Biogen’s multiple sclerosis days are nearly long behind them. With the acquisition of Apellis , their transformation into a balanced commercial-stage neuroscience, rare disease, and immunology company is finally complete.

This is a natural course of company’s life in our sector. Regeneron was on the ropes while its EYLEA franchise faced generic erosion, but now they’re a major player in immunology and certainly a burgeoning player in oncology and other disease areas as well. Someone like Sanofi was once known for being a major player in insulin; that was their bread and butter. But eventually that bread and butter ran out, and they had to pivot into areas like immunology and specialty care.

Not everyone can be a Gilead or a Vertex , two companies who have sunk deep roots into HIV and Cystic Fibrosis, respectively, that continue to power their businesses today. Most companies need to shed or molt their skin and transform into something new at one point or another.

The Gradual Shift Away from MS

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Biogen’s metamorphosis didn’t just happen overnight; it started in 2022 with the hiring of CEO Chris Viehbacher, who formerly led Sanofi . The company’s legacy multiple sclerosis (MS) franchise faced major patent cliffs. TECFIDERA, which was once a multi-billion dollar behemoth, had been decimated by generic competition, causing sales to plunge nearly 50% in 2025 alone. TYSABRI too, which was Biogen’s long reliable blockbuster, faced biosimilar competition in the same year. To add insult to injury, Roche’s OCREVUS was sort of the primary predator that forced Biogen to need to molt, despite Biogen receiving royalties on this product from their prior collaborations with Roche. OCREVUS continued to grow and take market share from Biogen’s legacy portfolio while 2025 patent cliffs loomed in the distance.

Viehbacher rather quickly kicked off a “fit for growth” initiative in November 2022 netting in a 15% headcount trim and achieving $1B in gross savings. In addition to that, he did a top-to-bottom pipeline review and focused on finding anchor assets that were clinical stage and could eventually become meaningful revenue drivers for the company.

Through that strategic exercise, they decided to focus on building out their CNS rare disease portfolio, as well as their immunology pipeline (which at the time as really just one key asset), with a special focus though on nephrology indications. What this amounted to was a BD spree. Notably, in July 2023, they acquired Reata for $7.3B, gaining access to SKYCLARYS for Friedreich’s Ataxia. Later, they acquired Hi-Bio for $1.15B, adding felzartamab to fuel their entrance into the wide world of nephrology. These two acquisitions were also complemented by multiple R&D collaborations with smaller biotechs focusing on other diseases in the Rare Disease and Immunology buckets.

In January 2026, they continued their efficiency efforts, reporting a 26% spend reduction in R&D, culminating it what appeared to be a solid foundation for the future of the company. New product launches had offset the MS generic erosion declines of the past year, the company was running more efficiently, and had a pipeline set up for multiple near-term late-stage data readouts across newly prioritized disease areas.

This was a company setting up to change into something completely different. The future of the company was staked on assets completely foreign to what existed in 2022, when Viehbacher took over. The optionality from the pipeline came from new high-risk areas, but notably only one MS asset still existed in the pipeline (BIIB091, a peripheral BTK inhibitor). MS has taken a back seat and is now upside only. Out with the old. In with the new.

So even before the announced Apellis acquisition, Biogen was clearly set up to be a rare disease, immunology, neurodegenerative disease player. So why did Biogen acquire Apellis now?

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I really like the format John Oliver uses for his hit satirical news comedy show Last Week Tonight. The first half of his show usually reflects back upon the last week in the news, with Oliver delivering the comedic angle of all the crazy shit happening in our world.

I wanted to create something digestible and reflective like that, that also could serve as a vehicle to provide my unique perspective on the week in Biopharma. The format below is what I came up with. I am hoping to crank these out each week and have these in your in box on Sundays, while you are getting your ducks in a row for your Monday meetings. I envision this series being available to both free and paid subscribers, with paid subscribers continuing to get my regular deep-dive content.

These posts will have three sections with roughly three things in each bucket that caught my attention:

• Press Release Decoder: going beyond the company speak, reading between the lines, thinking about what isn’t being said, to illustrate the strategic implications of a company’s moves that don’t make it into the press release

• Connecting the Dots: looking at stories that are either about the macro or from the mainstream news and how they may impact BioPharma

• Follow the Money: quick takes on some key deals that were struck and what they mean for those companies, their competitors, or the sector at-large

I’ll keep iterating on this “Last Week Tonight” series with the hope of it getting better and more useful to you. You might see new sections beyond these initial three or slight tweaks, so please bear with me. Any feedback you have is welcome!

As always, if you are getting value out of my content and you want to take it to the next level, please consider becoming a paid subscriber 🙏🏾.

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📡 PRESS RELEASE DECODER

Going beyond the press release

Rhythm Pharmaceuticals — Imcivree (Setmelanotide) Approved for Acquired Hypothalamic Obesity: A First-in-Class Rare Disease Win

Source: BioPharma Dive | Date: March 23, 2026

The FDA approved setmelanotide (Imcivree) for adults and children 4 and older with acquired hypothalamic obesity (AHO), a condition caused by hypothalamic brain injury — making this the first-ever approved therapy for AHO. The Phase 3 TRANSCEND trial demonstrated approximately 18 percentage points greater weight loss versus placebo, leveraging the drug’s MC4R agonism mechanism, which is mechanistically distinct from GLP-1 receptor agonists. Analysts project a $1B+ market opportunity across an estimated 2,000–10,000 diagnosed U.S. patients; consensus 2026 estimates for the new indication sit at ~$40M, and RYTM shares rose approximately 6% on the news.

BPS’ Take: has really created a beachhead in rare obesities prosecuting a single MOA across multiple drugs in its pipeline. While it is dwarfed by the broader GLP-1-focused obesity population, adding up these rare obesity markets, as RYTM has done, can amount to sizable market potential over time in a relatively low-competition arena. They’re a solid example of how building a rare disease business can still be right at the intersection of patient-impact and market opportunity. They’ve been a popular buyout target off and on over the years, and if they are able to prove that rare obesities can be a blockbuster set of indications, larger players were be interested.

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Corcept Lifyorli (Relacorilant) + Nab-Paclitaxel — FDA Full Approval for Platinum-Resistant Ovarian Cancer: First SGRA Crosses the Finish Line

Source: FDA.gov / Fierce Pharma | Date: March 26, 2026

The FDA granted full approval to relacorilant (Lifyorli) combined with nab-paclitaxel for platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer — making it the first FDA-approved selective glucocorticoid receptor antagonist (SGRA) for any oncology indication. This decision came after a prior Complete Response Letter for the drug in hypercortisolism (due to hypertension AEs) and arrived ahead of schedule, placing Corcept in a competitive position against the entrenched ovarian cancer standard of care with no existing SGRA-class competition in the market. The approval validates a mechanism that had previously been considered commercially speculative and opens a new drug class in a space where options remain limited for platinum-resistant patients.

BPS’ Take: Going from seeing the door shut on one approval and winning another in a major indication is quite the victory. There was certainly negative sentiment swirling about the ovarian cancer approval in the wake of the CRL, but this is a great example of how the benefit-risk of a drug changes based on the indication. The FDA essentially said: "We can't approve this for 10,000 rare disease patients with hypertension concerns." But then said: "We absolutely can approve it for 50,000+ PROC patients where a 4-month OS extension is meaningful and safety profile is acceptable." LIFYORLI enters platinum-resistant ovarian cancer (PROC) as a potentially broad-based option in a market that has become fragmented by therapies for biomarker-driven sub-groups (folate receptor alpha, HRD). Folate-receptor alpha targeting ADCs, like ELAHERE, are probably most under threat by this new approval, as LIFYORLI can address the entire PROC population and not just the FR-alpha high group.

🌐 CONNECTING THE DOTS

When the mainstream meets biopharma and vice versa

Trump’s MFN Drug Pricing Policy: The Fine Print Reveals a Framework Designed to Raise Foreign Prices, Not Lower U.S. Costs

Source: STAT News | Date: March 24, 2026

An HHS official disclosed to congressional Republicans that the Most Favored Nation (MFN) drug pricing framework is explicitly designed to allow manufacturers to “price wherever you want” in the U.S. so long as they do not underprice American consumers in foreign markets — a framing that inverts the popular understanding of MFN as a cost-reduction tool. Sixteen major drugmakers have already reached agreements under the framework, and the 3-year deal terms may expire before many affected drugs even launch in foreign markets. The revelation suggests MFN is being operationalized as a foreign price-raising mechanism rather than a domestic price-control tool.

BPS’ Take: For biopharma manufacturers, this reframing of MFN is commercially significant: if the policy succeeds in elevating ex-U.S. prices toward U.S. reference levels, it could partially neutralize one of the sector’s greatest structural headwinds — international price arbitrage — while leaving U.S. pricing power intact.

RFK Jr. Signals FDA Will Legalize ~14 Restricted Peptides, Opening Gray-Market Therapies to Compounding Pharmacies

Source: Politico / NPR | Date: March 22–26, 2026

On Joe Rogan’s podcast (late February), HHS Secretary Robert F. Kennedy Jr. declared himself “a big fan” of peptides and signaled that the FDA will reclassify approximately 14 of 19 peptides currently on the agency’s restricted list — including BPC-157, ipamorelin, and MOTS-c — back to legal compounding status within weeks. Kennedy frames the move as reversing what he calls an “illegal” 2023 Biden-era reclassification that he argues drove patients toward black-market suppliers and overseas manufacturers. If enacted, compounding pharmacies would be permitted to produce these peptides under state pharmacy boards, potentially legitimizing a market currently worth billions in gray-market sales and moving human-use peptide treatments from research-labeled products to pharmaceutical-grade compounded drugs.

BPS’ Take: The argument from compounders and RFK allies is somewhat logical: people are already using these peptides (often sourced from China and sold illicitly), so legitimizing pharmaceutical-grade compounding is harm reduction. Most peptides (BPC-157, CJC-1295, AOD-9604) that are super popular in the man-o-sphere lack rigorous human clinical trial data and have theoretical safety risks (cancer from growth hormone peptides, organ damage, immune reactions). The logic of green-lighting a lot of these vs. not federally legalizing other drugs we actually do have a lot of clinical research on is missing me, but that is a rant for another day.

Back to peptides - we already have really poor regulation of the supplements market, and these peptides have been hawked with specious claims by social media influencers even before this ruling. Bad news. Letting companies like HIMS, who have demonstrated a penchant to fastpass medicines to patients and disregard all kinds of laws in the process is a really dangerous thing. The decision also creates some odd competitive pressure on Novo Nordisk and Eli Lilly’s GLP-1 business. If these other peptides are legalized, telehealth platforms like HIMS (which acquired a peptide facility in early 2025) can now manufacture and market these other peptides as alternative weight loss drugs (that don’t have the backing of “evil big pharma”) and potentially blunt GLP-1 sales (while also potentially harming patients). No formal FDA rule change has occurred yet, despite RFK’s announcement, the move remains at the intention/negotiation stage.

