralgia.

• Impact:

  • First-in-Class Potential: There are currently no FDA-approved treatments for MOGAD; clinicians often rely on off-label immunosuppressants like rituximab or mycophenolate mofetil.

  • Rapid Onset: The treatment effect was observed as early as 8 weeks, providing rapid stabilization for high-risk patients.

  • Disability Prevention: Since disability in MOGAD is primarily driven by acute relapses rather than gradual progression, the high relapse-free rate directly correlates to better long-term functional outcomes and less reliance on high-dose “rescue” corticosteroids.

• Next steps: The trial sponsor has announced plans to submit the METEOROID data to global regulatory authorities (FDA, EMA) in 2026. The drug already holds Orphan Drug Designation, which may expedite the review process. Continued monitoring of the open-label extension phase will be crucial to assess long-term safety and the durability of the 87% relapse-free rate beyond the one-year mark.

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Descriptive data releases without numerical data

• AstraZeneca / Ultomiris (anti-C5 mAb) / Phase 3 (IgAN): The interim analysis met its first co-primary endpoint with “statistically significant and clinically meaningful” reduction in UPCR was observed as early as Week 10. The Phase 3 LUNA trial met its primary endpoint for proteinuria reduction at the 34-week mark (specific percentage data to be presented at a forthcoming medical meeting). The profile was consistent with Ultomiris’s established record in PNH and aHUS. No new safety signals were identified, though the drug maintains its Boxed Warning regarding the risk of serious meningococcal infections. The trial sponsor confirmed they will seek accelerated regulatory approval in key global markets (US, EU, Japan) based on this Week 34 proteinuria data. The trial will continue to its 106-week completion to evaluate the second co-primary endpoint: the long-term stabilization of kidney function (eGFR). Detailed results are expected to be presented at an upcoming major nephrology conference (likely ERA-EDTA or ASN Kidney Week).

• AstraZeneca / Tozorakimab (anti-IL33 mAb) / Phase 3 (COPD): The recent clinical successes for tozorakimab (presented in March and April 2026) represent a major milestone in respiratory medicine. This is the first IL-33-targeting biologic to demonstrate success in Phase 3 trials for COPD, notably succeeding where other IL-33 and ST2 inhibitors had previously failed. The trial sponsor reported that the trials were “statistically significant and highly clinically meaningful.” Crucially, tozorakimab showed benefit regardless of a patient’s blood eosinophil count. This distinguishes it from Dupixent (dupilumab), which is primarily effective in the eosinophilic (Type 2) subgroup. The drug was generally well-tolerated. The safety profile across all three trials was consistent with earlier Phase 2 data, with no major unexpected safety signals reported. Currently, biologics like Dupixent only address about 20–30% of the COPD population (those with high eosinophils). Tozorakimab has the potential to treat up to 80% of the total COPD population, including those without Type 2 inflammation. By targeting the oxidized form of IL-33, tozorakimab is the first therapy to directly address the mucus hypersecretion that leads to the “smoker’s cough” and obstructive symptoms. The trial sponsor plans to share the full data with global regulators (FDA, EMA) in 2026 for potential approval. The PROSPERO trial, a 104-week long-term extension study, is ongoing, with additional results expected in H1 2026. Beyond COPD, tozorakimab is in Phase 3 for severe viral lower respiratory tract disease and Phase 2 for asthma.

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Introduction

On April 29th, 2026, KalVista announced a definitive agreement that Chiesi Group would acquire them for approximately $1.9 billion, representing a 36% premium over the 30-day volume-weighted average share price. The centerpiece of this acquisition is Ekterly (plasma kallikrein inhibitor), which is the first FDA-approved oral, on-demand treatment for hereditary angioedema (HAE), a rare condition characterized by dangerous swelling. Clinical data from the Phase 3 KONFIDENT trial published in NEJM met its primary endpoint, demonstrating a statistically significant reduction in time to symptom relief compared to placebo in the trial population. By acquiring KalVista, Chiesi aims to expand its rare disease portfolio and significantly grow its commercial presence in the United States. Additionally, medical guidelines (2026 International Guideline on the Diagnosis and Management of Pediatric Patients with Hereditary Angioedema) were updated by the issuing medical committee to include Ekterly as a ‘strong recommendation’ for first-line therapy for the acute treatment of HAE attacks in adolescents aged 12 years and older. This transition from injectable treatments to an oral option is described as a major advancement for patient independence and early intervention.

HAE constitutes a blockbuster indication space, representing an aggregate revenue run rate of almost $2.5 billion according to quarterly press releases for 4Q 2025 associated with Takhyzro, Orladeyo, Ekterly, Firazyr, Cinryze*.

If executed, the proposed KalVista acquisition would constitute the second largest acquisition in the HAE space to date.

Here, I dive into the history of hereditary angioedema (HAE), the evolution of therapeutic approaches, and the story of KalVista.

What is HAE?

Not everyone is acquainted with HAE (after all, it is a rare disease), so allow me to provide a short explainer. Hereditary Angioedema (HAE) is a rare genetic disorder characterized by recurrent episodes of severe swelling (angioedema) that impacts approximately 10,000 people in the United States. Unlike common allergic reactions, HAE does not respond to antihistamines or epinephrine because it is driven by an overproduction of bradykinin, a peptide that causes blood vessels to leak fluid into surrounding tissues. HAE attacks typically manifest as non-pitting edema, meaning if you press a finger into the swollen area, it doesn’t leave a lasting indentation. Attacks impacts a number of body parts:

• Skin: The skin often looks pale or slightly pink, but it is not usually accompanied by hives (urticaria). If you see itchy, red welts, it is likely an allergy rather than HAE. It most frequently affects the hands, feet, face, and genitals. A hand can swell to double its size, making it impossible to grip objects or wear rings. Some patients experience a prodrome before the swelling starts, most notably Erythema Marginatum, a non-itchy, map-like red rash that looks like marble patterns on the skin.

• Gastrointestinal Tract: While you can’t see this from the outside, the lining of the intestines swells significantly. This causes the abdomen to look distended or bloated. The pain is often described as excruciating and is frequently mistaken for appendicitis or a ruptured organ. It is often accompanied by severe nausea and vomiting.

• Upper Airway: This appears as swelling of the tongue, soft palate, and throat. This is the most life-threatening form of HAE. It can progress quickly, leading to a tight feeling in the throat, difficulty swallowing, or a change in voice (hoarseness), eventually risking total airway obstruction.

HAE is also classified into three types:

• Type I (80-85% of cases): This is the most common type, in which the body doesn’t produce enough C1-Inhibitor protein.

• Type II (15-20% of cases): The body produces enough C1-Inhibitor, but the protein doesn’t function correctly.

• HAE with Normal C1-INH (<1% of cases): A rarer form where the C1 protein is fine, but other genetic mutations (like Factor XII) cause the same bradykinin buildup.

Despite its prevalence, the underdiagnosed nature of the disease causes a significant lag in these numbers. On average, it still takes 8 to 10 years for a patient to receive an accurate HAE diagnosis after their first attack. Approximately 25% of cases are the result of a spontaneous de novo mutation, meaning there is no family history to help guide the diagnosis.

A Swelling Suspicion

The history of Hereditary Angioedema (HAE) is a fascinating journey from early clinical observations to a sophisticated understanding of molecular genetics and targeted therapies. While early accounts of swelling go back to the 16th century, the disease was first formally distinguished from standard hives in the late 19th century. In 1882, Dr. Heinrich Quincke first described the clinical symptoms of angioedema, often referred to at the time as Quincke’s edema. A few years later in 1888, Dr. William Osler provided the definitive description of the hereditary nature of the disease. He tracked the condition through five generations of a family and famously named it Hereditary Angioneurotic Edema (HANE), a name that stuck for decades until the neurotic component was debunked.

For 75 years following Dr. Osler’s report, the underlying cause of HAE remained a mystery, and mortality rates from laryngeal edema were as high as 25–30%. Then in 1963, Virginia Donaldson and Jack Evans at Case Western Reserve University identified that HAE is caused by a deficiency in the C1 esterase inhibitor (C1-INH). This established HAE as the first human disease recognized to be caused by a deficiency of a complement control protein.

Before their work, scientists knew about the C1 esterase inhibitor (C1-INH), a protein that keeps the body’s complement system (part of the immune response) in check. However, no one had linked a deficiency of this protein to a specific human disease. The year before Donaldson’s breakthrough, a researcher named Nathaniel Landerman working at the University of Maryland School of Medicine published a study (1962) showing that patients with HAE were missing a specific “inhibitor of permeability” in their blood. Landerman found that these patients couldn’t properly shut down kallikrein, an enzyme that causes blood vessels to leak. This proved that HAE was a disease of missing brakes, a lack of a regulatory protein rather than the presence of a toxin.

While Landerman was looking at HAE, a scientist named Irwin Lepow at Case Western Reserve University had just discovered and characterized a protein that inhibited the first component of the complement system (C1). He called it C1-esterase inhibitor. Since Donaldson was working at the same institution and in the same scientific circles as Lepow, she was aware of this newly identified inhibitor protein. She and Evans theorized that the kallikrein inhibitor Landerman had described might actually be the same protein Lepow had just discovered.

Donaldson and Evans tested the serum of several patients with HAE. Indeed, they discovered that these patients completely lacked the serum globulin that inhibits the enzymatic activity of C1 esterase. Interestingly, Donaldson and Evans initially believed the swelling was caused by the complement system (since they found a C1 inhibitor deficiency), specifically a downstream fragment called C2 kinin. Research eventually showed that C2 kinin was too weak to cause the massive, localized edema seen in HAE patients. Furthermore, antihistamines and steroids (which usually work on immune-driven swelling) were useless, suggesting the immune explanation was incomplete.

In the late 1970s and early 80s, researchers began to look more closely at the Contact System (also known as the Kallikrein-Kinin system), which governs blood pressure and vascular permeability. Researchers realized that C1-INH was not just an inhibitor of C1. It was actually a broad-spectrum serine protease inhibitor (serpin) that regulated multiple enzymes, including Plasma Kallikrein and Factor XII. It was discovered that when C1-INH is missing, Plasma Kallikrein goes into overdrive. This enzyme cleaves a large protein called High-Molecular-Weight Kininogen (HMWK), and the byproduct of that cleavage is Bradykinin.

