Every year, roughly 83,000 Americans are diagnosed with bladder cancer. Of those, about 70-75% have what’s called non-muscle-invasive bladder cancer, or NMIBC -- meaning the tumor hasn’t grown into the muscular wall of the bladder. It’s still on the surface, the inner lining. That’s the good news. The less-good news is that NMIBC has a nasty habit of coming back after surgery, and somewhere between 30 and 40% of those patients have intermediate or high-risk disease that needs more than just tumor removal.

So what do doctors do for these patients?

They thread a catheter into the bladder and inject a tuberculosis vaccine: they hold it there for about two hours. They repeat this maneuver, once a week, for six weeks. And it works! Around half of high-risk patients will still be cancer-free five years later, which is significantly better than any chemotherapy drug available for this disease.

Yes, you read that right: the standard treatment for one of the most common cancers in the United States is a tuberculosis vaccine, poured directly into the bladder.

How on earth did we get here?

Bacteria and cancer: an old marriage

The vaccine in question is BCG -- full name Bacillus Calmette-Guérin -- christened for being the brainchild of two scientists Albert Calmette and Camille Guérin, who spent 13 years at the Pasteur Institute in Lille, France, painstakingly weakening a strain of bovine tuberculosis bacteria. Between 1908 and 1921, they subcultured this strain of bacteria approximately 230 times on glycerine-bile-potato medium (sound delicious, doesn’t it?) until its virulency was softened to “can cause strong immune response” from “can cause tuberculosis”. On July 18, 1921, the vaccine was given to a newborn baby at the Charité Hospital in Paris - a child whose mother had just died of tuberculosis. Miraculously, despite being maternally exposed, the baby never developed TB, and BCG went on to become the most widely administered vaccine in human history. To date, over four billion doses have been administered across the world.

What about the BCG-cancer connection? Well, that took another half-century of observations, experiments... and a fair amount of professional ridicule.

The intellectual paper trail starts with a New York bone surgeon named William B. Coley. In 1890, Coley lost a young patient to sarcoma and, haunted by it, started digging through hospital records for any case where a similar cancer had successfully resolved. He found one, and it was weird (in medical lingo, I believe this case would be considered a zebra.): a man with an inoperable cheek sarcoma whose tumor had completely disappeared after he contracted a life threatening streptococcal infection. Intrigued, Coley spent months tracking the guy down in the tenement slums of the Lower East Side of Manhattan. Eventually, he found him, alive -- free of cancer, seven years after he had survived the severe strep infection.

Coley spent the next four decades injecting bacterial mixtures -- heat-killed Streptococcus and Serratia marcescens, later called “Coley’s toxins” -- into more than a thousand cancer patients. He documented genuine remissions in sarcomas, lymphomas, and testicular cancers across 150 publications. His own supervisor at Memorial Hospital, a pathologist named James Ewing, thought it was dangerous nonsense and championed radiation therapy instead. The FDA went further, effectively banning Coley’s toxins in 1962 -- decades after his death. But Coley kept at it for his entire career, publishing case after case, because he’d seen the remissions with his own eyes. Today, he’s vindicated: he’s recognized as one of the fathers of cancer immunotherapy.

A few metropolitan areas south of Coley, another man with an astute eye was approaching a similar hypothesis about cancer after finding an interesting pattern in rows of numbers. His name was Raymond Pearl, a biostatistician at Johns Hopkins; and in 1929 while he was analyzing a dataset of 7,500 autopsies, he noticed something about decedents with a history of tuberculosis infection: they had significantly lower rates of cancer than those without. How he didn’t chalk this up to statistical bias, I don’t know. Critics at the time certainly tried -- maybe TB patients just died too young to develop cancer. But the finding lingered in the background of immunology for decades, the kind of anomaly that nobody could quite explain away or do anything with.

Then, in 1959, a young physician named Lloyd Old at the Sloan-Kettering Institute did something with it. He published a two-page paper in Nature that changed the game. Working with Donald Clarke and Baruj Benacerraf, Old showed that mice infected with BCG developed increased resistance to subsequently transplanted tumors. BCG-activated macrophages attacked the tumors and extended survival. It was the first direct experimental proof that you could deliberately mobilize the immune system against cancer.

(Old, by the way, went on to co-discover tumor necrosis factor, help identify p53, and author over 800 papers. When he died in 2011, Nature Immunology called him the “Father of Modern Tumor Immunology.”)