💰 FOLLOW THE MONEY

Deals, dollars, and what they signal

Merck & Co. Acquires Terns Pharmaceuticals for $6.7B — A Clear Post-Keytruda Signal in Hematology

Source: STAT News / Reuters / BioPharma Dive | Date: March 25–26, 2026

Merck will acquire Terns Pharmaceuticals at $53.00 per share in an all-cash transaction valued at approximately $6.7B in equity ($5.7B net of cash), with TERN-701 — an oral allosteric BCR::ABL1 TKI in Phase 1/2 development for chronic myeloid leukemia via the CARDINAL trial — as the primary asset driving the deal. Terns stock had surged approximately 6x over the prior six months, reflecting the market’s growing conviction in TERN-701’s potential best-in-class profile, and analysts are already flagging the possibility of rival bids. The acquisition deepens Merck’s hematology pipeline at a pivotal strategic moment as the company faces the looming patent expiration of Keytruda, its $25B+ blockbuster PD-1 inhibitor.

BPS’ Take: To be honest with you, CML was really off my radar. When I first started working in heme/onc I was told by my seniors that it was a solved problem. I was mostly under the impression that patients were rather well managed on the existing set of generic TKIs, notably GLEEVEC. But Terns’ story is a great example of how Oncology markets can turn into chronic disease markets. Even though patients can live a full life with existing treatments, there is still a risk of mutation driven relapse but also accumulation of toxicity from AEs over time. This explains why companies are willing to pay for "me-too" assets in diseases that looked "solved." The market isn't really about cure innovation anymore in these spaces, it's about managing a patient population with chronic disease.

CLL could be headed that direction, or perhaps is already there, with how strong the BTK inhibitor class has been and is becoming. In oncology, efficacy usually outweighs safety, but when efficacy tops out, it creates more room for companies to differentiate on safety, tolerability, and convenience, which is where Terns and Novartis’ asciminib come in.

On the Merck side of the coin, they clearly don’t feel like they’ve enough to fill the Keytruda patent cliff yet, so much so that they are interested in getting into heme/onc. I wonder if other high unmet need heme/onc areas like AML, MDS, and MF are on the table for them too.

Gilead Sciences Acquires Ouro Medicines for Up to $2.18B — Second Major Deal in Five Weeks as Autoimmune Pivot Accelerates

Source: BioPharma Dive / Reuters / WSJ | Date: March 23–24, 2026

Gilead will acquire Ouro Medicines for $1.675B upfront plus up to $500M in milestones, with the key asset being gamgertamig (OM336), a BCMA/CD3 bispecific antibody targeting autoimmune diseases; Galapagos co-finances 50% of the deal and receives Ouro assets and employees in exchange for up to 23% royalties, while Gilead retains global commercialization rights. The transaction follows Gilead’s $7.8B acquisition of Arcellx in February 2026 — making this the company’s second significant deal in approximately five weeks. Together, the two deals further Gilead’s efforts to diversify beyond their commercial dominance in HIV and growing Oncology business into auto-immune.

BPS’ Take: I guess the team finally has a product to develop? A savvy move by the folks to get Galapagos to pay for half this drug in this co-financing architecture. I guess you could argue this was Gilead’s money all along, since they own ~25% of Galapagos, have two board seats, and also gave them ~$4B upfront many moons ago when the two companies struck their fruitless R&D collaboration. Tomato, tomahto. Galapagos basically feels like Gilead’s EU R&D hub and if OM336 continues to look promising, it may just make mathematic sense for Gilead to acquire the remaining 3/4ths of the company vs. paying the 23% royalty.

Novartis Acquires Excellergy for Up to $2B — Second Major Deal in One Week as Allergic Disease Strategy Accelerates

Source: Reuters | Date: March 27, 2026

Novartis will acquire Excellergy for up to $2B in upfront and milestone payments for Exl-111, an anti-IgE biologic with longer half-life and tighter receptor binding than Xolair, targeting allergic diseases including potential food allergy applications. The deal marks Novartis’s second multi-billion-dollar acquisition in one week following the $3B Pikavation/Synnovation deal announced March 20, with close expected in H2 2026 pending regulatory clearance.

BPS’ Take: snuck this in on a Friday, but I thought this was far more interesting than the Pikavation deal they did earlier in the week. Novartis now joins Regeneron and (via the RAPT acquisition) as squarely targeting the Allergy space using an immune-mediated approach. All three companies are deploying quite different strategies (GSK has a better XOLAIR, REGN is combining a BCMAxCD3 with DUPIXENT, and this EXL-111 basically sequesters IgE) so it will be quite the race to watch to see which therapeutic approach wins out. Allergy treatment and prevention are massive market opportunities, and we shouldn’t be surprised if other Big BioPharma players move into this space via deals. The immune reset read-through from antibody based therapies in autoimmune diseases is real, and this area is a high priority for the current HHS administration to boot, meaning if you’re a drug developer, you may get the FDA red carpet treatment (vs. the unpredictable 180s we’ve been accustomed to with this administration).

Hope you enjoyed this first edition of “Last Week Tonight in Biopharma”. As this gets going a bit more, please send through any constructive feedback.

Have you noticed we have more tech people in Biotech now? Over the past few years there has been an influx of people from the software world becoming interested in our space. You have the group of longevity-curious tech CEOs bankrolling anti-aging companies (e.g. Bezos, Altman, Armstrong), large tech companies focusing some of their R&D on drug applications (Nvidia, Microsoft, Google), former software people becoming biotech founders (InSitro, XtalPi, InSilico), and traditionally tech/generalist-focused funds funding drug companies.

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Why Tech Capital Is Fleeing Software (and Coming to BioPharma)

You don’t need an oracle to tell you that AI has played a major role in this trend. But why now?

The main reason I see is that the trajectory of AI has shown us that things like software—the field these individuals typically come from—is quickly collapsing into a world that will be commoditized. We hear stories every day, discussing how AI can be applied in the hands of their own engineers. A “super engineer” with agentic capabilities that can now deploy hundreds of AI-based engineers and orchestrate development across a number of different coding tasks simultaneously. Companies in the tech sector praise how many tokens their engineers use, asking them to continually use more and more.

On the flip side, we see many stories about how tech companies are now contracting their workforces—getting rid of lower-level engineers, QA, and QC—unnecessary functions that they anticipate will no longer be required in a more fully AI-integrated world.

This was always going to be the end state. AI was invented on the computer and trained on the internet, which in some respects is the most complete example of human thinking that we have. All of these models were coded in languages created by humans. In a sense, coding is perhaps one of the most familiar things to AI models because it is exactly what they are built on. If AI was a car, humans would be the end-to-end manufacturer of it. We built every part, bolted them together, and made it run.

Scale the software future up to its final destination. Why would a large multinational corporation buy enterprise software from someone like Workday or Salesforce when in the very near future—and perhaps even now—they could deploy one engineer to create custom software for their entire organization with the help of an army of AI bots? Following this thread, you can quickly see that software is going to be a commodity in the new world. Businesses (and consumers) will be able to easily and cheaply build the software tools they need.

Perhaps the same could be said of things that we use on a day-to-day basis in biotech strategy: Excel models, slides, curated databases, and other complex documents. It is becoming ever more clear that the value of an individual producing those versus an AI is shrinking considerably. The future of deliverable-based work in our space is going to be more about an individual orchestrating several AI-based “analysts” to produce the necessary deliverables that will feed into a strategic synthesis by the human orchestrator.

So if software is going to be a commodity, it makes sense for tech capital to flee traditional software-based companies and reallocate elsewhere. And where might that be? Well, it’s in areas like biotech, where the rules are far more complicated and there still remains a ton of room for AI to add value. Unlike software, where humans created the underlying language and understand its intricacies well, in the field of biology, we were not born with instruction manuals. By some measures, we perhaps only know 10% of the rules that govern our bodies. Moreover, those rules are exposed to the pressure of evolution; they are dynamic and will likely change over the course of our species. In the car analogy, we are even less than mechanics. In some sense, we are still trying to figure out what we’re actually driving.

As we know, in biotech, it’s really hard to develop novel drugs, another reason why we are seeing a whole host of new companies spin up that are well-funded but focusing on pre-existing targets (aka “well-validated biology”). Areas like biotech, where there are still incredible amounts of unknown, are the perfect places for new AI-focused capital to come into. We’re already seeing the biggest companies in our space discuss how AI is accelerating some of the more low-hanging operational fruit in their businesses.

But quickly we’re seeing the potential of how AI can be used to speed up drug discovery, document writing, finding optimal clinical trial sites, and a whole host of other blocking and tackling type tasks that go into drug development. Don’t get me wrong, we’re not at the era yet where AI can develop a drug “soup to nuts” on its own. That 10% of known biology is still a really big barrier. There’s no replacement for doing true discovery work and pushing the boundaries of what we know about biology to discover new rules that govern our cells, organs, and systems.

There is also no replacement for running clinical trials. We need to test more novel biology in human subjects to get a truer understanding, and more importantly, better data that we can feed back into the multitude of specialized AI models that are coming out. Only then will we get closer and closer to “simulating human biology”.

A Story About a Dog that Illustrated a Narrative Gap

Lately, we've seen some interesting stories pop up in the mainstream news about people in the tech world applying basic AI tools to develop new medicines. The one that stands out the most to me is the story of the Australian tech entrepreneur, Paul Conygham, who used AI tools—including large language models and protein structure prediction software—to help design a custom DNA cancer vaccine tailored to his dog Rosie's tumor. Thankfully, Rosie's health has significantly improved after receiving this bespoke cancer vaccine.

However, the responding commentary on social media was somewhat triggering for me. There was a group of people saying, "Why can't we do this for all cancers?" or "Look, this guy just cured cancer using AI; this completely changes everything and the pharmaceutical industry is upended." Even worse, some took this case as evidence that drug companies are intentionally withholding cures or not applying technology in a patient-centric way.

As insiders, we know that perspective is misguided. Even in Rosie's case, she didn't have a complete response or total eradication of all tumors, and we need longer follow-up to see how effective the therapy was. While it was a remarkable feat, it lacks the context that this work is already being done at a much larger scale in human patients. A number of cancer vaccine studies are already in clinical trials, most notably led by mRNA manufacturers like BioNTech and Moderna, which are in phase 3 studies with promising phase 2 data to support them.

This situation made it clear to me that in biotech, we have an issue communicating the promise of our technologies to a wider audience, whereas tech leaders are able to do this much more expertly. Solving this problem is incredibly critical, especially as we see more tech people entering biotech riding the wave of AI innovation.

What We Can Learn From the Tech Bros

I think it’s important to say that we shouldn’t shun tech folks from coming into biotech. There is much more we can gain by melding the best of our expertise and cultures together.

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Last month, Sanofi announced that they would be moving on from CEO Paul Hudson and bringing on Merck KGaA’s CEO Belén Garijo to take over for him.

This change made me think a bit about Hudson’s performance relative to other CEOs, to figure out whether his ousting was warranted given his performance. In truth, I had forgotten that he had been in the role for as much time as he had (6.5 years). Going down that rabbit hole was interesting enough for me to expand this into a broader exercise examining CEO performance across a couple simple metrics.

So today we’ll take a quick look at the beginnings of this analysis. If it is interesting enough to you I’ll continue to build on this data set and add new layers (e.g. CEO pay/compensation, pipeline data, etc.) that will help uncover deeper insights into the relative performance of our sectors most impactful executives.

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Overview of Methods

Before we get to the more interesting findings, I want to discuss the methodology: how I collected this data, what is included in the analysis, and the current limitations.