Bradykinin is a potent vasodilator, far more powerful than histamine. Its discovery as the primary mediator changed everything because of how it interacts with the blood vessels:

• Binding the B2 Receptor: Bradykinin binds to B2 receptors on the endothelial cells lining the blood vessels.

• Opening the Floodgates: Once bound, it signals the cells to pull apart slightly, creating gaps in the vessel wall. Plasma (the liquid part of the blood) leaks through these gaps into the surrounding tissue, causing the massive “non-pitting” swelling characteristic of HAE.

• No Itch, Just Pain: Unlike histamine, bradykinin doesn’t stimulate the nerves that cause itching. Instead, it stimulates pain receptors and causes significant fluid shifts, explaining why HAE attacks are painful rather than itchy.

Today, we have a more complete picture of the mechanism that cause HAE. It is primarily driven by a deficiency or dysfunction of the C1 esterase inhibitor (C1-INH), leading to chronically overactive plasma kallikrein. This triggers uncontrolled cleavage of high-molecular-weight kininogen and sets off the excessive release of bradykinin, a potent inflammatory mediator that binds to B2 receptors on vascular endothelial cells. This binding signals the endothelial cells to retract, increasing vascular permeability and allowing plasma to leak into the surrounding interstitial tissues, which manifests clinically as the localized, non-pitting, and potentially life-threatening swelling characteristic of the disease.

This shift in understanding allowed the industry to move away from non-specific therapies and toward precise molecular targets.

From Blunt Instruments to Precision Strikes

The history of HAE therapy is a transition from brute force medicine, using repurposed steroids and blood products, to highly elegant, targeted molecular engineering. In the 1950s-1970s, before the molecular cause of HAE was understood, doctors relied on trial and error with medications designed for other conditions:

• Antifibrinolytics (Epsilon-aminocaproic acid & Tranexamic acid): Originally used to control bleeding, these were found to modestly reduce HAE attacks. They worked by indirectly slowing down the activation of the contact system, but they were often insufficient for severe cases.

• Fresh Frozen Plasma (FFP): In emergencies, doctors administered FFP to provide a top-off of C1-inhibitor. However, this was a double-edged sword: FFP also contains the substrates (like kininogen) that produce bradykinin, occasionally causing a paradoxical worsening of the attack before it got better.

• Methyltestosterone: Early observations showed that high-dose male hormones could reduce swelling, though the side effects were often as debilitating as the disease itself.

Following the 1963 discovery of the C1-INH deficiency, researchers looked for ways to turn on the body’s own production of the protein. In this vein, attenuated androgens (Danocrine, Stanozolol) were approved in the mid-1970s. These became the first-line long-term prophylaxis for decades. They stimulate the liver to increase the synthesis of C1-INH. While effective, they caused significant long-term side effects: weight gain, acne, virilization in women (deepening voice, hair growth), and a long-term risk of liver tumors (adenomas).

As biotechnology advanced, the focus shifted from stimulating the liver to simply replacing the missing protein directly. Plasma-derived C1-INH were extracted and highly purified from human donor plasma. In 2008, Cinryze became the first FDA-approved drug for preventing HAE attacks (prophylaxis). One year later in 2009, Berinert was approved for the acute treatment of attacks. To remove the reliance on human plasma, scientists engineered transgenic rabbits to produce human C1-INH in their milk, providing a highly concentrated alternative. In 2014, Ruconest became the first and only recombinant (plasma-free) C1-INH treatment available in the United States.

Once the Bradykinin Hypothesis was solidified, therapies began targeting the specific molecules that cause the leak:

• B2 Receptor Antagonists (Firazyr approved in 2009): Instead of stopping the production of bradykinin, this drug acts as a shield on the blood vessels, preventing bradykinin from docking and opening the floodgates.

• Plasma Kallikrein Inhibitors (Kalbitor approved in 2011): A potent inhibitor that stops the enzyme responsible for generating bradykinin in the first place.

As therapies improved, the goal shifted from surviving attacks to total freedom from attacks using long-acting biologics:

• Monoclonal Antibodies (Takhzyro approved in 2018): By specifically binding to and inhibiting active plasma kallikrein with a long half-life, it allowed patients to go from daily or weekly treatments to a single injection every two or four weeks.

• Oral Small Molecules (Orladeyo approved in 2020): This provided the first non-steroidal daily pill to prevent attacks, significantly reducing the treatment burden of needles and infusions.

KalVista, a Successful Pivot

The history of KalVista Pharmaceuticals is a study in strategic pivot and clinical persistence, culminating in the first oral on-demand treatment for HAE. While the company originally explored ophthalmology, its refocus on the kallikrein-kinin system eventually led to its acquisition by the Chiesi Group on April 29, 2026.

KalVista was formally launched in 2011 (though its U.S. entity was incorporated in 2004) by T. Andrew Crockett and experts from Harvard Medical School. The company began as an ophthalmology-focused entity, targeting Diabetic Macular Edema (DME). The team focused on small-molecule protease inhibitors. Their early lead candidate, KVD001, was an intravitreal injection designed to block plasma kallikrein in the eye. In November 2016, KalVista went public on the NASDAQ via a reverse merger with Carbylan Therapeutics.

As the company advanced its protease platform, it became clear that their oral kallikrein inhibitors had massive potential for systemic diseases like Hereditary Angioedema. They began developing KVD900 (now sebetralstat) for acute attacks and KVD824 for prophylaxis. In 2019, the DME program (KVD001) failed its Phase 2 trial. Shortly after, the prophylaxis candidate (KVD824) faced a temporary FDA clinical hold and was eventually terminated in 2022 due to liver enzyme elevations. Following these setbacks, KalVista pivoted entirely to HAE, focusing all resources on sebetralstat (an oral plasma kallikrein inhibitor) as a potential paradigm shifter for on-demand care.

The strategy to focus on oral on-demand treatment proved successful, addressing a major unmet need for patients who wanted to avoid injections during an attack. In February 2024, KalVista announced positive topline results from the pivotal Phase 3 KONFIDENT trial. The data showed that sebetralstat significantly reduced time to symptom relief compared to placebo (p < 0.001). The primary endpoint for KONFIDENT was the ‘time to beginning of symptom relief’ defined as at least “a little better” at two consecutive time points within 12 hours of first dose administration, assessed using a seven-point scale Patient Reported Global Impression of Change (PGI-C) ranging from “much worse” to “much better”. A total of 71 out of 93 (76%) patients administered sebetralstat 600 mg and 41 out of 84 (49%) patients administered placebo achieved the primary endpoint. The median time to beginning of symptom relief within 12 hours of first dose was 2.0 hours (95% CI: 1.5, 2.8) in patients administered sebetralstat 600 mg.

On July 3, 2025, the FDA approved Ekterly (sebetralstat) for the on-demand treatment of HAE in patients aged 12 and older. By late 2025 and early 2026, the drug received approvals in the EU, UK, Switzerland, and Japan, establishing KalVista as a global commercial-stage rare disease company.

On March 25, 2026, KalVista reported its financial results for the eight-month transition period ending December 31, 2025. The report highlights the successful commercial launch of Ekterly, the first oral on-demand treatment for HAE. The company generated $49.1 million in global net product revenue during the eight-month period following the U.S. launch on July 7, 2025. KalVista received a cumulative 1,702 patient start forms in the U.S. through February 2026, representing approximately 20% of the U.S. HAE patient population, according to the company.

KalVista also announced that they had completed enrollment for the open-label Phase 3 KONFIDENT-KID trial for children aged 2–11. In this demographic, the trauma of needles often leads to dangerous treatment delays. Currently, the only approved on-demand treatment for this age group in the U.S. is intravenous. Sebetralstat aims to be the first oral on-demand option, reducing the burden and anxiety associated with injections.

Less than a week later on March 30, 2026, KalVista reported interim findings in the KONFIDENT-KID trial (ages 2–11), which utilized a proprietary weight-based oral disintegrating tablet (ODT) formulation. As of December 15, 2025, data from 172 HAE attacks in 33 participants showed:

• Rapid Treatment: The median time to treatment was 25 minutes, with 67% of attacks treated within the first hour.

• Symptom Relief: In the largest cohort (150 mg dose), the median time to symptom relief was 1.5 hours, and complete resolution was achieved in 12 hours.

• Safety: In this interim analysis of the KONFIDENT-KID trial, sebetralstat was well tolerated, with no reports of serious or treatment-related adverse events observed among participants to date and no difficulty swallowing the ODT.

KalVista expressed plans to submit a New Drug Application (NDA) in the U.S. in Q3 2026, with a company-projected launch in 2027, subject to FDA clearance. A little more than a month later on April 29th, 2026, KalVista and Chiesi Group announced their acquisition agreement. Chiesi Group’s acquisition of KalVista was primarily motivated by a strategic objective to expand its global rare disease portfolio. They viewed Ekterly as a “differentiated” therapy that provides a potentially foundational advancement in HAE management by enabling earlier intervention and reducing the overall treatment burden. The Chiesi team cited Ekterly as being a potential “a key driver in helping Chiesi reach its 2030 strategic revenue target of €6 billion”, suggesting that they were impressed with its launch performance. Lastly, they signaled its role in “expanding [their] commercial infrastructure and market presence in the United States”.

Conclusion

From Dr. Osler’s first observations in 1888 to the molecular discovery of the C1-inhibitor in a Cleveland lab, the story of HAE has always been one of “missing brakes.” KalVista’s journey, from its early pivots in ophthalmology to the successful launch of the first oral on-demand therapy, adds the latest chapter to that history. For many, the therapeutic landscape is shifting away from complex infusions toward the option of an oral tablet. It is a fitting conclusion to KalVista’s independent chapter and a promising hope for HAE patients.