The 1960s and ‘70s: BCG mania, BCG disappointment, BCG revival

Old’s paper kicked off a wave of clinical experimentation. Researchers tested BCG in melanoma, leukemia, lung cancer, colon cancer, breast cancer - you name it. At UCLA, surgical oncologist Donald Morton injected BCG directly into melanoma tumors and saw 90% of the injected lesions shrink. Some uninjected tumors were disappearing too, suggesting that patients were experiencing a systemic immune response.

But the enthusiasm outran the evidence. Trial after trial in other cancers came back negative or inconclusive. A definitive randomized lung cancer study of 425 patients showed zero benefit. The pattern kept repeating: BCG would produce tantalizing local responses, then fail to deliver consistent results in controlled settings. By the mid-1970s, the oncology establishment was losing patience with BCG and with immunotherapy in general.

These setbacks didn’t dissuade a particular Alvaro Morales, a Colombian-Canadian urologist at Queen’s University in Kingston, Ontario.

You see -- Morales recognized something that, in retrospect, seems obvious. Earlier animal experiments by Baruch Zbar and Herbert Rapp at the National Cancer Institute had established four criteria for BCG to work against tumors:

• the patient’s immune system has to be functional

• there need to be enough live bacteria in the bolus

• the bacteria need to be injected in close physical proximity to the cancer cells

• the tumor burden had to be small

Superficial bladder cancer, Morales realized, met every single criterion. The bladder is a sealed, accessible cavity; you can catheterize BCG directly onto the tumor surface and hold it there - and the tumor burden after surgical resection is minimal. Most of the patients he was seeing were also immunocompetent. In short, he realized that the bladder was the ideal organ for BCG immunotherapy -- arguably the only ideal organ.

When Morales applied for a grant from the National Cancer Institute of Canada, the reviewer flatly rejected it: “BCG is not only ineffective and dangerous but a throwback to the stone age of tumor immunology.”

But the research was rescued by the Cancer Research Institute in New York - an organization founded in 1953 by none other than Helen Coley Nauts, who was William Coley’s daughter. After his passing, she had made it her life’s mission to preserve her father’s legacy of bacterial cancer therapy. The symmetry here is almost too neat!

Morales ran his trial at Kingston General Hospital starting in 1973. Having obtained samples of freeze-dried BCG from the Institut Armand Frappier in Montreal, he devised his protocol: 120 mg of BCG in saline; instilled through a catheter; retained in the bladder for two hours; rinse and repeat weekly for six weeks.

(One entertaining footnote: the six-week schedule was partly because the BCG shipped from the Frappier Institute came packaged six vials per box. It later turned out to be a genuinely excellent treatment duration... sometimes the universe just hands you one)

His 1976 paper in The Journal of Urology reported results in nine patients -- nine! The outcome: a twelve-fold reduction in tumor recurrence. And zero of the nine patients relapsed in the years following their treatment.

Predictably, however, the urological community’s response ranged from skeptical to hostile; BCG had burned too many people in too many other cancers. But confirmatory trials at Memorial Sloan Kettering and the University of Texas San Antonio replicated his findings, and a landmark Southwest Oncology Group trial published in the New England Journal of Medicine in 1991 settled it for good: for carcinoma in situ of the bladder, BCG produced a 70% complete response rate versus 34% for the best available chemotherapy. The five-year disease-free survival rate was a whopping 45% versus 18%.

With this irrefutable data readout in hand, BCG became a gold standard therapy for this disease. The FDA approved intravesical BCG in 1990, making it the first FDA-approved cancer immunotherapy in the United States. And it remains the only intravesical agent ever proven to prevent disease progression -- not just recurrence -- to muscle-invasive bladder cancer.

One catch: since 2012, the world has been in the grip of a chronic BCG shortage. Sanofi Pasteur’s manufacturing plant in Toronto was shuttered after flooding, mold contamination, and -- in a detail that captures the absurd fragility of this supply chain -- nesting birds in the air handling system. Sanofi permanently gave up on its BCG product in 2016, leaving Merck as the world’s sole major supplier. Despite Merck increasing production by over 100%, they still can’t meet global demand. BCG is a live organism; each batch takes about three months to produce under stringent sterility controls. The shortage has now lasted over 13 years, forcing doctors to ration doses, substitute inferior chemotherapy, or in some cases recommend full bladder removal for patients who might have kept their bladders if BCG were available. Merck has committed $650 million to a new facility expected to come online in late 2026. Until then, one of the most effective cancer drugs in the world remains one of the hardest to get.