First off, this dataset is comprised of 23 different CEOs spanning companies including AbbVie, Amgen, AstraZeneca, Biogen, Bristol Myers, Eli Lilly, GSK, Gilead, J&J, Merck, Novo Nordisk, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, Vertex, Bayer, and Merck KGaA.

The dataset looks at each CEO from their starting point all the way through to today. For certain companies—particularly ones like AbbVie, Novo Nordisk, and GSK that have had CEO changes during that period—I try to capture data from both CEOs individually. For CEOs who are new to their roles, they obviously won’t have as much data to go off of. For the most part these CEOs were excluded from substantive analyses. For Regeneron’s CEO, Len Schleifer, I had to start his data from 2012. This is partly because if I started it from 1988 when Regeneron was founded (or even 1991 when Regeneron IPO’d), it would make the data look a little wonky, but also because it was impossible to find correct financial data from back then.

Quantitative Data

The main pieces of data I collect, examine, or generate are:

• Market Cap: While not a perfect metric, how much a company grows or shrinks during a CEO’s tenure serves as a rough quantitative barometer of their performance.

• Tenure Milestones: I captured the market cap on the beginning date of each CEO’s tenure, as well as on their last day (or current day, if they are still in the role).

• Intervening Data: I collected market cap data at the end of each intervening year during their tenure

• Value Created and absolute growth percentage: This measures the raw growth in market cap from start to finish for each CEO.

• Compound annual growth rate (CAGR): functionally ignores yearly fluctuations and calculates a “smooth” rate of return of market cap growth or decline for each CEO’s tenure.

Certainly there were other metrics that we could have looked at—and I hope to layer these in for future analyses—but some limitations here are that I didn’t look at things like EBITDA, EPS, other profit metrics, or revenue growth. Those are all things that I hope to include in the future, but for simplicity on the quantitative side, I focused really just on market cap.

Qualitative Data

Qualitatively, I tried to capture a few different things. Obviously, CEOs don’t take over brand-new companies; the case of Regeneron aside, most of these CEOs are taking over companies that are dozens of years old with a previous track record and history. Not every CEO is dealt the same starting hand, so to speak.

For each CEO, I tried to provide a qualitative score of 1 through 5—what I’m calling a QHS (Qualitative Health Score). This is a highly subjective metric, but effectively, I tried to assess the forward-looking health of the business when the CEO stepped into their role and compare that to what the future outlook of their businesses looks like today (or at the time they ended their role as CEO).

To attribute a QHS score I looked several factors, including but not limited to:

• Revenue and pipeline diversification (or over-concentration)

• External and internal sentiment about the company

• Sales trends for major products

• Patent cliff risk and sufficiency of maneuvers to delay or fill them

• Pressure to execute M&A, major deals completed, and where possible, the success or shortcomings of those deals in contributing to revenue growth

• Major outliers in the balance sheet (e.g., companies carrying lots of debt)

The goal was to effectively provide a a “vibe check” for the compare right before the CEO took office and what that vibe looks like today.

The larger table above includes information that you can read through, discussing my determinations of what the company state was at the start, as well as the rationale for the QHS score change. However, this scorecard, so to speak, does a more simplified job of showing you which CEOs improved, declined, or had stable QHS scores over the course of their tenure, based on my qualitative attributions.

Notably, most CEOs remained relatively stable in terms of their QHS scores. You had a range of cases here. Some cases like Bayer, which started off at a QHA score of 1 in overall pretty poor health and continued to stay there. Bayer, as we know, was saddled with a significant amount of debt following the Monsanto acquisition and was also tied up in a legal battle with several class action lawsuits related to Roundup. They had a declining pharma business and have struggled to generate growth, remaining “down in the dumps” while awaiting a turnaround.

At the other end, companies like Vertex—whose CEO, Reshma Kewalramani, took over a company with very bright prospects, especially in cystic fibrosis where Vertex is the unchallenged leader—continued to maintain a positive outlook for the company over the course of her tenure, including multiple late stage programs in new areas like pain, genetic medicines, cell therapy, and rare disease, thus far.

The biggest riser here, to no surprise, was AstraZeneca. Pascal Soriot’s story involves taking over the company when it was significantly beaten up and facing multiple patent cliffs for major products. He orchestrated a turnaround story that many other Big Pharma teams use as an example to follow.

The other is obviously Dave Ricks at Eli Lilly, who—largely because of the multiple successes in GLP-1-based assets—has now helped Lilly reach the status of being the first trillion-dollar healthcare company.

With that out of the way, let’s look at a few different data visualizations from this dataset and tease out some insights about CEO performance.

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Charts! Charts! Charts!

I think the most digestible way to look at some of this data is by grouping the CEOs into cohorts. I organized their performances into these cohorts based on how much time they have spent in their role:

• Short tenure: less than 4years

• Medium tenure: 4 to 10 years

• Long tenure: 10 years and over

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In this episode, Shivu and Kenny discuss how you as a caregiver or patient can use public resources like clinicaltrials.gov and Large Language Models (LLMs) like ChatGPT to discover the latest treatment options for a particular disease and empower yourself to have a more productive conversation with your doctor. Kenny and Shivu discuss an example of this situation from an episode of Apple TV’s “Shrinking”, starring Harrison Ford. In the episode they go through a demo of how they would find new treatment options for Ford’s character, a patient suffering from Parkinson’s Disease who has exhausted all available treatment options.

CHAPTERS

00:00 Introduction to Clinical Trials

03:04 The Importance of Patient Involvement

06:13 Navigating Clinical Trials: A Practical Guide

09:06 Using AI to Enhance Patient Care

11:53 Drafting Effective Communication with Doctors

14:27 Empowering Patients Through Knowledge

17:46 Finding the Right Treatment Options

20:30 The Role of Research in Patient Advocacy

23:03 Conclusion and Future Directions

34:38 Outro

Questions? Email us at: ⁠⁠mailto:drugdealinpod@gmail.com⁠⁠
Follow ⁠Shivu on X⁠(@bigpharmasharma): https://x.com/BigPharmaSharma
Sign up for Shivu’s newsletter: https://www.bigpharmasharma.com/⁠ ⁠
Follow ⁠Kenny⁠ on Linkedin: https://www.linkedin.com/in/kennylalwani/

DISCLAIMER: The views and opinions expressed in this podcast are for informational and educational purposes only. They are not intended as medical advice and should not be used as a substitute for professional medical judgment or guidance. Always consult a qualified healthcare provider with any questions you may have regarding a medical condition or treatment.

If you are a close watcher of the cell therapy field, as I am, by now you’ve heard that Gilead acquired Arcellx for an implied value of $7.8B. The deal includes an additional $5 per share contingent value right (CVR) if the companies’ BCMA CAR-T program, anito-cel, is able to achieve $6B+ in sales by the end of 2029. It also comes at at 68% premium to Arcellx’s 30-day volume-weighted average (VWAP) share price as of February 20, 2026.

If your news feeds are anything like mine, you’ve also probably been inundated with a copious amount of room temperature AI-slop on this deal (especially in the “HR App”). Nearly all of these “analyses” are basically extrapolations of abstractions from the press release. All of these condense down to some form of, “This deal reflects Gilead’s conviction in anito-cel! Big Pharma interest in autologous cell therapy has been reinvigorated! This will open up the gates for more auto cell therapy acquisitions!”.

Now that that’s out of the way we can start talking specifics. As someone who has spent a large chunk of his career shaping strategy in the effort to advance ex vivo cell therapy products (including at Gilead/Kite), I would love for this acquisition to mean that this class, especially autologous, are back in vogue writ-large. The reality, reflected in the details and context leading up to this deal, paint a different story.

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Understanding the ‘Why Now?’

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If you haven’t checked the vibes in the room, the entire BioPharma community is in an uproar at Center for Biologics Evaluation and Research (CBER) director Vinay Prasad’s latest action. Per reports, Moderna received the rare refusal-to-file (RTF) letter from CBER after using a precious priority review voucher (PRV) for its mRNA-based influenza (flu) vaccine, mRNA-1010. It appears this wasn’t a group decision either. Prasad unilaterally decided to issue the RTF, while his reviewers were in support of accepting Moderna’s filing for review.

In the RTF (which Moderna released here), Prasad esentially says that Moderna’s application is incomplete because it lacks an appropriate comparator, namely that the main study used in Moderna’s filing package (called P304) examining adults ages 50 years old and older, was comparing Moderna’s drug to standard-dose flu vaccine, instead of the high-dose flu vaccine, which is recommended in use for the 65 and older group.

But Moderna is mad because they already had confirmation from the FDA that their design was acceptable, and further addressed questions about comparison to high-dose vaccines with supplementary Phase 3 immunogenicity data. Based on Moderna’s recounting of their interactions, they were given no reason to believe that their filing would not at least be reviewed. You usually don’t spend a PRV (which fetch $100-$200M on the open market) unless you felt high confidence in your application being accepted.

Prasad (and his boss Marty Makary, head of the FDA) defended the decision, effectively arguing that a high-dose comparator should have been used in the main study for 65+ age group because that is the current standard of care in the US (although not in much of the rest of the world).

This latest saga at the FDA involving Vinay Prasad seems like more of the same, but there are far reaching implications to this action that the BioPharma sector should consider.

A Major Setback for Vaccine Development and Investment

Moderna is left swimming up stream without a paddle. They ran multiple 40K+ size global studies all to have the FDA basically say their studies are effectively useless and not even worth considering. That’s obviously millions of dollars flushed down the drain and a steel vault door shut in the face of America’s leading mRNA manufacturer.

More importantly, it’s one less effective medicine available for patients, not just for this flu season (which has been quite severe) but many flu seasons to come. Moderna has come out and said that they aren’t even going to continue investing in P3 vaccine trials for infectious diseases in the US or anywhere else. While they will still likely take mRNA-1010 into international markets, it doesn’t make financial sense for the company to continue pursuing these sorts of vaccines if the US market is going to be off limits to them.

Of course some of this commentary is posturing by Moderna's CEO, but I don't blame him. Vaccines are unique in how heavily the US market subsidizes global access. American reimbursement rates and market size essentially bankroll the development and distribution pipelines that supply the rest of the world. Cut off US market access for mRNA vaccines, and the economics collapse for Moderna domestically and for every international market counting on these products. If Moderna follows through on retreating from infectious disease development, foreign regulators may not have as many mRNA vaccines to approve. The only salvage pathway would be out-licensing to partners willing to shoulder the clinical and commercial burden ex-US. This is a scenario that delays timelines, fragments supply chains, and ultimately could leave patients waiting longer for innovation.

Why should any other mRNA vaccine developers feel differently? Each of them, certainly smaller and less financial endowed than Moderna, is probably thinking the same thing. Is it worth continuing to pursue our infectious disease programs?

Investors too could be more likely to shy away from mRNA plays as well. The FDA’s shifting standard and lack of predictability adds immense late-stage to risk. No investor wants to fork over tens of millions of dollars only for their portfolio companies major inflection catalyst to be rendered moot because of a sudden unpredictable change in opinion at the FDA. This lack of consistency reverberates through all levels of the BioPharma ecosystem.

Miscommunications Abound

It is important to look at the timeline of events here to really understand what went wrong and why. And what stands out is a clear communication issue.