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Introduction

For centuries, the human body has served as a canvas for demonstrating wealth, survival, and social status, shifting from the celebrated curves of the Renaissance to the digitally-perfected thinness of the modern era. But beneath these changing cultural silhouettes lies a complex biological machinery that the world is only just beginning to understand. In Part 1 of our two-part series on obesity, we trace the evolution of obesity from a perceived moral failing to a recognized chronic disease, explore the hormones that govern our weight, and share the genetic breakthroughs that are finally rewriting the willpower myth.

In Part 2, we explore the evolution of obesity treatments and how the field climbed out of a century-long dark age and emerged into the current golden age.

The Weight of Society

The perception of body weight in Western society has undergone a dramatic and complicated transformation, shifting from a celebrated symbol of survival and wealth to a modern marker of health and self-discipline. Historically, this evolution is often summarized as a move from “large as high status” to “thin as high status.”

For most of human history, excess body weight was rare and often seen as a sign of wealth and vitality. Artifacts like the Venus of Willendorf (dated approx. 25,000 BCE) suggest that larger bodies were associated with fertility and the ability to survive food scarcity. In the Renaissance and Baroque periods, artists like Peter Paul Rubens (1577–1640) painted full-figured women as the pinnacle of beauty, leading to the term “Rubinesque”. High body fat signaled that a person was wealthy enough to avoid manual labor and afford a rich diet. In Europe, being portly remained a marker of the elite. However, religious texts occasionally framed gluttony as a moral failing, beginning a long history of social stigma.

Before the 20th century, most clothes were tailor-made or adjusted at home. The rise of Ready-to-Wear clothing changed the human relationship with size. For the first time, people had to fit into standard sizes rather than clothes being made to fit them. If a garment didn’t fit, the fault shifted from the tailor to the wearer’s body. At the turn of the century, the ideal was still somewhat robust, epitomized by the “Gibson Girl”, a representation of the feminine ideal as depicted in illustrations of artist Charles Dana Gibson. The most distinctive feature of the look was the S-bend corset. Unlike previous corsets that squeezed the waist evenly, the S-bend pushed the chest forward and the hips back. The corset cinched the waist dramatically, creating a sharp contrast between the full bust and the flared hips. The Gibson Girl look would dominate American fashion and social ideals from the 1890s to the early 1910s.

The 1920s saw one of the most drastic shifts in the history of the Western female silhouette. Following World War I, women dropped the restrictive corset in favor of a straight, tubular look. This silhouette, characterized by a flat chest, dropped waist, and straight lines, was fueled by a desire for liberation after the constraints of WWI. To achieve this, women began binding their chests and dieting aggressively to maintain a youthful frame. The burgeoning film industry began exporting this specific aesthetic globally. On-screen stars like Clara Bow became the visual blueprint for what modernity looked like. The tubular look allowed for freedom of movement. Bow, known for her kinetic screen presence, showed women that fashion didn’t have to be restrictive; you could dance the Charleston and move freely.

While the 1950s celebrated a curvier ideal (Marilyn Monroe), this was often a managed curviness, a tiny waist achieved through shapewear. Fashion models like Dovima or Suzy Parker were elegant, mature, and possessed womanly “New Look” silhouettes. By the 1960s, the ideal moved from slim to extremely thin. In 1966, the model Lesley Lawson, nicknamed Twiggy, arrived on the scene. Twiggy was only 16 when she became a global sensation. Her frame, which was naturally 5’6” and roughly 91 lbs, represented a radical departure from the hourglass. Her look coincided with the rise of the miniskirt. Leggy, angular thinness became a requirement for the new fashions coming out of London’s Carnaby Street.

The 1970s and 1980s introduced a slightly more athletic version of the thin ideal, but it remained geographically and socioeconomically exclusive. Models like Christie Brinkley and Elle Macpherson (nicknamed “The Body”) promoted a look that was tall, tanned, and fit. While this looked “healthier” than Twiggy, it was actually harder to achieve for the average person. It required a combination of extreme thinness plus muscle tone, a look that required significant time and money spent at the newly popular aerobics studios and gyms. High-fashion designers like Karl Lagerfeld (Chanel) and Gianni Versace began designing clothes that were increasingly narrow, cut specifically for the 5’10”, size 0-2 frame of the Supermodel.

The 1990s saw a reversion to ultra-thin ideals. Kate Moss became the face of this movement. Unlike the 5’11” Amazonian supermodels of the previous decade, she was shorter (5’7”) and possessed a much more delicate look that felt accessible yet elite. The goal was an angular, hanger-like frame. Clothes were often slip dresses or oversized knits that hung loosely off the body, emphasizing thinness by showing how much space was left in the garment. The fashion of this era didn’t exist in a vacuum; it was heavily tied to the grunge music scene emerging from the Pacific Northwest (Nirvana, Pearl Jam). The aesthetic celebrated a lack of grooming. Pale skin, unwashed hair, and dark circles under the eyes were seen as authentic and anti-establishment. In this context, being extremely thin was a way to look like you didn’t care about the mainstream fitness or wellness culture of the 80s. It was a visual rejection of the California tan and the aerobics body.

By the late 1990s, this look became so pervasive that it sparked a massive public health debate. Nutritionists and doctors raised alarms that the “minimalist waif” look was unattainable for most healthy adults and was contributing to a rise in eating disorders. In response to the criticism, the fashion industry slowly began to shift back toward a more athletic “Brazilian” look (led by Gisele Bündchen in the early 2000s), though the baseline for sample size thinness remained much lower than it had been in the 1950s.

The 2000s pushed the thin ideal into the mainstream through the handiwork of Alexander McQueen, then head designer of Givenchy. McQueen first introduced the “Bumster” look in his 1993 Taxi Driver collection and refined it in 1996’s Dante. His goal wasn’t actually about being “sexy” in a traditional sense; he wanted to elongate the spine. By dropping the waistline to the very top of the hip bone, he shifted the visual focus from the waist to the base of the spine. However, when this look trickled down into 2000s mainstream retail resulting in the “Y2K look”: ultra-low-rise jeans and midriff-baring tops that made the stomach and hips the primary area of scrutiny. This created a cultural anxiety around even minor amounts of body fat on the hips and lower abdomenal area, leading to the derogatory term “muffin top.” Professional retouchers used Photoshop to slim down models in magazines. The public knew these images were altered, but they were still the only images available.

The 2010s marked a dramatic pivot away from the thin ideal. As Instagram (launched in 2010) became the dominant cultural force, the flat silhouette of the previous decades was replaced by a hyper-curvaceous ideal. This decade popularized a very specific silhouette: a tiny waist and flat stomach (the “skinny” legacy) paired with exaggerated hips and a large butt (the “curvy” addition). The middle of the decade saw the rise of “Fitness Inspiration” or “Fitspo.” Thinness was rebranded as strength. Being toned became the new requirement, meaning that not only did one have to be low-weight, but they also had to have visible muscle definition.

The history of weight is a narrative of shifting signals, where the human body has served as a canvas for demonstrating everything from economic prosperity and survival to moral discipline and social status. For centuries, the robust figure was a celebrated symbol of the elite’s abundance, yet the industrialization of the 19th century and the rise of statistical “averages” began a slow march toward the pathologization of body mass. This transformation accelerated in the 20th and 21st centuries, as thinness was rebranded first as a marker of youthful rebellion, then as an indicator of financial wellness, and finally as a digitally-perfected aesthetic that often ignored biological reality. This complex legacy, a mixture of actuarial math, fashion extremes, and socioeconomic signaling, has created a modern paradox: society continues to treat weight as a personal choice and a visual status symbol, even as clinical science increasingly recognizes obesity as a complex, chronic disease driven by metabolic, genetic, and environmental factors rather than simple willpower.

Obesity, Disease or Distraction?

Hippocrates was among the first to recognize obesity as a medical concern, noting that “sudden death is more common in those who are naturally fat than in the lean.” He prescribed exercise and specific diets, though the focus remained largely on “humoral” balance. In the 18th century, conditions like gout (associated with rich foods) were seen as “the disease of kings,” almost a status symbol among the aristocracy. So, how did the medical establishment start to formally recognize obesity as a disease?

It began with the modern medical quantification of weight. Adolphe Quetelet was a 19th-century Belgian mathematician, astronomer, and statistician and is often considered one of the founding fathers of modern sociology. Quetelet was fascinated by the application of probability and statistics to human characteristics. He believed that human traits, both physical and moral, followed a normal distribution (the “Bell Curve”). In the 1830s, Quetelet began analyzing data from French and Scottish soldiers to determine how body weight related to height. He observed several key patterns:

• Non-Linear Growth: He realized that weight does not increase in a 1:1 ratio with height (linear). If it did, tall people would be impossibly thin and short people would be impossibly wide.

• The Square Law: Through his observations, he determined that after the initial growth spurt of puberty, “the weight increases as the square of the height.”

With these ratios in hand, Quetelet coined the Quetelet Index, or what we now refer to as the Body Mass Index (BMI). Body Mass Index (BMI) is a numerical value derived from the weight and height of an individual. It is widely used as a screening tool to categorize whether a person is at a healthy weight for their height.

In the early 20th century, life insurance companies faced a problem: they needed a way to predict when people would die to set profitable premiums. They looked back at Adolphe Quetelet’s work and realized his Quetelet Index (the term “BMI” hadn’t yet been coined) was the most efficient way to categorize large groups of people. In 1942, Louis Dublin, a statistician for the life insurance company Metropolitan Life, used Quetelet’s concepts to create the first “Ideal Weight” tables. These tables weren’t based on how people looked, but on mortality data. In this care, “ideal” simply meant the weights associated with the lowest mortality rates among policyholders. To account for the variability that Quetelet’s math ignored, the industry invented the categories of “Small,” “Medium,” and “Large” frames, though they never actually provided a scientific way to measure someone’s frame.