Why I like this story beyond bladder cancer

The BCG story is, on its surface, a fun piece of medical history. But I think it’s also one of the best illustrations of two things that keep showing up in the history of drug discovery, both that I find endlessly fascinating:

1. Sometimes, the most improbable corners of medicine collide

A tuberculosis vaccine, derived from cow bacteria, attenuated over 13 years in a French laboratory, ends up as a bladder cancer treatment in Canada, funded by the daughter of a 19th-century bone surgeon who injected streptococcal bacteria into sarcoma patients. If you pitched this as a novel, your editor would send it back with “too contrived” scrawled in the margins.

But it happened!

Drug repurposing stories like this are common enough that you’d think we’d stop being surprised, but the improbability of the connections never quite loses its punch. Odds are you’ve heard of these, but I’ll run through them anyway:

• Thalidomide - the drug that caused a generation of birth defects - turned out to inhibit blood vessel growth and is now a frontline treatment for multiple myeloma.

• Viagra (boners) and minoxidil (hair) were both failed blood pressure medications that ended up being great for older guys.

• Metformin, the world’s most prescribed diabetes drug, started life as a treatment derived from French lilac, a folk remedy for frequent urination that had been known since the Middle Ages

I can go on, obviously - but if you’d like to read about more interesting drug repurposing stories, read Derek Lowe’s piece on the topic

2. Physicians notice things that bench scientists miss

The BCG-cancer connection was assembled, piece by piece, by people who were paying attention. First, it was Coley noticing that a cancer patient’s infection coincided with tumor regression - and instead of writing it off as an anecdote, he pursued it for forty years. Then it took Pearl noticing the inverse relationship between TB and cancer in autopsy data. And Old proving the mechanism in mice. And Morales recognizing the bladder as uniquely suited organ for testing BCG efficacy in cancer and designing a trial around that insight.

Each of these steps required someone who was both a practicing clinician and a curious scientist -- someone who could stand at the bedside and see a pattern, then walk to the bench and test it. This physician-as-discoverer archetype comes up again and again in the history of medicine, and I find it really cool how many examples like these rhyme with the BCG story. I’ll indulge you with a few:

In April 2012, six-year-old Emily Whitehead became the first child to receive CAR-T cell therapy for her relapsed acute lymphoblastic leukemia at the Children’s Hospital of Philadelphia. Her lab-engineered T cells were at war with her cancer - in the process, triggering a catastrophic cytokine storm in her body. Her blood pressure cratered to 53/29, and she developed a 105°F fever. She was put on a ventilator; doctors told her parents she had a one-in-a-thousand chance of surviving the night.

The treatment team, working with CAR-T pioneer Carl June at Penn, ordered a broad cytokine panel - 30 analytes - and the results showed that one protein, interleukin-6, was wildly elevated. IL-6 is not even produced by T cells, so nobody in the field would have predicted it was the culprit. But it happened to be one of the very few cytokines that had a specific FDA-approved drug to block it: tocilizumab, a monoclonal antibody used to treat rheumatoid arthritis. And Carl June happened to know about tocilizumab because his own daughter, about a year older than Emily, had arthritis and was being treated with it.

He advocated for them to give it a try. After all, there wasn’t much left that they could do: so they gave Emily the drug. Within hours, she stabilized. She woke up on her seventh birthday. And eight days later, she was declared cancer-free.

Tocilizumab went on to become the standard treatment for cytokine release syndrome in CAR-T therapy, receiving adjunct FDA approval for that indication along with CAR-T’s approval for ALL in 2017. It was eventually also approved for COVID-19-related cytokine storm during the pandemic.

An arthritis drug, repurposed by a cancer researcher who recognized the connection because of his daughter’s medical condition, now manages a life-threatening side effect of one of the most advanced cancer therapies ever developed and also treats the immune overreaction caused by Covid. Pretty neat story.

OK, one more. In 1961, a young Navy surgeon named Judah Folkman was stationed at the National Naval Medical Center, tasked with developing artificial blood substitutes. While perfusing rabbit thyroid glands with hemoglobin, he noticed something kind of odd: tumors -- often a common sight in the glands of these rabbits -- weren’t growing the way they did when the glands received actual blood. Specifically, he found that they couldn’t recruit new blood vessels. Without that supply line, they stayed tiny.

Folkman spent the next decade formalizing that observation into a hypothesis: tumors depend on growing new blood vessels -- angiogenesis -- and if you could block that process, you could starve cancers into submission. He published the theory in the New England Journal of Medicine in 1971.

The scientific community’s response was vicious. Like Morales and Coley, Folkman was called a charlatan. The eminent virologist John Enders, when asked to review one of Folkman’s early papers, reportedly told him not to worry about anyone stealing his ideas - they were “theft-proof” because nobody would believe them.