There is a disconnect between the higher ups at the FDA, like Prasad and Makary, and long-time staffers who work under them. From the outset in April 2024, the vaccine team at the FDA defines Moderna’s trial design as “acceptable” but “recommends” they use high-dose. Moderna opts to go the standard-dose route that was deemed “acceptable”. Prasad gets involved on this project after the study has already started (July 2025) and raises concerns. By August, FDA staff tell Moderna that the lack of a high-dose group in the control arm is going to be a “significant issue” (assuming that they got verbal guidance from Prasad on this here and are trying to flag that for Moderna) and requests additional analyses, which the company provided. This included data from a separate Phase 3 study comparing mRNA-1010 with a high-dose flu vaccine, but focusing on antibody levels rather than actual efficacy. Prasad has long been a critic of immunogenicity data as a substitute for outcomes in the approval of vaccines, and releases several internal FDA memos guiding the agency to move away from valuing these sorts of data points for approval.

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Summary

In this episode, Shivu and Kenny review their predictions for 2025 and make new predictions for 2026. They discuss trends in mergers and acquisitions, market performance, the impact of AI in drug development, and the rise of digital advertising in the pharmaceutical industry. They also explore the evolving landscape of biotech companies, regulatory changes from the FDA, and the growing interest in metabolic diseases and psychedelics. Finally, they introduce the ‘pharm to table’ model in pharma, emphasizing direct-to-patient commercial channels and how these increase patient agency.

Chapters

00:00 Introduction and Overview of Predictions

04:37 Grading 2025 Predictions

10:35 Shivu’s 2025 Predictions and Grades

16:53 2026 Predictions: Emerging Trends

22:50 Regulatory Landscape and the FDA’s Role

30:46 Predictability in Drug Approval Processes

30:51 The Metabolic Space and GLP-1s

33:08 Big Pharma’s Entry into Obesity and Diabetes

34:56 The Risk of Commoditization in Drug Markets

37:06 Differentiation in the GLP-1 Market

39:40 The Rise of Psychedelics in Psychiatry

47:21 Pharm-to-Table Model in Pharma

54:06 Empowering Patients through Direct Access

DISCLAIMER: The views and opinions expressed in this podcast are for informational and educational purposes only. They are not intended as medical advice and should not be used as a substitute for professional medical judgment or guidance. Always consult a qualified healthcare provider with any questions you may have regarding a medical condition or treatment.

JPM is always a tone-setter for the year in BioPharma. Everybody tunes into what the biggest companies in our space have to say. What’s their M&A appetite? How are they thinking about China? What about Trump? Platforms or Products? Their commentary dictates how other parts of our sector view their own businesses.

At some level, our sector is the truest expression of 'trickle-down economics.' When Big Pharma decides to buy or partner, that capital recycles back into VCs and public investors, eventually funding the next generation of Series A startups. More M&A at the top means bigger and more exits, and may in turn influence a functional IPO window and a reason for early-stage investors to keep writing checks.

So every year what is said during this week is important, even if it feels like there are less and less people hovering around San Francisco during this time of the year. The streets are less lively. The random bump-ins are less frequent. The after-parties have more elbow-room. Still the tone is set from the top - and that’s what today’s post is all about.

I dug through transcripts and slides from all the Big Biopharma companies1, connected the dots, and pulled out several key themes, insights, and implications that portend to shape the year ahead. Let’s get into it.

M&A Philosophy Divide

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Often times you hear a lot of the same talking points on key topics across the Big Biopharma CEOs. M&A can sometimes fall into this category. “We’re interested in bolt-on deals”. “We have an appetite for late-stage de-risked assets”. “We like pipeline-in-a-product type deals with clinically de-risked programs”. Certainly we’ve heard all that before and heard versions of that even at this JPM.

The real striking divide this time around was M&A philosophy. The matrix I created above is a helpful framing for where each major players sees themselves with regards to their desire to do deals and their LOE exposure (% of 2025 revenues facing erosion in the next 5 years).

Most companies sit in the bottom right quadrant, called “Growth Opportunists”. They have relatively moderate to low LOE exposure over the next five years, strong balance sheets, and are able to do deals more selectively with less pressing need for large late-stage acquisitions that bring in near-term revenues. They can jump into big meaty transactions if they want to, but it’s not as pertinent. It’s perhaps surprising to see a company like AbbVie and Roche in this quadrant, however both companies are largely past their major patent cliffs, digesting previously large acquisitions or big partnerships, and cultivating those programs now in-house.

The more interesting groups sit in the other three quadrants though.

In the top right you have companies (I am calling ‘Crisis Responders’) who have the highest percentage of their revenues threatened by patent cliffs and have naturally been the most acquisitive, and would seem to continue to be given their JPM commentary. BMS and Merck aiming to fill the forthcoming PD-1 revenue gaps with their slurry of late stage acquisitions are great examples of an aggressive external innovation strategy. Others in this group, like J&J and Amgen who do have rather significant revenues at risk over the next five years, appeared more balanced in their internal/external innovation split, and are more focused on early stage deals (per their comments) with optionality for larger deals if the right one comes up. Still, in those cases, deals to build the pipeline will likely play a roel

In contrast to this group sits Regeneron, a lone ranger of sorts. Its commercial revenues are at a relatively high (~30%) LOE risk, but their management made it a point to take a contrarian position against large-scale M&A, arguing that such deals lead to “value destruction”. Instead, Regeneron is betting on themselves, focusing 95% of its R&D resources on internal programs to organically grow out of oncoming patent cliffs and formulation strategies like transitioning its retina franchise from EYLEA to EYLEA HD to mitigate biosimilar erosion (note: it appears they are looking to take forward a similar strategy to stave off DUPIXENT patent cliffs in 2030).

As a strategy guy, I love that Regeneron came into JPM with such conviction on their plan. It shows a deep evaluation both of their own company strengths (which has long been their proprietary genetic and antibody platforms) and performance of their peers’ strategies. Regeneron is uniquely equipped to organically grow out of their patent cliffs, because of the strength of their platforms and they know it.

The bottom left, “organic innovators” bucket, is an interesting one too and tells a tale of two stories. On the one hand you have companies like Vertex and Lilly who are well equipped with cash-printing machines (GLP-1s and CF franchise), and have redeployed that capital heavily towards internal R&D but also towards select bolt-on product acquisitions and platform buys that can enhance R&D capabilities. If Regeneron is the home chef that is so good at cooking that eating out would just be a waste of money, Vertex and Lilly are equally talented home chefs, but love a nice fine dining tasting menu every once in a while. Had either of these companies been in the same LOE situation as Regeneron, they probably would also be telling the JPM crowd that they didn’t feel a significant urgency to do big deals, because their R&D engine has had a strong track record of hitting home runs. They could organically grow through their cliffs and pull the trigger on a big deal only if it really made a ton of sense.

On the other hand you have folks like Bayer and Takeda who I think would love to be able to do more deal, but really can’t because they are saddled with debt and/or insufficient firepower. In turn, they are more focused on growing their existing internal portfolios and making the most of what they have now.

An easy takeaway from this chart is that the right half of the slide are going to be your active buyers, bidding each other up and out for the next great product, while the companies on the left will be more or less staying put.

Policy Overhang Resolution: IRA, MFN, Tariffs

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Welcome back! I hope all of you experienced a restful holiday and are having a strong start to the new year. January in Biopharma is signified by the JP Morgan Healthcare Conference (JPM). This is where deal discussions begin for the coming year and also where major deals get announced. Anecdotally, we have seen M&A appetite from Big Pharma/Biotech pick up over the last few years. Buzz and rumors are accordingly picking up as well. Much of this has to do with everyone’s favorite two words [pause for effect]: Patent Cliffs!

2026 will be marked by healthy M&A activity from the top 15-20 or so players in our sector. And to that end, I thought a great way to kick off the year headed into JPM is to highlight who I think has a strong chance of getting acquired this year. Below I’ve stated the case for six companies (and maybe a bonus one or two) that I think will be acquired over the course of 2026.

If you enjoy strategic analyses, insights, and opinions about Biotech and Pharma from an insider’s perspective, you can get access to all Big Pharma Sharma content by becoming a paid subscriber. Thanks for your support!

2026 will be marked by healthy M&A activity from the Top 15-20 or so players in our sector. And to that end, I thought a great way to kick off the year headed into JPM is to highlight who I think has a strong chance of getting acquired this year.

Below I’ve stated the case for six companies (and maybe a bonus one or two) that I think will be acquired over the course of 2026.

If you enjoy strategic analyses, insights, and opinions about the Biotech and Pharma from an insider’s perspective, you can get access to all Big Pharma Sharma content becoming a paid subscriber. Thanks for your support!

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The final day of the American Society of Hematology (ASH) meeting is always a good one because of late-breaking presentations. ASH 2025 did not disappoint, with two huge data readouts that seem poised to impact the treatment of multiple myeloma (MM) in the near and long-term.

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MajesTEC-3 May Spell Trouble for CAR-T in the Near Term

J&J arguably had the most jaw-dropping data at ASH with MajesTEC-3. The study examined a combo of DARZALEX (daratumumab, dara, anti-CD38 mAb) with TECVAYLI (teclistamab, tec, BCMAxCD3 TCE) vs. Standard of Care combo therapies (Dara + dexamethasone + pomalidomide OR bortezomib) in patients with 2L-4L MM. The results, across 587 patients, were concurrently published in NEJM, with J&J calling these results “unprecedented” and if you look at the survival curves, it is clear why.

A hazard ration of 0.17 is pretty insane and 83% overall survival at three years, with the curves seemingly flat-lining is equally insane.

TEC is currently only approved in late-line (5L+) setting as a monotherapy in MM. If you’ve been following this space closely, you know that this 2L-4L setting is where JNJ, along with its partner Legend, already have CARVYKTI (BCMA CAR-T) approved via the CARTITUDE-4 study. J&J has now filed the DAR+TEC combo for FDA approval under the new real-time oncology review program. Approval of this new regimen would give J&J an option for every sort of patient in 2L+ multiple myeloma. CAR-T for those who can get it and DARA+TEC for everyone else.

Notably there were 5% of patients who died due to infections while on treatment, however after amending the trial protocol to reinforce IgG treatment and infection prophylaxis measures, only one infection-related death occurred.

What surprised me though is that when you look at the side-by-side between these two data sets, it’s really hard to see a difference between what you can get with DARA+TEC vs. what you can get with CARVYKTI alone. Efficacy-wise the combo looks on-par to slightly better than CAR-T. Safety-wise it looks to be better in the areas of most concern (CRS, ICANS, long-term cytopenias, and long-term neuro AEs). The infections are certainly concerning, but it seems as though being vigilant with prophylaxis measures can mitigate that

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If you want to read the prevailing view as to why BCMA CAR-T is still better than this combo, you should check out Arcellx’s ASH 2025 investor event deck. The first section does a nice job laying out the CAR-T bull thesis in 2L+ MM in detail, but the broad strokes go a little something like this:

• CD38 utilization in 1L MM is increasing significantly

• MajesTEC-03 has no data in patients who are CD38 refractory

• CD38 refractory patients do not perform as well on subsequent therapy in the 2L+ setting

• TCEs have worse real-world safety and efficacy than CAR-T, especially with regards to infections and non-relapse mortality

The Arcellx folks draft a very fair argument, and in comparison to their product, anito-cel, they may offer a better risk-benefit trade-off when compared to DARA+TEC, whenever they generate comparable data to CARITUDE-4. At least in Arcellx’s ASH update in the potentially pivotal iMMAgine-1 study in late-line MM, anito-cell looks to be at minimum on-par to CARVYKTI in efficacy and better than it on safety. And like any study, even the best ones are not without their warts and inconveniences. 67% of patients needed to skip at least one TEC dose, roughly 29% needed dose reductions, and 33% needed to delay dosing due to an AE. This regimen will also require vigilant infection management and IgG supplementation, and these are some of the down sides of continuous treatment, in comparison to something definitive like CAR-T.