By the 1950s, the insurance industry had data tables, but they lacked a clinical “seal of approval.” This is where Ancel Keys entered the picture. Keys was a physiologist famous for the Seven Countries Study, the first major study to examine how dietary patterns and lifestyle affect cardiovascular disease across different nations and cultures. He wanted to study heart disease but needed a simple way to measure largeness in thousands of participants without using expensive lab equipment. Keys tested various formulas against actual body fat measurements (using skinfold calipers and underwater weighing). He found that Quetelet’s 140-year-old index was the most accurate proxy for body fat percentage. In a landmark paper published in 1972, Keys officially dubbed the formula the Body Mass Index (BMI). He explicitly stated it was better than the insurance tables because it was purely mathematical and didn’t rely on the vague “frame sizes” the insurance companies used.

Nevertheless, most medical institutions in the first half of the 20th century viewed weight as a statistical risk factor, not a disease in itself. Medical consensus often mirrored societal bias, treating excess weight as a symptom of poor discipline or a deficit in character. Since the data came from insurance companies rather than biological labs, doctors often focused on the consequences (diabetes, heart disease) rather than the cause. If a patient didn’t have a secondary condition, they weren’t considered sick.

The shift toward viewing obesity as a disease was driven by a move from epidemiological observation (seeing that heavy people died sooner) to biological explanation (understanding why the body resists weight loss and how excess weight increases the risk of mortality). Large-scale studies provided the first undeniable link between excess weight and mortality. The Framingham Heart Study (FHS) was one of the most significant and longest-running epidemiological studies in medical history. The study set out to identify the common factors or characteristics that contribute to cardiovascular disease by following 5,209 adult residents of Framingham, Massachusetts who had not yet developed overt symptoms of heart disease or suffered a heart attack or stroke. By examining their bloodwork for over nearly 80 years and correlating it with clinical outcomes, researchers could pinpoint the risk factors that were associated with higher incidence of heart attack or stroke over the average person’s lifetime. The first official publication describing the Framingham Heart Study was published in March 1951 in the American Journal of Public Health. It was one of the first studies to prove that obesity was a direct, independent risk factor for cardiovascular disease. It showed that even if a person didn’t smoke or have high cholesterol, excess weight alone significantly shortened lifespan.

Nevertheless, there was a 34-year chasm between Framingham Heart Study’s first publication and recognition of obesity as a disease by major medical institutions. This occurred for a few reasons:

• The belief that obesity would “fix itself”: In the 1960s and 70s, the medical focus was almost entirely on smoking cessation and managing blood pressure. Obesity was seen as a “secondary” concern that would naturally resolve if patients just followed the emerging (and now heavily scrutinized) “Food Pyramid” guidelines. There was no recognized medical specialty for obesity and most doctors felt unequipped to treat weight. They often viewed dieting as something that happened in the home or at commercial clubs like Weight Watchers (founded in 1963), not in a clinical setting.

• The industrialization of food: The 1950s through the 1970s saw a massive shift in the American food landscape that outpaced medical policy. High fructose corn syrup (HFCS) began first entered the American food supply in 1967 by the Clinton Corn Processing Company. When the price of cane sugar skyrocketed in 1974 due to a global double-crop failure (European Beet Failure, Cuban Drought) and the sunsetting of the Sugar Act of 1937, manufacturers increasingly turned to HFCS. By the 1990s, HFCS was in almost everything, from bread and yogurt to salad dressings and infant formula. By 1999, the average American consumed roughly 63 pounds per year, up seven-fold from 9 pounds per year in 1977. As the food supply became increasingly industrialized, the average weight began to climb. Medical institutions initially responded with a “blame the patient” approach.

• The absence of a biological mechanism: Until the mid-1980s, the prevailing scientific belief was that the human body was a simple “Calorie In, Calorie Out” machine. Without a clear biological mechanism to explain why some people struggled more with weight than others, there was no medical way to intervene.

By the mid-1980s, the pressure to recognize obesity became undeniable. The skyrocketing costs of treating Type 2 diabetes and heart disease (risk factors associated with obesity) began to threaten the stability of the healthcare system. Furthermore, thirty years of Framingham data and subsequent studies like the National Health and Nutrition Examination Survey (NHANES) suggested that the obesity epidemic was not an individual failure but a population-wide trend. NHANES II (1976–1980) showed a sudden and dramatic spike in the average American’s weight compared to NHANES I (1971–1974). This proved that the issue was not just a few “unmotivated” individuals, but a population-wide shift.

The National Institutes of Health (NIH) was one of the first major federal bodies to sound the alarm, though their initial stance was more about “risk” than “disease.” At the 1985 Consensus Conference, the NIH convened a panel that concluded obesity is a “disease” in the sense that it is a condition that impairs health. However, the report was cautious, focusing heavily on the association with other diseases like diabetes and hypertension.

Thirteen years later in 1998, the NIH released the first federal clinical guidelines based on BMI. By standardizing the BMI categories (25.0-29.9 for overweight; ≥30.0 for obesity), they effectively medicalized the condition for millions of Americans overnight. The NIH’s shift was driven by the desire to move clinical practice toward evidence-based weight management.

Despite the NIH’s shifting stance, the Medicare Coverage Issues Manual explicitly stated that “obesity is not considered a disease” until 2004, which acted as a total barrier to any form of treatment coverage. The change occurred, when the Centers for Medicare & Medicaid Services (CMS) officially removed that sentence from its manual. Following this, Medicare began covering certain intensive behavioral therapy (IBT) sessions and FDA-approved bariatric surgical procedures for patients meeting specific BMI and comorbidity thresholds. As of today (April 2026), Medicare still does not cover medications specifically for chronic weight management. This is not due to a clinical decision by CMS, but rather a statutory restriction. When the Medicare Part D prescription drug benefit was created in 2003, the law included a list of excluded drugs. This list specifically prohibited coverage for agents used for weight loss, anorexia, or weight gain. At the time, weight-loss drugs were often viewed more as “lifestyle” or “cosmetic” interventions rather than essential medicine. Medicare can cover these same medications if they are FDA-approved to treat a different condition that is not weight loss. For example, if a GLP-1 (Ozempic, Mounjaro) is prescribed to treat Type 2 diabetes or to reduce the risk of major adverse cardiovascular events (MACE) in adults with established heart disease, it may be covered.

The most significant turning point came in June 2013, when the American Medical Association (AMA) House of Delegates voted to recognize obesity as a disease. This was a rebellion against the AMA’s own Council on Science and Public Health. The Council actually recommended against the move, arguing that BMI was a flawed metric and that “disease” implies a specific pathology that wasn’t consistently present in everyone with a high BMI. Proponents argued that the willpower model had failed for decades. They insisted that by labeling it a disease, they would reduce social stigma, increase funding for research, and force insurance companies to cover treatments. The delegates overrode the council, officially declaring that obesity involves “multiple pathophysiological aspects” including genetic, environmental, and endocrine factors.

Once the AMA moved, other major global institutions followed, though with varying degrees of nuance. In 2017, the World Obesity Federation pushed the definition further, arguing that obesity fits all the criteria of a disease: it has a known cause (energy imbalance), characteristic signs/symptoms, and leads to harm. In 2021, the European Commission finally recognized obesity as a “chronic relapsing disease,” which paved the way for better access to care across the EU.

Even with these recognitions, the debate remains alive in the medical community today around two main points:

• The Flaw of BMI: Many doctors argue that using BMI as the sole diagnostic tool for a “disease” is scientifically unsound, as it ignores muscle mass and metabolic health.

• The Stigma Paradox: Some advocates worry that the “disease” label takes away a person’s sense of agency, while others argue it is the only way to get the medical system to take the condition, and the patient, seriously.

Hormones In, Hormones Out

The transformation of obesity from a lifestyle issue to a biological disease was driven by the discovery of an invisible signaling system, a hormonal conversation between the stomach, fat tissue, and the brain. For decades, we believed the body was like a bucket; if you poured in more calories than you leaked out, you got heavier (“calories in, calories out”). These discoveries proved the body actually has a biological thermostat that fights to maintain a body weight set point.

It all started in 1949 at the Jackson Laboratory in Bar Harbor, Maine, the world’s premier center for mouse genetics. A research technician named Margaret Dickie was working in a colony of mice when she noticed something bizarre. Two siblings in a litter were rapidly becoming much larger than their cage mates. By the time these mice were a few weeks old, they were roughly three times the weight of their normal siblings. They were round, lethargic, and possessed an insatiable appetite. Researchers realized this was a spontaneous genetic mutation because the trait only appeared if both parents carried the hidden gene. The scientists used cross-breeding experiments to determine that it was a recessive mutation (mice needed both copies of the gene to have the obese phenotype) and they labeled the hypothetical gene as ob (for obese).

Before this accident, scientists had no reliable way to study the biology of weight. Humans were too genetically diverse and their environments were too varied to control for. The ob/ob mouse provided two valuable insights:

• Genetic Uniformity: Every ob/ob mouse was genetically identical, allowing researchers to isolate weight as the only variable.

• A Biological Driver: It proved that an error in the genetic code could override all other behaviors. These mice weren’t choosing to overeat, so much as their biology was forcing them to.

While the mice were discovered in 1949, the mechanism by which mutations in the ob gene caused obesity remained a mystery for nearly half a century. Scientists spent decades trying to figure out what that single ob gene was supposed to do. Some thought the mice had a slow metabolism; others thought their stomachs were simply larger.

It wasn’t until Douglas Coleman’s parabiosis experiments in the 1960s that researchers realized the ob/ob mice were missing a signal in their blood. In these parabiosis experiments, Coleman physically joined the circulatory systems of the ob/ob mice to a healthy mouse. He noticed that the ob/ob mouse stopped overeating and lost weight. This proved that the healthy mouse was sending a satiety factor through the blood that the ob/ob mouse was missing.