The key factor in Arcellx’s case against DARA+TEC is the patients who are DARA refractory. In MajesTEC-03 it’s 0%, but in CARTITUDE-4 it’s much more (roughly 20%). It begs the question, despite how transformational MajesTEC-03 data appears to be on its surface, how often will it get utilized if most patients are coming to 2L treatment already failing a prior CD38-based regimen?

I think there is nuance here that is worth exploring. CD38 is a weird target in that there is good evidence that it gradually recovers after patients are off DARA for some time. A physicians unwillingness to try another CD38 also is affected by the combo partner. Sometimes adding a new combo partner can reinvigorate response despite prior refractory status. Other physicians also consider the dose frequency of DARA.

Depending on whether you are transplant-eligible or ineligible in the frontline setting, you may get a different DARA-based regimen, with some requiring continuous treatment or maintenance, and others being a fixed treatment duration too. Perhaps the power of MajesTEC-03 will also influence how DARA is used in 1L - shifting to more fixed treatment duration to avoid DARA-refractory disease.

For what it’s worth, I think the prevailing evidence in cell therapy points to sequencing CAR-Ts ahead of bispecifics generally. You have less likelihood of driving treatment resistance and exhausting your T-cells. It’s better make your CAR-T product when your T-cells are the healthiest. There are also non-BCMA options, like GPRC5DxCD3 bispecifics that can rescue response if patients fail BCMA. The challenge is that even if getting CAR-T first is better, most community hospitals don’t have access to it (although that is growing), and we may see more patients who exhaust a BCMA bsAb option earlier in their care journey. I think this dynamic really adds pressure for cell therapy developers to move into the frontline setting, sooner rather than later with a definitive treatment option.

When we play this out at the commercial level though, I think it will be really hard for community physicians to ignore the strength of DARA+TEC. Community docs aren’t typically keen to refer their patients out of their care to get CAR-T at an Authorized Treatment Center (ATC), until they’ve exhausted enough options within their sphere of care. That’s why studies like Arcellx’s iMMagine-5 in the community setting, and continued on-boarding of larger community hospitals in the commercial setting are key to increasing CAR-T adoption at an earlier line of therapy. As management of AEs and comfort with out-patient use increase, this also makes adoption in community hospitals easier. Per Legend , CARVYKTI is actually available at 131 ATCs, 38 of which are community hospitals.

The immediacy of treatment will play a role here as well. Right now BCMA CAR-Ts still take a month vein-to-vein. Arcellx and Kite will likely shrink that to 17-days or less if/when they launch. There is still an inordinately high percentage of patients who still require bridging therapy with BCMA CAR-T as well and while manufacturing capacity continues to increase, centers still complain about finding manufacturing slots. Being able to treat a patient right away and preserve CAR-T for later would seem to be the initial dynamic that sets in as community penetration slowly increases.

I am curious to see how Legend and J&J message CARVYKTI now. Perhaps there will be differences in how both commercial teams approach that, with the Legend team needing to perhaps adopt some of the counter-messaging the Arcellx team has already put forth.

Early In Vivo BCMA CAR-T Data Looks Good!

The other myeloma late-breaker was from Kelonia (another J&J affiliated company; they didn’t become the leader in myeloma just by sitting around you know) who shared first clinical data of its in vivo BCMA CAR-T, KLN-1010.

The data set was quite small, just four 4L+ patients, which is not usually big enough to get the late-break stage at ASH. That fact that it did tells you how excited people were for these results.

All four patients achieved MRD-negative response, with the patients response deepening to CR at 6-months. Notably the AE profile showed no ICANS, CRS G1-2, and no delayed neurotoxicities. Expectedly, the cytopenia profile was quite low as well, given in vivo CAR-Ts are not administered with lymphodepletion.

Look, it is still early days with in vivo CAR-Ts, but these results (at lower dose levels) are certainly encouraging. As more patients get treated, it will be important to see how many responses can convert to CRs. Kinetically, it was good to see Cmax being in line with CARVYKTI, suggesting that this product may have enough horsepower to generate persistent responses.

In heme/onc, if in vivo meets the CARVYKTI efficacy bar, continues to show a more moderate safety profile, and avoids long-term AEs, it means CAR-T will have entered the final stages of evolution. That’s a big reason why auto BCMA CAR-T stocks were down after these data (and the Majestic-03) abstracts were released. The Kelonia data shows that in vivo remains on that course, for now.

Vinay Prasad Wants to see Superiority in CAR-T Studies

During ASH, we got word that Vinay Prasad, the controversial CBER director, delivered some revised guidance on what he would like to see for CAR-T studies moving forward in JAMA. The tweet above from Ned Pagliarulo does a nice jobs summarizing the key points. Prasad wants to see RCTs with survival endpoints for earlier line settings. Single-arm studies could still be ok for late-line therapy or rare diseases. He also wants to see superiority studies against current CAR-Ts, and is perhaps only situationally interested in equivalence or non-inferiority vs. auto CAR-Ts.

On the surface this doesn’t feel a whole lot different than what precedent has been. Single-arm studies for settings without established SoC and RCTs with survival endpoints for earlier line settings have been the norm so far and what leading companies like Kite have done to advance Yescarta.

There are some potential questions to consider here though:

Do new CAR-Ts now need to go h2h vs. commercial CAR-Ts? If so, how do you run that study as a small company? Are you paying Gilead, BMS, JNJ, etc. to mfg. their commercial CAR-Ts? Reimbursing patients for commercial CAR-T? Either way that can get very expensive very fast. Will FDA let you go up against non-CAR-T SoC instead?

Companies like Lyell are already doing this it seems with its P3 study of Ronde-Cel (CD19/20 CAR-T) vs. commercial CD19 CAR-Ts. Credit to Lyell for dishing out the capital and taking on the risk to go head-to-head against commercial CAR-Ts. As I wrote a little while back, this was a choice other companies, for example Caribou, chose to eschew, perhaps due to the heavy financial lift. Lyell is unique in some ways, in that they have always been able to raise loads of capital, since its inception. I’m not sure there are too many small companies who have the finances to take on a challenge like this. Going up against YESCARTA and BREYANZI is surely a high bar, but if it pans out, it is really powerful data that would show clear superiority.

If superiority studies will be the preferred and non-inferiority seemingly more difficult (reading in between the lines of Prasad’s comments), in vivo CAR-Ts could be negatively impacted, depending on how efficacy is measured. Thus far efficacy has looked nominally lower (still early), but the advantages of immediate treatment are important in the current state of cell therapy. If measuring efficacy by ITT vs. mITT (only patients who make it to auto CAR-T), perhaps this favors formats like in vivo.

Furthermore, what does this new guidance mean for companies like Arcellx who are already at the proverbial goal line with anito-cel in a single-arm P2 study design? The good thing is they do have their confirmatory Phase 3 study ongoing (iMMagine-3), which looks to mimic CARTITUDE-4. With how capricious and unreliable this FDA seem to be though, I wonder if they will find this study design to be insufficient. Perhaps Prasad & Co. want to see anito-cel vs. TEC+DARA. Perhaps they demand Arcellx and Gilead include CARVYKTI in the comparator arm.

There is palpable regulatory risk here for me that wasn’t there before. Given how this FDA handled similar cased like Uniqure and Replimune , I have difficulty raising my confidence level to 100% that this FDA will play ball with the company’s regulatory plan. I am hopeful that they do. As I’ve written and stated before in the case of Replimune, it would be unfair for the FDA to hold companies like Arcellx who are already far down the accelerated + confirmatory approval path to new guidance that would further delay commercialization of a promising treatment, like anito-cel. But these days, you just never know. Both companies are doing and saying all the right things to reassure stakeholders, and I’m hopeful that this fear of mine is misplaced.

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So is this really the beginning of the end?

It’s probably too early to say definitively. However, the combination of the great MajesTEC-03 data, strong early in vivo BCMA CAR-T clinical signal, and new regulatory scrutiny should collectively raise the alert level for autologous CAR-T players that are relatively advanced, like Arcellx. The competitive landscape just got significantly harder, and the regulatory goalposts appear to be moving. There are still important cards left to play—community adoption data, 1L studies, and commercial execution will all matter tremendously. But the threats are real, both near-term and long-term, and companies that underestimate this convergence do so at their own peril. The autologous CAR-T story isn’t over, but it just got a lot more complicated.

In this deep dive into biopharma M&A trends, Shivu and Kenny analyze 10 years of acquisition data from major pharma players, revealing rising deal volumes and the increasing prevalence of Contingent Value Rights (CVRs) as risk mitigation tools. The hosts dissect the unprecedented Pfizer-Novo bidding war over Metsera, examining how this “interloper” situation reflects broader industry dynamics around patent cliffs and portfolio diversification strategies. The episode provides insider perspectives on why investors never seem satisfied with “enough” M&A activity and how companies balance internal R&D with external acquisitions in their portfolio approach.

CHAPTERS

00:00 Introduction to M&A in Biopharma

03:35 Understanding Contingent Value Rights (CVRs)

06:47 Recent M&A Deals and Trends

13:17 Impact of Patent Cliffs on M&A Activity

17:43 The Portfolio Approach to Drug Development

22:00 Current Trends in Deal Volume and CVR Usage

28:58 Valuation Trends in Late-Stage Companies

32:51 The Buyer-Seller Dynamic in Pharma Deals

38:27 Evaluating CVRs and Acquirer Capabilities

42:31 GenMab’s Strategic Acquisition and Market Positioning

48:11 The Rise of the Biotech Middle Class

55:49 The Aggressive Landscape of Pharma Hiring

56:56 Innovation in RNA Interventions

57:53 The Metsera Bidding War Begins

01:00:11 Pfizer’s Acquisition Strategy Unfolds

01:03:48 Regulatory Implications and Government Influence

01:07:41 The Future of Metabolic Disease Treatments

01:10:27 Interloper Behavior in Pharma Acquisitions

01:15:35 The Role of Government Relationships in Pharma

01:19:05 Concluding Thoughts on M&A Trends

01:22:14 OUTRO

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DISCLAIMER: The views and opinions expressed in this podcast are for informational and educational purposes only. They are not intended as medical advice and should not be used as a substitute for professional medical judgment or guidance. Always consult a qualified healthcare provider with any questions you may have regarding a medical condition or treatment.

We are in an era of unprecedented change and upheaval in the scientific and medical community, with federal funding challenges, FDA leadership shifts, and financial market uncertainty and malaise combined with scientific uncertainty. You see this reflected in the public markets with the XBI at roughly 40% below its peak in 2021. These dynamics have presented a particular challenge for the emerging biotech landscape with some areas harder hit than others.

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Cell therapy has been particularly hit hard, now being characterized as being an “out of favor” modality by investors. Many companies are filing for bankruptcy, laying off staff, merging, or simply abandoning the field completely. Commensurately, new company creation has collapsed. What was once a booming bastion of VC dollars has now seen few and far between. Total funding into cell therapy companies was roughly $9B in 2021 and has steadily declined, with annualized numbers at roughly $1B for 2025. We have seen a collapse in the number of funding rounds as well, most notably in the earlier Series A and B stages that are a fraction of what they once were.

What is masked in this downturn is the tremendous scientific, manufacturing and medical progress that continues to be made in the broader field of cancer therapeutics. Cancer treatment encompasses both established therapies—radiation, chemotherapy, targeted agents—and emerging modalities like bispecific antibodies, ADCs, mRNA vaccines, and radioligand therapies. Yet cell therapy remains one of the few approaches offering curative potential. We know this intimately, having lived the highs and lows of this field as experienced cell therapy executives who have spent nearly the last decade endeavoring to fully realize cell therapy’s promise and potential in solid tumors.

So how did we get here? How did we get to the place where a technology that has the power to cure solid tumors has fallen “out of favor”? And more importantly, what needs to happen to prevent progress from falling through the cracks?

The Overcrowding, Stumble, and Eventual Success of Heme CAR-T’s

The first CAR-T therapies targeted CD19 for B-cell malignancies and were brought to bear by partnerships between pioneering biotechs and leading research institutions. Kite with the NCI, Novartis with UPenn, and Juno with Sloan-Kettering and Fred Hutch, worked swiftly to accelerate these programs through clinical trials in record time. On August 30th, 2017, Novartis’ Kymriah became the first CAR-T therapy to achieve US approval, initially in pediatric acute lymphoblastic leukemia (ALL). Not too long after, Kite won approval of Yescarta for DLBCL on October 18th, 2017. From IND to approval Kymriah and Yescarta only took roughly 5 and 3 years, respectively - a testament to the curative potential showcased by both these products throughout its clinical journey.

This was a magical moment in the history of cell therapy - a therapy that cured cancer was now commercially available to patients. As is well chronicled, Emily Whitehead was the first pediatric patient treated with a CD19 targeted CAR T (what ultimately became Novartis’ Kymriah) for ALL. In 2022, she celebrated 10 years being cancer-free and in 2024-2025, many investigators called her “cured”. The promise and potential led to an explosion in interest in the field, with up to 2,500 cell therapy projects in development in the early 2020’s (2020-2021).

But what gets under-appreciated about bringing an entirely new therapeutic modality to market is the blocking and tackling required to commercialize and achieve the requisite scale. It is fair to say that these two initial products struggled right out of the gate with complicated deliveries, manufacturing failures, slow academic center training and approval. Ultimately, they did not meet revenue expectations in the early years of the commercialization. Over time the CAR-T market grew meaningfully as new BCMA targeting CAR-Ts came on line and the forerunning CD19 CAR-T class expanded into earlier lines of therapy, leading to Kite/Gilead’s YESCARTA and Legend/J&J’s CARVYKTI becoming blockbuster products with annual sales >$1B.

Despite this status, for much of the CAR-T class (all but CARVYKTI) sales have begun to flatline recently. The reasons for this are multi-faceted. Competition from the non-cell therapy class has eroded CAR-T market share, especially from the growth of the bispecific class, which offer strong (albeit likely not curative) efficacy, safety, and immediate treatment potential and a more site of care, making this class better suited for community hospitals where a significant amount of the heme/onc market exists. Additionally, incremental advances and novel cell therapy approvals that could have continued to advance the scientific frontier have slowed. Cell therapy has effectively ceded market share to competitive classes in oncology and/or pivoted to other diseases (e.g. autoimmune diseases) and other approaches such as in vivo CAR T.

So while CAR-Ts do offer curative potential in certain heme/onc diseases, the competitive dynamics they face, along with the manufacturing/logistical barriers, protracted time to treatment, and narrow patient eligibility limit the ability to address the unmet need that still remains.

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The Solid Tumor Cell Therapy Challenge: Targeting isn’t Easy

While hematologic cell therapies have achieved commercial success, translating these advances to solid tumors has proven challenging—until now. The key obstacle is target complexity. Heme malignancies present single, stable targets like CD19 or BCMA that are expressed across the entire tumor and healthy tissue that regenerates easily. In the case of B-cell lymphoma, every B-cell in the body will express CD19, malignant or otherwise. If one can eradicate everything that has CD19 surface marker, the tumor is removed as well. Once healthy B-cells regenerate, a patient can go on to live a normal cancer-free life. Solid tumors display multiple unstable targets that shift over time, allowing tumors to evolve and evade single-antigen therapies. Moreover the universally expressed single extracellular antigens one would typically target with a CAR-T also reside on healthy tissues that won’t regenerate so easily, leading to significant toxicity risk.

You either need to target the wide swatch of these unstable tumor-specific targets, or zero-in on one that is highly expressed in a select sliver of patients. Two solid tumor cell therapies demonstrate how to overcome this: Iovance’s Amtagvi (approved) and Immatics’ IMA203.

Approved February 2024 for metastatic melanoma, AMTAGVI takes a patient’s own tumor-fighting immune cells (TILs), expands them by the billions outside the body, then infuses them back. Unlike CAR-Ts that target one antigen, these naturally-occurring cells recognize multiple tumor targets simultaneously—making it harder for cancer to escape.

IMA203 engineers T cells to hunt intracellular cancer proteins that CAR-Ts can’t reach. By targeting PRAME—a cancer-testis antigen hidden inside tumor cells—it expands what’s druggable beyond surface proteins. The manufacturing process and administration are pretty much the same as CAR-T, the only catch is that the targeting modality is a TCR, which means it is HLA-restricted. This means that only patients with a specific HLA-type (in this case HLA-A2) can receive this treatment.

ICYMI Cell Therapy for Solid Tumors Works

One of the most critical measures of a treatment’s effectiveness is called Complete Response rate or CR’s. It is a subset of the Objective Response Rate (ORR), which includes both Complete Response (CR) and Partial Response (PR) and one of the most commonly used metrics for the effectiveness of a cancer therapy. When you can completely eliminate a cancer, there is a better chance it never comes back - i.e. leading to greater progression free and overall survival.

The early innings of solid tumor cell therapy have proven fruitful, representing a meaningful advance for patients who have no other treatment and options. While the logistics and manufacturing advantages of other approaches is well documented, the ability to generate high response rates and in some applications meaningful CR rates, should not be ignored. Most solid tumor doctors, save a couple tumor types, aren’t even accustomed to seeing complete responses in their patients at all with the most advanced non-cell therapy modalities like ADCs and bispecifics.

Importantly, this is just the beginning. The efficacy of these base profiles can further be tuned up with the programmable enhancements that overcome key solid tumor barriers or combination with other therapies. The data to date shows a clear signal and we have the toolbox of enabling technologies (gene editing, cytokine modules, anti-TME elements, etc.) to continue driving up the CR rate in these tumor types and others that have yet to be tapped.

The Investment Imperative: Don’t Abandon the Final Mile

We are at risk of losing technological momentum and US leadership in this critical technology precisely when breakthrough solutions are materializing. The next generation of cell therapies is actively addressing the fundamental barriers that have historically constrained the field—and this progress is happening across both biological and operational fronts.

The Barriers Are Being Solved—Right Now

The biological challenges—targeting complexity, limited potency, poor persistence, TME suppression—are yielding to innovative engineering approaches emerging from labs and entering clinical validation. Multi-antigen platforms, intracellular targeting, enhanced co-stimulation, and TME resistance modules are no longer theoretical; they’re generating clinical data.

Simultaneously, operational advances are making cell therapy scalable and accessible. Manufacturing timelines have compressed from weeks to days. Costs are dropping 50-70%. Point-of-care production and outpatient administration are eliminating the logistical barriers that limited first-generation products. Off-the-shelf approaches like allogeneic, iPSC, and in vivo are showing immense promise. What once required specialized academic centers can increasingly be delivered in community hospitals where most patients receive care.

Many of these innovations are in clinical development now, with data emerging and regulatory paths clarifying. We have the toolbox. We have proof it works in patients. We have multiple shots on goal.

This is not the time to give up. The field needs thoughtful, bold investment to get us not to the finish line but to the next era of medicine where cell-based therapies lead the way to curative opportunities across therapeutic areas.

Rather than marking the cell therapy class as “out of favor,” investors should prioritize technologies demonstrating genuine solutions to these barriers—greater patient eligibility, shorter time to treatment, reduced manufacturing complexity, validated TME-overcoming capabilities. Capital should flow to differentiated platforms with clear line of sight to addressing unmet biological and operational challenges, not to undifferentiated programs replicating past mistakes.

The Developer’s Responsibility: Differentiation Over Duplication

On the other hand, drug developers must learn from history. The field famously saw 150-200+ unique CD19 CAR-T programs in the 2020-2021 timeframe—an unwarranted number given the actual unmet need and commercial opportunity. There was no way all of these could succeed in the market, and a mass culling was predictable and necessary.

Today’s developers should ask hard questions before initiating programs: Does this approach solve a real biological barrier that existing therapies don’t address? Does it meaningfully reduce manufacturing cost or complexity? Does it expand the treatable patient population? Without clear affirmative answers, they risk perpetuating the cycle of overcrowding that contributed to today’s environment.

🎯 The Cell Therapy Reality Check: We’re Closer Than We Think
We have regulatory precedent (AMTAGVI approved February 2024)
We have proof of concept (meaningful CRs in solid tumors)
We have the engineering toolkit to iterate and optimize
We have solutions emerging for both biological and operational barriers

The question isn’t whether cell therapy can cure solid tumors—it’s whether we’ll sustain investment through the engineering optimization phase that separates breakthrough technologies from abandoned potential.

This is the moment for bold, thoughtful capital allocation to differentiated platforms. The next era of medicine—where cell-based therapies deliver durable cures across oncology and beyond—is within reach.

Cell therapy holds tremendous potential to cure solid tumors. We have proof we can meaningfully shrink tumors through AMTAGVI, IMA203, and other earlier-stage programs. We have regulatory precedent. We have multiple shots on goal. Cell therapy’s programmability offers unique advantages to quickly iterate, tinker, and enhance that other approaches can’t quite replicate.

The Choice: Sustain rational capital allocation through the difficult development phase, or abandon the modality with the strongest curative potential just as technical hurdles become solvable.

Cell therapy for solid tumors isn’t failing—it’s transitioning from proof-of-concept to engineering optimization. The work gets harder before it gets easier, but that’s exactly when sustained investment separates breakthrough technologies from abandoned potential.

If we want to cure solid tumors, we need to keep investing in cell therapy, even when it’s hard. Don’t confuse market correction with fundamental failure. Don’t flinch at the finish line.

It’s been a while since my last post. I’ve been tied up working on a few new things (more on that in the future). But while I was off we had a slew of interesting oncology data readouts that I am catching up on, specifically at ESMO. I’ll have a dedicated ESMO post for subscribers soon, but for today I wanted to discuss the interested data update from Caribou Biosciences .

The company announced new data for its lead health donor allogeneic CD19 CAR-T program, vispa-cel (CB-010), in 2L+ relapsed/refractory (R/R) large B-cell lymphoma (LBCL). It also provided a minor update on its BCMA CAR-T program, but I will focus my comments on the CD19 update, given that was more interesting and material to the company’s future.