In 1986, Dr. Jeffrey Friedman at Rockefeller University set out to find the specific gene responsible for the ob/ob mutation. He used a technique called positional cloning, which is essentially looking for a needle in a haystack by slowly narrowing down the location on the chromosome. Dr. Friedman’s team spent eight years mapping the mouse genome. They slowly narrowed the search from an entire chromosome down to a specific region containing several hundred genes. In 1994, they identified a gene that was expressed only in adipose tissue (fat cells). In the ob/ob mice, this gene was mutated and broken, meaning they couldn’t produce the protein it coded for. Once the gene was isolated, Dr. Friedman’s team used it to produce the protein in a lab. They named it leptin, from the Greek word leptos, meaning “thin.” When they injected the synthetic leptin protein back into the ob/ob mice, the effect was staggering. The mice, which had previously been obsessed with food, suddenly lost their appetite. Their metabolic rates increased, and they shed the excess fat rapidly. Dr. Friedman then showed that humans also have the ob gene and produce leptin (LEP). This proved that the weight-regulation system seen in mice was a fundamental part of human biology.

Dr. Friedman’s discovery shattered the thermodynamic view of obesity that more “calories in” than “calories out” was an easy goal to accomplish through sheer force of will. Instead, obesity was in part a neuroendocrine disease that results from broken hormone signaling. His findings established three scientific pillars:

• Adipose is an Endocrine Organ: It proved fat isn’t just storage; it is a vital organ that talks to the brain.

• The Biological Set Point: It explained why dieting is so hard. When you lose fat, your leptin levels drop, and your brain thinks you are starving, triggering intense hunger to return you to your body weight set point.

• Leptin Resistance: While Friedman initially hoped leptin would be a treatment, he discovered that most people with obesity have high leptin levels. Their brains have become resistant to the signal, much like a type 2 diabetic is resistant to insulin.

Dr. Friedman’s cloning of the gene encoding leptin (LEP) in 1994 triggered a flurry of activity in obesity genetics, where researchers used positional cloning, a tedious process of mapping where a a gene’s location on a chromosome without knowing what the gene actually does. In 1995, researchers cloned the leptin receptor gene (LEPR) responsible for the db/db mouse, proving it was the receiver for the leptin signal. In 1997, using candidate gene approaches (looking at genes already known to be involved in brain signaling), researchers identified mutations in children with severe obesity, red hair, and adrenal insufficiency (POMC) or severe digestive issues (PCSK1). The following year in 1998, scientist identified the gene encoding the Melanocortin-4 receptor (MC4R) as the end-point for satiety signals in the brain. When they screened patients with extreme early-onset obesity, they found the mutations.

While Dr. Jeffrey Friedman’s 1994 discovery of leptin identified the “brakes” of the energy system, the scientific community was still hunting for the “gas pedal.” In 1999, Dr. Masayasu Kojima and his team at the Kurume University School of Medicine in Japan finally identified ghrelin, the first (and only) known hormone that signals the brain to start eating. Kojima’s discovery was a masterclass in reverse pharmacology, relying heavily on synthetic molecules created by pharmaceutical companies years earlier.

The story starts with scientists trying to create a better medicine, not trying to find a new hormone. In the late 1970s, researchers at the pharmaceutical company Merck were experimenting with small, synthetic molecules to see if they could trigger the release of Growth Hormone (GH). They eventually created a class of drugs called Growth Hormone Secretagogues (GHS). These worked incredibly well in the lab, but they were entirely man-made; they didn’t exist in nature. By the mid-90s, gene-mapping technology had advanced significantly. Scientists at Merck, led by Andrew Howard, decided to work backward. They took these synthetic GHS drugs and used them as bait to see what protein they were sticking to in the brain. They successfully isolated a specific protein on the surface of cells in the pituitary gland and hypothalamus, two regions in the brain. When the synthetic drug contacted this protein, the cell reacted. They found the gene that coded for this protein and named it the GHS Receptor (GHS-R).

At this point, they had a receptor that responded perfectly to a synthetic hormone (the Merck drugs). However, evolution doesn’t build receptors for synthetic hormones. This meant there had to be a natural, biological hormone already inside the human body that usually turned that lock. In biology, a receptor with no known natural partner is called an orphan receptor. From 1996 to 1999, the GHS-R was one of the most famous orphan receptors in science. Everyone knew it was there, and they knew it probably controlled hunger and growth, but they couldn’t find the source of the hunger signal.

This is where Dr. Masayasu Kojima stepped in. Instead of looking for a hormone and then finding what it did, he used the receptor as a hook and went fishing for the hormone. He created a tester cell line that had the GHS-R receptor on its surface and a calcium-sensitive fluorescent dye. If any substance touched the receptor and activated it, the cell would immediately release calcium and glow. He then took crude extracts from various rat tissues (stomach, brain, heart, etc.) and poured them over these tester cells. When he poured the extract from the stomach, the cells lit up. To isolate the specific hormone, Dr. Kojima used High-Performance Liquid Chromatography (HPLC) to filter the stomach extract into so-called fractions, different mixtures containing molecules with different sizes, charges, and hydrophobicites (how much they repel water). He repeated this process over and over, changing the chemical conditions each time, until he had a single, pure peak on his mass spectrometry graph, a single protein substance that consistently activated the GHS-R receptor. That molecule turned out to be a 28-amino acid peptide that he named ghrelin. Dr. Kojima even identified a unique structural characteristic of the stomach-derived hormone. His mass spectrometry graph showed a mystery mass attached to the third amino acid in the chain. He realized a fatty acid called n-octanoic acid was hanging off the side of the hormone. This fatty acid tail is what allows ghrelin to cross the blood-brain barrier and hit the receptor. Without that specific oily tail, the hormone would be locked out of the brain and never reach its receptor.

Dr. Masayasu Kojima and his colleagues published their groundbreaking discovery of ghrelin in the prestigious scientific journal Nature on December 9, 1999. The paper was revolutionary because it fundamentally changed how we understand the gut-brain axis. The key takeaways included:

• The First Hunger Hormone: It identified the first (and still only) known hormone produced in the periphery (the stomach) that travels to the brain to directly stimulate hunger.

• The Orphan Solution: It solved the 3-year mystery of the GHS Receptor (the “lock”) by providing its natural “key.”

• Chemical Uniqueness: It revealed that ghrelin requires a specific fatty acid (n-octanoic acid) to function, a chemical modification that was previously unheard of in mammalian hormones.

• Revealed the Enteroendocrine System: It proved that the stomach, an organ previously thought of only for digestion, was actually a critical part of the endocrine system, regulating both growth hormone levels and energy balance.

The publication of this paper is often cited as the definitive end of the willpower-only era of weight management, providing the final biological proof needed for medical institutions to begin categorizing obesity as a complex metabolic disease.

The next quantum leap forward in obesity genetics was ushered in by the Human Genome Project, an international scientific research collaboration aimed at mapping the DNA sequence of the average human. The identification of the FTO gene was the first major success of the Genome-Wide Association Study (GWAS), a research approach that correlates genetic variations (genotype) with a particular disease or trait (phenotype). Researchers scanned the DNA of 38,000 people. They didn’t have a guess or a candidate, the computer simply flagged a specific region on Chromosome 16 (FTO) that was consistently different in people with higher BMIs. As computers got faster and biobanks (like the UK Biobank) grew to 500,000+ people, researchers discovered TMEM18, NEGR1, and over 1,000 other loci. These were found by comparing the full genomes of hundreds of thousands of people to find the signal in the noise.

Today, genetic obesity is typically categorized by how hard-coded the weight gain is. As of 2026, we categorize these genes into three distinct buckets:

• Monogenic (single-gene)

• Syndromic (part of a larger syndrome)

• Polygenic (thousands of small variants)

Monogenic obesity is caused by mutations in one gene in the Leptin-Melanocortin Pathway. These are rare, highly penetrant mutations. If a person has a defect in these genes, severe, early-onset obesity is almost guaranteed, regardless of diet or exercise.

Syndromic obesity is caused by mutations that lead to multi-system disorders. In these cases, obesity is a hallmark feature, but it is accompanied by other symptoms like intellectual disability, vision loss, or organ malformation. They include:

• PWS (Prader-Willi Syndrome): Caused by a loss of expression in the 15q11.2–q13 region on the paternal chromosome. The loss of these paternal genes causes structural and functional defects in the hypothalamus. In a healthy brain, the hypothalamus balances “hunger” signals (AgRP/NPY neurons) and “satiety” signals (POMC neurons). The loss of key genes in PWS patients cause the brain to behave as if the body is in a state of constant, severe starvation. The condition is famously associated with hyperphagia, an insatiable and life-threatening hunger.

• BBS (Bardet-Biedl Syndrome): Linked to mutations in at least 21 genes (e.g., BBS1, BBS10). It is a ciliopathy, where the tiny hairs on cells (cilia) in the hypothalamus (the brain’s appetite control center) can’t sense hormones properly.

• Albright’s Hereditary Osteodystrophy: Mutations in the GNAS gene leads to obesity, short stature, and bone formation in unusual places.

Polygenic obesity accounts for relatively less severe phenotypes that don’t cause obesity in most cases, but nevertheless increase the susceptibility to developing obesity. These were largely discovered through the GWAS studies and include:

• FTO (The “Fat Mass” Gene): The most famous GWAS hit. It influences whether your body stores energy as white fat or burns it as beige/brown fat.

• MC4R (Common Variants): While rare mutations cause monogenic obesity, common small variations in MC4R contribute to the weight of millions of people.

• TMEM18 & NEGR1: Highly expressed in the brain; they influence synaptic plasticity and how your brain “wires” its hunger cues.

• KCNMA1: A more recent addition to the GWAS catalog (highlighted in 2026 data) that influences neuronal excitability and energy intake.

While these genetic factors teach us how body weight set points work, <5% of cases of obesity have monogenic & syndromic roots. The vast majority of obesity cases, the remaining 95%, are polygenic. This means there isn’t one broken gene, but rather hundreds or thousands of tiny variations (SNPs) that cumulatively increase a person’s risk of obesity. While genetics accounts for one contributing factor for how our bodies manage energy, the disease is typically a mixture of factors, including biological predispositions, environmental influences (such as the availability of ultra-processed foods), socioeconomic conditions, and lifestyle habits.