Recall, Caribou has had some ups and downs with this lead program, and last year pivoted to employing an HLA matching strategy in an effort to boost the persistence of its cells. This isn’t quite the full vision of what healthy-donor allo’ was supposed to be, where cell doses manufactured from any donor could go into any patient. But the realities of their data were that persistence was reducing the efficacy profile of its product, prompting them to tinker and deploy an HLA-matching strategy, similar to what Atara has tried to with Tab-Cel. It is still off-the-shelf treatment, but commercially, doctors would have the added step of HLA-typing their patients and checking with Caribou to confirm that that patient’s HLA-type is covered by donor pool. For reference, Caribou needs 10 batches to be available to cover 98% of LBCL patients. The previous 4+ HLA allele formula required 13 batches of product to cover 90% of the target patient population.

In this most recent update, Caribou reported data from the ‘optimized cohort’, encompassing patients who received product that matched two ore more HLA alleles and was derived from “young” donors (aka under 30 years old).

Side note: when I saw that they were qualifying “young” as under 30, I immediately felt old and washed. Sadly I am no longer “young” in the biotech sense. I am grizzled grey-bearded veteran. Aka “old”.

The data looked pretty solid in comparison to YESCARTA (axi-cel) and BREYANZI (liso-cel), the two leading CD19 CAR-Ts in this space, with comparable efficacy albeit in a much smaller patient population. A profile that is on par with current CAR-Ts but with the convenience of an off-the-shelf approach, could tip the scales and enable more patients to choose CAR-T as a 2L option. Right now that isn’t happening all that much (25% according to Caribou), due to limited/no availability at community hospitals. Caribou is hoping a safety profile with low G3+ CRS and ICANS can penetrate into this Community hospitals, where physicians are typically using non-cell therapy treatment options and waiting to refer-out patients for CAR-T in the third line setting.

Next up for Caribou is determining whether this 2+ HLA matching strategy can work in a prospective fashion, followed by a P3 study in ASCT and CAR-T ineligible 2L patients.

Shares were up nearly 180% into the market open and roughly 30% when trading open but then came back down to earthy with the company ending the day flat. That tells me investors liked the headline numbers, but post investor call some harsh realities about the path ahead set in. It is unclear exactly what those are, but I have some ideas on what they might be.

How are they going to pay for the confirmatory Phase 3 study?

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There were two interesting news items this week that I wanted to provide my thoughts on. Neither of them were worth a full post each. I thought about just tackling these via posts on X and Notes, but instead decided to combine them into one short post.

Let’s get into it!

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GenMab’s Halloween Costume

The News: GenMab acquired bispecific antibody developer, Merus, for $8B (41% premium), adding petosemtamab (EGFR x LGR5 bsAb) which is in pivotal studies in 1L and 2L head & neck cancer.

So I’ve discussed Merus’ petosemtamab (peto) before and the interested race that is forming in the head & neck squamous cell carcinoma (HNSCC) space. I am not at all surprised Merus got acquired. Given peto it is a late stage oncology asset, with P3 data expected in 2026 (implying a potential approval in 2027), I would have guessed it would be one of the big fish in our industry doing the acquiring. An $8B acquisition for a late-stage asset is the sort of deal a Big Pharma does to plug-up a patent cliff. Instead, we saw a mid-size player with roughly $3B in cash raise $5.5B in debt to go out and do this. We got a glimpse of what GenMab is wearing for Halloween, and guess what? It’s a BMS costume.

I like this move a lot for GenMab. Not just because peto looks like a good drug that has a strong chance of approval in a disease where patients where patients do not have a whole lot of options outside of chemotherapy and PD-1 antibodies (check out my previous post where there is a nice data comparison table). The move fits with a larger strategic shift the company has been making for the past several years. For the longest time, GenMab was an antibody partner of choice for Big Pharma. Those partnerships led to some incredibly successful drugs and equally successful royalty streams, largely from J&J and best-selling multiple myeloma drug, DARZALEX.

On the surface, this is a nice business model if you can get it. Crank out great antibodies and let your Big Pharma partners do the work of commercialization, while you count your royalty checks. However, the other side of the coin here is that as a company you are really at the whim of your current partners and your ability to find future partners. Your revenue streams are entirely out of your control and building a sustainable business requires a high clinical and commercial hit-rate, with the commercial part being the part you have very little say in.

GenMab realized this a few years ago and set out to diversify its revenue streams, pivoting to retaining commercial rights for its programs but focusing in Oncology. I’m sure the impending patent cliff for DARZALEX (potentially 2029) also accelerated this thinking quite a bit. Successful launches of TIVDAK (co-commercialized with Pfizer/Seagen) and EPKINLY (Co-commercialized with AbbVie) got them the commercial reps they needed and now the company feels they are ready to go it alone. The acquisition of Merus is the capstone to this maturation, but those in the know will tell you the forbearer to this was its $1.8B acquisition of ADC company Profound Bio. That deal brought-in Riva-S ( FR-alfa ADC for gynecological cancers) that is set to compete with AbbVie’s ELAHERE starting in 2027.

So it’s clear to me GenMab’s longer-term vision is to be a diversified Big Pharma type player, but in the short-run, can they get to a healthy interim stage? The Wartortle to their Blastoise evolution goals?

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On Monday, Pfizer announced it is acquiring Metsera and its obesity pipeline. The deal values MTSR at ~$4.9B upfront and up to $7.3B based on milestones outlined in a contingent value right (CVR).

Key to the acquisition is Metsera’s diverse pipeline of obesity assets, spanning both oral and injectable GLP-1RAs, and combinatory mechanisms of actions like GIPR, Glucagon, and Amylin. Metsera’s lead asset is MET-097i a potential once-monthly formulation of GLP-1RA with improved efficacy and lower GI AEs (nausea, vomiting, diarrhea) compared to on-market competitors. Notably 097i is entering late-stage studies next year and its oral form could enter the clinic by the end of this year.

A smart move for Pfizer

This deal makes a ton of sense for Pfizer, who to this point had endeavored to make their mark in the GLP-1 space with its own pipeline. However, over the course of the last few years, Pfizer discontinued danuglipron, lotiglipron, and PF-06954522, the first two due to concerning liver enzyme elevations seen in clinical studies. Leading up to the Metsera acquisition, Pfizer management was pretty open about its interest in doing a deal to re-enter this space with differentiated long-acting and oral GLP-1 candidates. Metsera seems to fit that bill to a tee.

The Metsera pipeline checks the differentiation box, potentially offering more potent weight loss, with less side effects, easier titration, and more flexible dosing options. On Pfizer’s post-deal call, they alluded to having seen some of Metsera’s forthcoming VESPER-3 data disclosure, which reinforced confidence in MET-097i differentiated profile. I am not going to do a full side-by-side of the data vs. competitors, but the chart below from the folks at Morgan Stanley does a nice job highlighting how the early efficacy results are tracking. MET-097i has shown roughly 10% weight loss at just under three months. This tracks with Amgen’s MariTide and looks to be outpacing Lilly’s ZEPBOUND. Although this is perhaps slightly behind retatrutide at this early time point.

Moreover, it is clear that the future of this class is one of combinations. We started with GLP-1s like WEGOVY, have progressed to GLP-1 + GIPR targeting agents like ZEPBOUND, and are nearing entry of GLP-1 + GIPR + Glucagon (Lilly’s retatrutide). Beyond that, companies are pursuing amylin analogs in combination with GLP-1s, as well as muscle preserving targets like myostatin and activin-A. Metsera comes furnished with injectable and oral forms of all these, sans muscle preservers, providing Pfizer with a healthy palette of diverse molecules to help address multiple customer segments within obesity, but more importantly, the wide swath of adjacent diseases where GLP-1 based treatment has started to show therapeutic promise.

Putting myself in Pfizer’s shoes, the real kicker, beyond the potential for a better product profile, is how the potency and dosing of Metsera’s molecules lower API requirements and impact COGs. Metsera has a nice slide on this below, and assuming their calculations are true, this COGs delta could prove to be a valuable commercial advantage. What we’ve seen from the early returns in the obesity market is that it is heavily consumer-driven. Most (pretty much all aside from a few) don’t cover GLP-1s for weight loss. That may change with time and more data, but I don’t see the consumer/cash pay portion of this market going away anytime soon. Right now it’s roughly $500/month for WEGOVY or ZEPBOUND. As a latecomer to this market with two well-established competitors that are far ahead, having this COGS advantage is key as it afford Pfizer more price flexibility in a cash-pay market. Coming in at a lower price is one way you can drive up your market share as a third or fourth to market player.

Overall I like this deal for Pfizer and I imagine they will continue to invest heavily in building out the clinical programs for Metsera’s portfolio beyond obesity, both to help stem revenue loss from LOEs of ELIQUIS and eventually leverage that commercial footprint towards its budding obesity portfolio.

Tiring of the lazy corporate strategy by FOMO analysis

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DISCLAIMER: The views and opinions expressed in this podcast are for informational and educational purposes only. They are not intended as medical advice and should not be used as a substitute for professional medical judgment or guidance. Always consult a qualified healthcare provider with any questions you may have regarding a medical condition or treatment.

Fda Makary Timeline 20250825015842

473KB ∙ PDF file

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CHAPTERS:

00:00 The FDA's Independence and Scope

02:53 Timeline of Instability at the FDA

14:00 Impact of Instability on Drug Development

19:54 Case Study: RepliMune's Regulatory Journey

34:00 Navigating FDA Interactions and Accelerated Approvals

58:03 The Role of a Healthy FDA: History and Function

01:12:40 Organizational Culture and Stability in Regulatory Agencies

01:15:24 Navigating Institutional Changes at the FDA

01:18:45 The Importance of Consistency in Health Guidelines

01:22:27 Transparency and Data Disclosure in Drug Approvals

01:25:18 The Case for an Independent FDA

01:29:53 Lessons from the Federal Reserve's Independence

01:35:11 Engendering Trust in Health Institutions

01:41:49 Final Thoughts

CONTACT US:

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I woke up yesterday morning to some surprising news. Gilead (Kite) just entered into the highly competitive in vivo cell therapy space with its acquisition of Interius BioTherapeutics for $350M. This follows string of recent deal activity which saw AbbVie acquire Capstan (for up to $2.1B) and AstraZeneca acquire EsoBiotec (for up to $1B).

This deal is significant for a number of reasons, as it is the first acquisition in this space by a leading commercial cell therapy player. While Kite’s CD19 CAR-T franchise continues to be a category leader, its place on that pedestal has been threatened as of late by growth of J&J’s CARVYKTI in Multiple Myeloma, in-class competition from BMS’ BREYANZI, as well as out-of-class bispecific antibodies that can readily be given off-the-shelf and more easily administered in the community-setting, while still retaining an attractive therapeutic profile. The latter two factors have combined to flatline CD19 CAR-T sales for Gilead over the past several quarters.

Why now for Gilead/Kite and how does this fit?

We all know manufacturing autologous cell therapies is really expensive. Kite and others have steadily pushed down costs by increasing scale and exploring faster/shorter manufacturing methods, but those methods have their fundamental limits, which now close to 8-years post-acquisition, I would think we are already at or well-past. In vivo, in oversimplified terms, helps transform autologous cell therapy into gene therapy. Rather than manufacturing your product outside the patients body and shipping it back to them, you can infuse the patients body with a vector that makes the product right inside them. This eliminates the complicated logistics, protracted turnaround time, and manufacturing investment that have bogged down autologous CAR-T.

Having worked on the Kite deal itself during my Gilead days, helping to shape the company’s strategy post-acquisition, and seeing how things have unfolded since then, I can tell you that in vivo was always the final frontier. The surprise to me is that all the steps in between to get to in vivo have largely not worked well or have been slow to progress. Healthy-donor allogeneic approaches from companies like Allogene, Caribou, CRISPR, and Precision Biosciences have had their set backs and delays. The field of “non-classical” (aka non-T-cell) based approaches like NKs, NK-Ts, and gamma-deltas have moved slowly and faced hurdles generating potent and persistent product. IPSC derived approaches, like those of Fate and Century Therapeutics were all the rage for a time and at one point felt like they caught up to healthy-donor allogeneic approaches, before running into their own product challenges. Fast-CAR approaches (which I’ve written about extensively before) have also shown promise, but also have their own speed limitations related to regularly requirements for release-testing. Decentralized models, like what the folks at Galapagos were (are?) championing also looked super interesting, but again progress has seemed to stagnate.

All of this comes at a time, over the last few years, where biotech at large has been hit really hard by the macroeconomic headwinds - but cell therapy, the most capital intensive segment of biotech, especially so. We’ve seen companies shut down, get acquired for pennies, and also pivot into autoimmune disease to try an breath new life only to then be acquired for a discount. The stories have been all too common. Amidst this climate, where forbearing technologies had run into hurdles and either slowed or gone by the way side, the field of in vivo cell therapy has been able to catch up and reach an inflection point.

Kite too has invested in many if not all of the above precursor approaches either themselves or via partners, but nothing has gained much traction. The pipeline remains thin and is a shadow of what was once a grand vision of multiple successive iPhone-like generations of iteratively better products across key verticals. What was once thought to be a platform acquisition has in-practice become more of a pipeline-in-a-product type acquisition. There’s nothing wrong with that, it’s just different than what the initial vision was and the reasons for this deserve its own post. Either way its still a company that is manufacturing a phenomenal drug (and potentially another one on the way in anito-cel) that is generating blockbuster revenues, albeit potentially hitting a commercial ceiling with its current label.

Buying into in vivo takes the cap off that commercial ceiling over the long term, enabling CD19-based CAR-T therapies to treat more patients at lower COGS and importantly, in more indications - including immunology and inflammation (I&I). This has been an area where Gilead/Kite has indicated interest, but not taking significant public steps forward in. Now having a portfolio of in vivo assets in-hand, the company can more easily adapt to commercial scale, pricing, and rebate-shenanigans required to be a commercial success in that space. Certainly all of this new stuff needs to work and have the clinical data to prove it, but I commend the company for taking its medicine and going down the in vivo path, albeit after some of its up and coming competitors have.

The In Vivo Party - Who’s Arrived? Who still hasn’t shown up?

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Moderna's Q2 2025 earnings call revealed a company at a critical juncture. Revenue hit $142 million, beating estimates, but management announced they're cutting 10% of the workforce. Here's an organization sitting on $7.5 billion in cash yet reducing headcount to save about $1.5B.

Morgan Stanley held their Equal-weight rating unchanged despite the beat - that $31 price target tells you everything about where the market stands on platform premiums these days. They've stopped paying for potential and started demanding proof.

In a previous post, I flagged this strategic drift - their platform-centric, TA-agnostic approach risked creating exactly these constraints. We're now watching those predictions play out in real time.

The Revenue Cliff: Post-COVID Economics Take Hold

The Q2 numbers strip away any remaining illusions about COVID tailwinds. Revenue cratered 41% year-over-year to $142 million, posting an $825 million net loss. COVID vaccine sales contributed just $114 million quarterly - pocket change compared to pandemic peaks.

Management slashed full-year guidance from $2.5 billion down to $1.5-2.2 billion, citing UK delivery timing that exposes their continued reliance on government contracts over commercial markets.

Cost reduction targets are aggressive: $1 billion cuts this year, another $500 million in 2026, shooting for breakeven by 2028. OpEx dropped 27% to $1.1 billion, but the math still doesn't work at current revenue run rates.

Their virus programs matter for deepening their vaccine franchise. CMV Phase 3 data this fall, RSV mRESVIA approvals, COVID/flu combo resubmission - success maintains their infectious disease positioning. Setbacks would sting but wouldn't fundamentally change their vaccine company identity.

We saw many of the other COVID darlings (Pfizer, and BioNTech notably) leverage their windfalls to exact a string of BD&L that prepared their pipelines and commercial revenue streams for the post COVID era. Moderna at one point was seeing $18B in peak COVID-era revenues for Spikevax. Obviously, no one thought that that would continue as the pandemic waned and moved into an endemic phase. While its peers invested their profits in new drugs, Moderna was a bit hamstrung by their corporate strategy. They are an mRNA only-company and are agnostic to TA. That’s not a bad thing, but it is a choice. There are less things to buy for an mRNA company than an Oncology company (BioNTech). Still, there was a hope that the peak was supposed to fund platform expansion. Instead, we're observing a steady decline.

We saw many of the other COVID darlings (Pfizer, and BioNTech notably) leverage their windfalls to exact a string of BD&L that prepared their pipelines and commercial revenue streams for the post COVID era. Moderna at one point was seeing $18B in peak COVID-era revenues for Spikevax. Obviously, no one thought that that would continue as the pandemic waned and moved into an endemic phase. While its peers invested their profits in new drugs, Moderna was a bit hamstrung by their corporate strategy. They are an mRNA only-company and are agnostic to TA. That’s not a bad thing, but it is a choice. There are less things to buy for an mRNA company than an Oncology company (BioNTech). Still, there was a hope that the peak was supposed to fund platform expansion. Instead, we're observing a steady decline.

The Alnylam Playbook: How Platform Companies Can Evolve

Want to understand what Moderna could have done differently in the post-COVID era? Look at Alnylam. Both companies built around RNA technologies facing identical delivery challenges. Their approaches to solving those challenges reveal completely different strategic philosophies.

Alnylam ran disciplined platform evolution. Started narrow with rare genetic diseases - clear target validation, predictable regulatory paths. Onpattro for hATTR in 2018. Givlaari for acute hepatic porphyria in 2019. Oxlumo for primary hyperoxaluria in 2020. Each commercial success built therapeutic expertise, regulatory relationships, and cash flow enabling systematic expansion into cardiovascular, CNS, and infectious disease applications.

In contrast, Moderna was shot out of a cannon, with mRNA programs in every disease area under the sun. They were incredibly well funded as a private company and spread themselves too thin in the early days. Multiple irons in the fire waiting for one hit. In some ways the pandemic forced them into picking lane. They were the right technology at the right place at the right time, but pre-COVID, never did you get the sense that they had an organizing principle behind their corporate strategy other than “mRNA for everything”. Maybe when the “hit” came, they were banking on that being the forcing function for their corporate strategy.

Alnylam invested relentlessly in solving core platform limitations internally. They evolved from basic LNPs to breakthrough GalNAc conjugate technology for targeted hepatocyte delivery, then Enhanced Stabilization Chemistry for improved siRNA stability. These were iterative improvements that summed to fundamental breakthroughs to unlock new therapeutic applications.

However, Moderna chose differently. Their platform investments focus on "second-generation LNPs" with improved stability and manufacturing scale. Meaningful advances, but incremental improvements to vaccine-optimized technology rather than breakthroughs needed for broader therapeutic applications. Their LNP tech remains stuck in systemic distribution mode - fine for immune activation, limited for tissue-specific targeting that would more easily unlock other lucrative TAs like autoimmune, metabolic, or CNS applications.

It's funny to think that at one point Moderna was a $180B company (Sep ’21) and is now roughly an $11B company. Alnylam around that time was in the $22-$23B range but today is at a record high of $55B.

The partnership pattern I analyzed previously tells another part of the story. Moderna consistently plays delivery truck while partners own therapeutic biology. For instance, in their cell therapy partnership with Carisma, Carisma drives CAR-Macrophage innovation while Moderna provides LNP manufacturing. With Vertex, it is Vertex who controls gene editing science and regulatory strategy while Moderna handles delivery infrastructure. You can argue that both of these partnerships were solid endeavors. Maybe in the Carisma case, the Moderna folks picked the wrong cell-type and perhaps opting to participate in in vivo CAR-T for something like auto-immune disease would have led to a more fruitful partnership.

Putting partner selection aside though, these types of deals reflects organizational DNA optimized for immune activation and mRNA manufacturing, not the comprehensive platform capabilities and evolutionary plan needed for independent value capture that a company like Alnylam is currently living.

Oncology: Where Strategic Fate Gets Decided

Vaccine programs affect performance within established capabilities. Moderna’s most anticipated oncology program is intismeran (INT, Neoantigen mRNA vaccine), partnered with Merck. The lead program is in adjuvant melanoma, in combination with pembrolizumab, with readouts set to determine what kind of company Moderna becomes. This could be the first real proof that mRNA medicines have a commercial future beyond preventing or mitigating the severity of infectious diseases.

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AbbVie has long been one of the biggest and most significant acquirers in the Big Pharma sector since its inception in 2012. They have only ever had one CEO, Richard (Rick) Gonzalez, until its recent shift, to his successor, Robert (Rob) Michael. And the new CEO has been busy. Rattling off a small handful of key deals to bolster AbbVie’s future pipeline.

What struck me was not the impetus to “get some deals done” right away. This is a common occurrence when Big Pharma have leadership hand-offs. New leadership means new strategy, and one of the biggest ways you mark the new direction of your ship is by doing some deals. The thing that caught my attention though was the types of deals that AbbVie has done in its new chapter. It’s still early days into Michael’s tenure, but the company’s early maneuvers seem to signal a major departure from the Rick Gonzalez era – one that has left behind the company’s penchant for large late-stage transactions to one that is defined by smaller earlier stage deals.

AbbVie Under Rick Gonzalez: Big Game Hunting

Just take a look at the table above. It is littered with some of the most famous and infamous deals in recent Biopharma history.

Buying Pharmacyclics for $21B was my first ‘WTF?’ moment in my career. $21B for an encumbered drug (J&J owned ex-US rights from previous deal with Pharmacyclics) , but in hindsight IMBRUVICA became one of the most consequential drugs in heme/onc, registering $12B global peak sales. It now faces heavy in-class competition, but it had a multi-year run where it was incredibly unchallenged.

An even bigger ‘WTF?’ moment was AbbVie buying Allergan for $63B. Why would a company with foundational businesses in immunology and heme/con buy an aesthetics, eye care, neuroscience company? This sort of deal was a strategy defining deal in the first chapter of AbbVie. TA synergies didn’t matter as much as topline and bottom-line growth.

What about the deals that didn’t happen? Remember when AbbVie was set to buy Shire during the whole tax inversion craze of the 2010’s? This was a time in biotech history where big US companies would look to buy smaller companies domiciled in tax-favorable nations, enabling them to benefit from lower corporate tax rates, increase profits and potentially make it easier to repatriate foreign dollars. AbbVie was set to take on the rare disease/neuro powerhouse, Shire, for $55B, but the deal fell apart after the US Treasury rules changed to limit the tax benefits of these sorts of transactions. R.I.P. ShAbbVie, but under Gonzalez cash was king and tax rate was queen

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