Conclusion

The history of obesity is a narrative of shifting mirrors. For centuries, we looked at the scale and saw a reflection of our character, our status, or our self-discipline. But as we have moved from the artistic curves of the Renaissance to the precise mapping of hormones the regulate hunger and obesity-related genes, that mirror has been replaced by a microscope. The discovery of leptin and ghrelin didn’t just provide us with new biological vocabulary; it fundamentally reclassified obesity as a neuroendocrine struggle, a war between a modern environment and an ancient, survival-focused thermostat. We now know that for many, the body weight set point is less of a choice, and more of a genetic and hormonal blueprint.

However, understanding the biology was only half the battle. While science spent the late 20th century uncovering the ‘why’ of weight, the medical world was simultaneously struggling with the ‘how’ of treatment, navigating a dark age of dangerous pills and failed interventions.

Stay tuned for Part 2, where we explore the evolution of obesity treatments and how the field climbed out of a century-long dark age and emerged into the current golden age of GLP-1s.

To contact us, please send us an email at biotechreadout@gmail.com

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Introduction

On April 27, 2026, Eli Lilly and Company announced a definitive agreement to acquire Ajax Therapeutics for up to $2.3 billion in cash, inclusive of an upfront payment and subsequent payments upon the achievement of certain clinical and regulatory milestones. This acquisition centers on Ajax’s lead program AJ1-11095, a small molecule JAK2 inhibitor currently in a Phase 1 clinical trial called AJX-101 (NCT06343805). Eli Lilly emphasized that the primary value-add for AJ1-11095 is its ability to selectively bind and inhibitor the Type II conformation of JAK2, whereas other JAK inhibitors typically bind its Type I conformation. This could potentially provide two points of differentiation:

1. Provide a novel treatment option for those patients who become resistant to Type I JAK2 inhibitors. This is currently being evaluated in the Phase 1 AJX-101 trial, which has recruited patients with myelofibrosis who have previously been treated with a Type I JAK2 inhibitor.

2. Deliver deeper and more durable efficacy than existing JAK2 inhibitors. This hypothesis isn’t yet being evaluated in a clinical trial.

Myeloproliferative neoplasms (MPNs) like myelofibrosis (MF) and polycythemia vera (PV) already constitute a blockbuster indication space, representing an aggregate revenue run rate of more than $6.6 billion per year and growing 13% year over year as of 4Q 2025 according to quarterly press releases associated with Jakafi/Jakavi, Ojjaara/Omjjara, Vonjo, and Inrebic*. Despite this, the competitive field is relatively sparse compared to other indication spaces with 4 approved medicines and 9 in clinical development.

If executed, the proposed Ajax acquisition would constitute the largest acquisition in the MF space to date ($2.3B versus $1.9B for Sierra Oncology, $1.4B for Imago Bioscience, and $600M for MorphoSys).

Here, we dive into the history of myelofibrosis, polycythemia vera, and JAK inhibitors and also explore how Ajax Therapeutics’ lead program could advance the cutting edge of treatment.

Double, Double Toil and Trouble

The discovery and clinical classification of myelofibrosis (MF) and polycythemia vera (PV) span over 150 years, evolving from isolated case observations in the 19th century to the unified molecular understanding we have today. Before they were understood as related blood cancers, PV and MF were described as distinct, puzzling medical anomalies.

The first definitive description of what we now call primary myelofibrosis is credited to the German physician Dr. Gustav Heuck. In 1879, he detailed two cases of leukemia that were atypical because they featured significant bone marrow scarring (fibrosis) and massive enlargement of the spleen and liver (extramedullary hematopoiesis). The disease manifests in a debilitating clinical profile that includes splenomegaly (massive splenic enlargement due to extramedullary hematopoiesis), constitutional symptoms (severe fatigue, night sweats, and bone pain), cytopenias (progressive anemia and compromised marrow function), and reduced survival.

The French physician Dr. Louis Henri Vaquez provided the first description of PV. He observed a 40-year-old male patient with chronic cyanosis (bluish skin), distended veins, and a massive red blood cell count. In 1903, the renowned Dr. William Osler published a series of similar cases, further cementing the condition in medical literature, which was sometimes referred to as “Vaquez-Osler disease.”

For decades, these conditions were treated as separate diseases. The turning point came in 1951, when Dr. William Dameshek, a founding editor of the journal Blood, published a seminal editorial. He hypothesized that PV, MF, and chronic myeloid leukemia (CML) were not separate entities but rather different manifestations of the same underlying problem: a myelostimulatory factor causing the bone marrow to overproduce cells. Critically, he noted that these diseases often overlapped or transformed into one another. For instance, a patient with polycythemia vera might eventually develop “spent-phase” myelofibrosis. He grouped them under the umbrella term myeloproliferative disorders (MPDs).

The undiscovered stimulus Dr. Dameshek hypothesized in 1951 was finally identified more than half a century later. The discovery of the JAK2 mutation in 2005 is considered the Big Bang of modern hematology. It transformed myeloproliferative neoplasms (MPNs) from poorly understood clinical syndromes into molecularly defined blood cancers. In a rare occurrence in the scientific community, four independent research groups (led by teams in France, the UK, Switzerland, and the USA) published the discovery of the same mutation within a few months of each other. They identified a single point mutation in the Janus Kinase 2 gene (JAK2), specifically a substitution of phenylalanine for valine at codon 617 (JAK2^V617F), with each paper shedding additional light:

• The French Team (James et al. Nature): Demonstrated that the mutation induces cytokine-independent growth in cells, mimicking the disease’s hyperproliferative nature.

• The UK Team (Baxter et al. Lancet): Identified the mutation in 97% of PV patients and about half of those with ET and MF, confirming it as a common thread across Dr. Dameshek’s unified categories.

• The Swiss Team (Kralovics et al. NEJM): Noted the transition from heterozygosity (one copy) to homozygosity (two copies) in some patients, explaining why some cases (like PV) appear more aggressive than others.

• The US Team (Levine et al. Cancer Cell): Validated JAK2 as a drugable target, providing the first major evidence that inhibiting this specific protein could potentially treat the disease.

The breakthrough was enabled by a technological convergence. The human genome had been sequenced and high-throughput sequencing of the kinome (the set of all kinases) became possible. The story isn’t just that they found the same thing, but how the ‘V617F quartet’ each arrived at a related conclusion in different ways:

• The French Team: They used a bottom-up biochemical approach. They noticed that cells from PV patients grew even when you blocked every other growth factor except for the JAK-STAT pathway. They essentially followed the smoke until they found the fire at JAK2 codon 617.

• The Swiss Team: They used a top-down genetic approach called Uniparental Disomy (UPD) mapping. They looked at Chromosome 9, where they noticed many patients had two identical copies of a specific region from one parent (rather than one from each). They realized the “bad” mutation was likely hidden in that duplicated section and JAK2 was right in the middle of it.

• The UK Team: This was a clinical-genomic powerhouse effort. They screened hundreds of patient samples from the Cancer Genome Project, looking specifically at kinases already known to be involved in blood production.

• The US Team: They used a high-throughput sequencing screen of the tyrosine kinome. They systematically sequenced the most likely candidate genes across many patients until the JAK2^V617F mutation appeared as a glaring, repeated hit.

Before this discovery, the field of MPNs was relatively niche. Ross Levine (one of the US lead authors) famously noted that at the 2004 ASH (American Society of Hematology) annual meeting, the MPN session was held on a Tuesday morning in a small room with about 50 people. After these four papers were published in early 2005, the field exploded. By the 2005 ASH meeting, the sessions were packed into massive ballrooms with thousands of attendees.

In science, being “scooped” can be devastating for a career or a lab’s funding. Once it became clear that multiple groups were breathing down the neck of the same discovery, the journals (Nature, The Lancet, NEJM, and Cancer Cell) moved with uncharacteristic speed. Rather than one group winning and the others losing, the simultaneous publication acted as a global confirmation that the finding was robust and undeniably true. Since these groups published within weeks of each other, they are almost always cited together in scientific literature as a block, ensuring that all four teams receive credit for ushering in the era of precision medicine for blood cancers.

Following the 2005 JAK2 breakthrough, researchers hypothesized that if JAK2 was mutated, perhaps the receptors that JAK2 binds to were also mutated. In 2006, research groups at Broad Institute/Harvard and the Mayo Clinic published papers in PLoS Medicine and Blood identifying mutations in the Thrombopoietin Receptor (MPL). They found that a specific spot in the protein, tryptophan at position 515, was frequently mutated to leucine (W515L) or lysine (W515K). MPL is the receptor for thrombopoietin, the hormone that stimulates platelet production. The mutation changes the receptor’s shape so that it behaves as if it is constantly activated, even when no thrombopoietin is present. This keeps the JAK2 protein attached to it in a state of permanent activation. MPL mutations are rare, found in only 5-10% of MF and ET cases, and virtually never in PV.

In 2008, the World Health Organization (WHO) formally changed the name from “myeloproliferative disorders” to “myeloproliferative neoplasms” (MPNs), officially recognizing MF and PV as blood cancers. This reclassification was much more than a semantic update; it was a fundamental shift in how the medical community viewed these diseases. Before 2005, the term “disorder” was used because doctors weren’t entirely sure if these were true cancers or simply over-enthusiastic bone marrow reactions. Conditions like PV and ET were often seen as chronic, manageable issues that someone lived with, unlike the aggressive nature of acute leukemias. The identification of JAK2 mutations suggested that these were clonal diseases. This means they originate from a single rogue stem cell that has acquired a genetic mutation giving it a survival advantage, the epitome of a neoplasm (a new, abnormal growth of tissue).

The 2008 WHO update also took the wild west of clinical diagnosis and turned it into a rigorous checklist. To be diagnosed with an MPN like PV, a patient now had to meet specific Major and Minor criteria, heavily weighted toward molecular testing. For the first time, testing for the JAK2^V617F mutation (or similar markers) became a Major Criterion. If you had the mutation and a high red blood cell count, the diagnosis was almost certain. The WHO mandated a closer look at the architecture of the bone marrow. Pathologists began looking for specific clusters of megakaryocytes (the cells that make platelets) which are a hallmark of MPNs.

Recognizing these as neoplasms changed the urgency of the field in three key ways:

1. Pharma/Biotech Investment: Labeling a condition as a “neoplasm” or “cancer” often opens up different regulatory pathways and incentive structures for drug development. This helped pave the way for the clinical trials that led to the approval of JAK inhibitors.

2. Risk Stratification: Doctors began focusing more on leukemic transformation.”Since these were now recognized as cancers, the goal shifted from just managing symptoms to preventing the disease from evolving into Acute Myeloid Leukemia (AML).

3. Access to Care: The “cancer” designation often improved insurance coverage for expensive specialized treatments and made it easier for patients to access oncology centers and clinical trials that were previously reserved for more traditional malignancies.

Five years later in 2013, researchers uncovered a third driver mutation of MPNs. At the time, roughly 30% of MF and ET patients lacked JAK2 or MPL mutations, suggesting that another identified factor was a play. Two teams, led by Robert Kralovics (Vienna) and Tony Green (Cambridge), used Whole Exome Sequencing to scan the entire genetic code of JAK2-negative patients and identified mutations in Calreticulin (CALR). They published their results simultaneously in NEJM (Nangalia et al. NEJM, Klampfl et al. NEJM). CALR normally lives inside the cell (endoplasmic reticulum) helping proteins fold. However, the mutated CALR develops a pathological attraction to the MPL receptor. It binds to MPL inside the cell and escorts it to the surface, holding it in an active position. They identified CALR mutations in 70-84% of patients with non-mutated JAK2 and indicated that these mutations occur early in the disease’s clonal evolution. Beyond identifying the mutation, they highlighted that patients with CALR mutations had a lower risk of thrombosis and better overall survival compared to those with JAK2 mutations.

The prevalence of the three driver mutations (JAK2, MPL, CALR) varies significantly depending on which specific myeloproliferative neoplasm (MPN) is being discussed. Essentially, these mutations are mutually exclusive (a patient rarely has more than one), and together they account for approximately 90% of all classical MPN cases.

• Polycythemia Vera is nearly 100% JAK2-driven: While about 95% of PV patients have the V617F mutation, the remaining few usually have mutations in JAK2 Exon 12. If a patient has high red blood cell counts but lacks any JAK2 mutation, clinicians typically look for secondary causes (like lung disease or smoking) rather than an MPN.

• The CALR/MPL Split: You will notice that CALR and MPL mutations are essentially non-existent in PV. They are almost exclusively found in ET and MF, where the primary problem is platelet overproduction or marrow scarring rather than red cell excess.

• Prognostic Value: These numbers aren’t just for diagnosis; they dictate the prognosis. For example, in Myelofibrosis, a patient with a CALR mutation (specifically Type 1) generally has a significantly longer median survival compared to a patient who is “Triple Negative” or carries a JAK2 mutation.

• The Triple Negative Gap: About 10-15% of ET and PMF patients lack all three drivers. These cases are the current focus of intense research. In some of these “triple-negative” patients, deep sequencing reveals “atypical” or “non-canonical” mutations in JAK2 or MPL that standard tests missed.

Hitting the JAK-pot

The development of JAK inhibitors is a story of accelerated evolution in medicine. Within just six years of the genetic discovery of JAK2 in 2005, the first targeted therapy was approved by the FDA, a remarkably fast timeline for drug development. Even before the JAK2 mutation was identified in 2005, researchers knew that the JAK-STAT (Janus Kinase - Signal Transducer and Activator of Transcription) pathway was the master regulator of blood cell production. Scientists had already been experimenting with broad kinase inhibitors in other cancers. Once the JAK2^V617F mutation was confirmed as the driver, pharmaceutical companies shifted from general research to a targeted race for a JAK2-specific molecule.

Incyte Corporation led the charge with a small molecule called INCB018424, later known as ruxolitinib and marketed as Jakafi by Incyte within the United States and Jakavi by Novartis outside the U.S. (Europe, Canada, etc.). Early in development, researchers realized ruxolitinib didn’t just help patients with the JAK2 mutation, it helped almost everyone with MF. This is because even “Triple Negative” patients have hyperactive JAK signaling. Two large Phase 3 trials (COMFORT-I and COMFORT-II) demonstrated that ruxolitinib dramatically reduced spleen size and improved debilitating symptoms (night sweats, fatigue, bone pain) compared to placebo or best available therapy (see below). In 2011, ruxolitinib (brand name Jakafi) became the first FDA-approved treatment for Myelofibrosis. It was later approved for Polycythemia Vera in 2014.

The success of Jakafi sparked a gold rush, but the journey was not without its challenges. Fedratinib was the biggest competitor to ruxolitinib. However, in 2013, the FDA placed a clinical hold on its development due to reports of Wernicke’s encephalopathy (a serious brain condition) in some patients. The drug languished for years before being rescued by Impact Biomedicines (later acquired by Celgene/Bristol-Myers Squibb) and was finally approved in 2019 and marketed as Inrebic after a re-analysis of safety data. Regulators found the incidence of WE was actually very low (approximately 1.3%) and manageable with thiamine monitoring. Inrebic offered the first second-line option for patients who were resistant or intolerant to Jakafi, specifically targeting the JAK2 and FLT3 kinases.

Recent years have seen the development of second-generation inhibitors designed to solve the limitations of Jakafi, specifically the dose-limiting toxicities of anemia and thrombocytopenia that left nearly 40% of myelofibrosis patients underserved:

• Pacritinib (Vonjo, 2022): Developed specifically for patients with cytopenic myelofibrosis (those with very low platelet counts, <50,000/μL), who previously had no safe treatment options. Unlike its predecessors, Vonjo inhibits JAK2 and IRAK1 without significantly inhibiting JAK1. This JAK1-sparing profile allows it to shrink the spleen without causing the same degree of bone marrow suppression.

• Momelotinib (Ojjaara, 2023): This drug was unique because it inhibits not just JAK2, but also ACVR1. This dual action helps reduce levels of hepcidin, effectively treating the anemia that often plagues MF patients. By inhibiting ACVR1, Ojjaara lowers hepcidin levels, unlocking the body’s iron stores for red blood cell production. The pivotal Phase 3 MOMENTUM trial showed that patients on Ojjaara were significantly more likely to become transfusion independent compared to those on other therapies.

In the pre-JAK inhibitor era (before 2011), the median survival for high-risk myelofibrosis was often cited at roughly 2 to 3 years. Today, for patients treated with modern therapies, that trajectory has significantly shifted. The most robust numbers come from the long-term follow-ups of the COMFORT-I and COMFORT-II trials for Jakafi. Pooled analysis of these trials showed a reduction in the risk of death by approximately 30% to 35% compared to placebo or “Best Available Therapy” (BAT). In COMFORT-II, the survival probability at 3 years was 79% for those on Jakafi, compared to only 59% for those on traditional therapies. Since many patients in the control groups eventually switched to the JAK inhibitor (crossover), the “true” survival benefit was initially hidden. When researchers adjusted for this crossover, the estimated 3-year survival for the control group dropped to 31% versus 78% in the Jakafi arm, highlighting a wide gap in favor of the JAK inhibitor. The numbers also revealed a fascinating biological link: patients who achieved a ≥35% reduction in spleen volume had significantly longer survival than those who did not. This suggested that shrinking the spleen wasn’t just about comfort, it was a surrogate for changing the disease’s course.

The survival improvement in PV is even more dramatic, largely because the disease is more indolent and management of blood thickness (hematocrit) has become highly standardized. The foundational 1962 study describing the natural history of PV reported that patients who received treated with phlebotomy alone had a median survival of about 3.5 years. In a more recent survival model presented at ASH 2024, median survival is approximately 24-28 years in patients <60 years old.

The numbers support the claim that survival in MF and PV are improving due to two main factors:

1. Reduction in Thromboembolic Events: By better controlling hematocrit (in PV) and reducing inflammatory cytokines (in MF), the immediate “killer” (blood clots and strokes) has been significantly curbed.

2. Phenotype-Specific Dosing: Second generation JAK inhibitors (Vonjo, Ojjaara) allow patients with low blood counts to stay on therapy longer. Previously, these patients would have had to stop treatment, leading to rapid disease progression.

Jacking up JAK2

The first and second generation of targeted therapies for Myelofibrosis comprises Type I JAK2 inhibitors. These agents are designed to target the protein in its “active” state, technically referred to as the DFG-in conformation. Despite their success in improving quality of life, Type I inhibitors leave some room for improvement:

• Lack of Molecular Remission: These agents excel at reducing spleen volume and inflammatory symptoms but can leave behind treatment-resistant clones that lead to relapsed disease.

• High Discontinuation Rates: Clinical data indicates that most patients discontinue Type I therapy within 2 to 3 years due to a loss of response, disease progression, or treatment-limiting adverse events.

• Persistent Bone Marrow Fibrosis: After 24 months on Jakafi, only 15% of patients showed a histopathologic improvement in fibrosis grade, while the vast majority simply stabilized or continued to worsen.

The primary reason for these limitations lies in the biochemical “loophole” inherent in Type I binding, which allows cancer cells to hide in plain sight through alternative signaling architectures. When a Type I inhibitor binds to JAK2 in its active DFG-in state, it paradoxically stabilizes the protein in a way that facilitates heterodimerization. In this state, inhibited JAK2 can form complexes with other members of the JAK family, specifically JAK1 or TYK2. In other words, Type I inhibitors jam the lock while the door is open, but the hinges (other JAKs) still let the signal through. Type II inhibitors are designed to lock the door before it ever opens.

This molecular bypass allows for the continued, or persistent, activation of downstream effectors STAT3 and STAT5. Consequently, the malignant cells remain viable and continue to drive disease progression despite the presence of the inhibitor. This phenomenon, known as clonal persistence, necessitates a shift toward targeting the protein in its resting state. To overcome this resistance, the next generation of drug design has shifted focus toward targeting the protein’s inactive architecture.

The shift to Type II JAK2 inhibitors represents a next step in MPN therapy. These agents target the protein in its inactive or resting conformation, known as DFG-out. Ajax Therapeutics’ lead program AJ1-11095 is a first-in-class Type II inhibitor developed through advanced computational structure-based design. Its primary mechanism of action is to bind and lock JAK2 in the DFG-out state, which prevents the formation of the JAK2/JAK1 and JAK2/TYK2 complexes that drive clonal persistence. By maintaining the protein in an inactive state, Type II inhibitors aim to achieve what Type I agents cannot: the systematic reduction of the disease-driving clone. The transition from theoretical design to clinical application is supported by robust laboratory evidence demonstrating a fundamental change in the disease environment.

Preclinical evaluations of AJ1-11095 and its predecessor, AJ1-10502, utilized sophisticated mouse models, including the hMPL^W515L adoptive transfer model and the dual Dre/Cre-recombinase Jak2^VF model. These studies provide the foundation for the “3 Pillars of Efficacy” required for disease modification:

1. Reduction of Mutant Allele Burden: Compared to Type I agents, AJ1-11095 demonstrated a significant reduction in the percentage of mutant cells within the bone marrow and spleen (see below), specifically targeting hematopoietic stem cells (HSCs) and granulocyte-macrophage progenitors (GMPs).

2. Spleen and Symptom Control: Preclinical models showed dramatic and dose-dependent reductions in splenomegaly and leukocytosis, often approaching levels seen with genetic deletion of the JAK2 mutant.

3. Reduction of Fibrosis: Most critically, histopathologic analysis through reticulin staining revealed lower bone marrow fibrosis, suggesting suggesting the potential for restoration of the healthy marrow microenvironment.

While preclinical mouse models hint at these ‘3 Pillars of Efficacy,’ it remains to be seen if these results will translate into human subjects in the ongoing AJX-101 trial. A distinguishing feature of AJ1-11095 is its selectivity for Type II, which is paramount for minimizing off-target toxicities. Biochemical assays confirm that AJ1-11095 is:

• 780x more selective for JAK2 over JAK1

• >3840x more selective for JAK2 over JAK3

• 150x more selective for JAK2 over TYK2

The clinical utility of AJ1-11095 is currently being evaluated in AJX-101, a Phase 1, multicenter, open-label dose-escalation and expansion study. This trial targets a high-unmet-need population: adults with primary or post-ET/PV Myelofibrosis who have failed or relapsed after prior Type I therapy and possess DIPSS Intermediate-2 or High-risk disease. The study employs a conventional 3+3 design for initial cohorts, with subsequent dose escalation guided by a modified Fibonacci sequence. The starting dose was established at 25 mg once daily. The trial seeks to define the Maximum Tolerated Dose (MTD) and the Recommended Phase 2 Dose (RP2D). Key secondary endpoints include a 35% reduction in spleen volume (SVR35) and a 50% reduction in Total Symptom Score (TSS50) at 24 weeks. AJ1-11095 recently received Orphan Drug Designation from the FDA in December 2025 and Eli Lilly expects initial proof-of-concept data later in 2026.

The ability to target the “inactive” DFG-out state (Type II) represents a potential improvement in the treatment of myeloproliferative neoplasms (MPNs) like myelofibrosis (MF) and polycythemia vera (PV). While the first decade of JAK2 inhibition focused on symptomatic management, the emergence of Type II inhibitors like AJ1-11095 offers a potential path toward disease modification. An inhibitor that can disrupt the biochemical mechanisms of clonal persistence, could ultimately result in deeper molecular remissions and improved long-term outcomes for patients.

The Rise of Ajax Therapeutics

The story of Ajax Therapeutics is a textbook example of how academic breakthroughs, specialized venture capital, and cutting-edge computational chemistry can converge to disrupt an established drug class. The company’s trajectory has shifted from a stealth startup to a major acquisition target, culminating in a $2.3 billion deal with Eli Lilly in April 2026.

Ajax Therapeutics was established based on pioneering research from the laboratory of Dr. Ross Levine at Memorial Sloan Kettering Cancer Center (MSKKC). Dr. Levine, a world-renowned expert in myeloproliferative neoplasms (MPNs), co-founded the company alongside other experts in oncology and drug discovery to translate insights into the molecular drivers of blood cancers into targeted therapies.

In 2014, Dr. Levine published a landmark paper in the journal Blood showing that Type II inhibitors (which bind to the inactive state of the JAK2 enzyme) could theoretically offer deeper, more durable responses. This scientific insight sat in the academic realm until the right technical partnership could be formed to solve the massive chemistry challenge of making these molecules selective. In this paper, Levine’s team used an innovative “knock-in/knock-out” mouse model to prove that completely removing the JAK2 V617F mutation leads to a more pronounced suppression of the disease compared to Type I inhibitors (we discussed this in the earlier section). While many researchers were looking for new targets, this paper proved that JAK2 was still the right target, it just wasn’t being hit hard enough. This realization led directly to the pursuit of Type II inhibitors (ie. those developed by Ajax), which bind to the inactive state of the protein and prevent persistent JAK-STAT signaling from occuring.

Ajax Therapeutics was formally founded in 2019 by Dr. Levine, Olli Silvennoinen, and Martin Vogelbaum (who transitioned from an investor to the CEO role). Unlike many startups that spend years in the wilderness, Ajax had a running start due to a unique founding partnership:

• Schrödinger, Inc.: Instead of building a traditional wet lab immediately, Ajax relied heavily on Schrödinger’s computational drug discovery platform. This allowed them to “digitally” design and test thousands of molecules to find a Type II inhibitor that was highly selective for the JAK2 V617F mutation—something previously considered nearly impossible.

• Strategic Backing: From the beginning, Eli Lilly was a founding strategic investor. This is a rare setup where a Big Pharma company helps build the startup from the ground up, providing a clear eventual exit path.

By 2021, Ajax closed a $40 million Series B led by HealthCap. This phase was about building the team, hiring experts like Dr. Craig Masse (formerly of Nimbus) and Dr. Christina Riordan, to move from digital designs to actual manufacturing and regulatory filings.

In April 2024, the company reached escape velocity with a $95 million Series C led by Goldman Sachs Alternatives. This capital was used to launch the AJX-101 Phase 1 trial for their lead candidate, AJ1-11095. This trial targeted the most difficult patient population: those who had already failed or stopped responding to first-generation JAK inhibitors.

The story reached its climax on April 27, 2026. Eli Lilly, seeing the early Phase 1 data and wanting to solidify its oncology portfolio, exercised its position as a strategic partner to fully acquire the company.

Conclusion

From Dr. Gustav Heuck’s first descriptions in 1879 to the “Big Bang” of the 2005 JAK2 discovery, the story of MPNs has been one of slowly unlocking a molecular puzzle. Ajax Therapeutics represents the latest, and perhaps most precise, piece of that puzzle. By solving the chemistry challenge that long plagued Type I inhibitors, Ajax has bridged the gap between Dr. Ross Levine’s 2014 hypothesis and a tangible therapy. As Eli Lilly takes the reins, the narrative of myelofibrosis moves from a history of accidental observations to a future of intentional, structure-based design. The “running start” that began in a MSKCC lab is now a sprint toward a potentially new standard of care for patients with myelofibrosis.

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Disclaimers

Investigational Status Disclaimer

The therapeutic candidates discussed in this newsletter are currently in clinical development and have not been approved for commercial sale by the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or other global regulatory authorities. Their safety and efficacy have not been established. References to pipeline products and ongoing clinical trials involve significant risks and uncertainties. Statements regarding the potential safety, potency, or efficacy of investigational drugs reflect current hypotheses and are not a guarantee of future performance or regulatory clearance. The outcome of clinical trials is inherently unpredictable, and clinical results from earlier stages may not be predictive of results in later, larger-scale trials. This article includes discussion of AJ1-11095, an investigational compound not yet approved by the FDA. Statements regarding its mechanism are based on early-stage data and are not predictive of final clinical outcomes.

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Weekly Readout

A digest of new clinical data from the past week.

These include…

Landmark events in medine:

• 1st FDA-approval of a PROTAC (link)

• 1st clinical trial of obesity drug semaglutide in alcohol use disorder (link)

• 1st FDA-approval for genetic hearing loss (link)

Potentially first-in-disease medicines, based on positive clinical data:

• In non-obstructive hypertrophic cardiomyopathy (nHCM) (link)

• In a rare but devastating liver disease called primary sclerosing cholangitis (PSC) (link)

• in vivo CRISPR gene-editing therapy (link)

• Oral non-hormonal treatment for hair loss in nearly 30 year (link)

Potentially best-in-disease or best-in-class medicines, based on positive clinical data:

• For second-line HR+ HER2- metastatic breast cancer regardless of PIK3CA mutation status (link)

• For hidradenitis huppurativa (HS) (link)

• For inactive thyroid eye disease (TED) (link)

• For plaque psoriasis (link)

Frontiers in Medicine

Exploring the frontiers of our understanding and treatments for disease.

These include…

Obesity

• Part 1 - Societal perception, recognition as a disease, and the discovery of its hormonal & genetic drivers

• Part 2 - Evolution of treatments: from dark age to golden age

CAR-T

• Part 1 - Immunology Civil War, the discovery of T-cells, and their rebirth as medicines

• Part 2 - Beyond autologous CAR-T: allogeneic, in vivo, and T-cell engagers (TCE)

• Part 3 - coming soon!

Acquisitions

Exploring the innovation behind acquired companies.

These include…

Science-driven companies, which start with a novel research finding or biological thesis:

• Eli Lilly to Acquire Engage Bio, a founder-led startup aiming to solve gene therapy’s “last mile” problem (link)

• Bayer to Acquire Perfuse, a long-acting diabetic eye disease play (link)

• Chiesi to Acquire KalVista, an oral HAE play (link)

• Eli Lilly to Acquire Ajax, a differentiated JAK play (link)

• Eli Lilly to Acquire Kelonia, digging into the in vivo CAR-T gold rush (link)

Asset-driven companies, which are focused on building a pipeline of (usually in-licensed) drugs that are ‘potentially better versions’ of other drugs that have already achieved clinical/commercial success:

• UCB to Acquire Candid, scooping a reverse merger for a TCE pipeline (link)