But these taunts didn’t deter him. And for over a decade, Folkman worked in relative isolation, insisting that the future of cancer treatment was cutting off blood supply rather than cutting out tumors.

He turned out to be right of course. His lab discovered angiostatin, endostatin, and the anti-angiogenic properties of thalidomide. And in 2004, the first angiogenesis inhibitor - bevacizumab (Avastin) - was approved by the FDA for colon cancer. Today, over a dozen anti-angiogenic drugs are approved for various cancers, and more than 1.5 million patients have received them.

The takeaway of BCG

There is a recurring pattern in medicine where the people who see something new are the people positioned at unusual intersections - whether it be a bone surgeon reading old case files to do right by a former patient he couldn’t cure; a urologist who understood immunology criteria for bacterial therapy; a Navy surgeon watching tumors in rabbit glands; or a cancer researcher who happened to know an arthritis medication because of his daughter.

A century-old preparation of weakened cow bacteria, developed to prevent tuberculosis in French infants, remains one of the most effective cancer treatments available. We are still discovering how it works - a 2025 study in Cancer Cell showed that BCG can actually travel to the bone marrow and reprogram stem cells to produce immune cells with enhanced anti-tumor capability, a shock to the formerly well accepted theory that BCG operated only locally in the bladder.

When the 2018 Nobel Prize in Physiology or Medicine was awarded to James Allison and Tasuku Honjo for their work on immune checkpoint inhibitors - research which served as the basis of drugs like Keytruda and Opdivo that have transformed oncology - it was the culmination of a story that runs in a direct line from Coley’s bacterial injections in the 1890s, through Old’s BCG mouse experiments in the 1950s, through Morales’ nine-patient trial in the 1970s. BCG was the proof of concept: you can turn the immune system against cancer. Everything that followed built on that foundation.

And all of it because a couple of French researchers spent 13 years passing a cow bacterium through growth medium, and decades later, a urologist in Ontario realized a bladder was the perfect container to pour it into.

Last May, during a conversation with Ross Douthat, Peter Thiel turned his gaze toward the pharmaceutical industry and delivered a verdict characteristic of his specific brand of eschatological libertarianism. “If we look at biotech, something like dementia, Alzheimer’s - we’ve made zero progress in forty to fifty years,” he said. “People are completely …

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Disclosure: This profile was commissioned by Axiom Bio. The company provided access to its offices, team, and partner meetings and reviewed drafts for factual accuracy.

Consider the hepatocyte. It is a polyhedral thing, roughly twenty micrometers across - a speck of biology responsible for most of the chemical processing in the human body.

If you could shrink yourself down and step inside, you would find no open floor plan. The interior is a scene of claustrophobic efficiency. The cytoplasm is crammed with the crinkled ovals of mitochondria and the vast, studded pleats of the endoplasmic reticulum, layered tight to maximize the surface area for chemical reaction.

In a healthy liver, these cells stack together in plates, forming the banks of the sinusoidal channels where blood flows. Every Tylenol you swallow must pass through this chemical gauntlet. Mr. Hepatocyte decides what stays and what goes.

Most pass safely. But some do not. Some drugs trigger a rapid, unstoppable cascade of biochemical dominoes to fall: causing the cell to stress, to swell, or to tear itself apart. This is a fundamental gamble of drug development: and for fifty years, we have tried to predict this catastrophe by feeding drugs to rats and dogs. But a rat is not a human, and a dog is not a miniature man. Biology is eccentric, and when we rely on proxies, we often guess wrong.

The cost of those guesses is specific and large. In a single month in 2024, liver toxicity flagged three major drugs, wiping out $5 billion in market value in a single week (1, 2, 3).

Of the recent failures, Pfizer’s lotiglipron and danuglipron offer a stark example. The drugs were promising candidates for the lucrative obesity market until mid-stage trials revealed elevated transaminases - enzymes that leak into the bloodstream when liver cells die. That, for Pfizer, was enough. They scrapped the molecules.

And these drugs are far from being an outlier. Hepatotoxicity remains the leading cause of drug withdrawals. Even the medicines that make it to market often do so with caveats: in 2020 and 2021, 60 percent of newly approved drugs carried warnings about liver toxicity on their labels.

In a second-floor office in San Francisco’s South Park, a company called Axiom Bio is attempting to stop guessing. They are betting that the best way to predict what a drug will do to a human liver is to ask the liver itself.

To a visitor, the room reads as a standard software studio, a grid of monitors and ergonomics that could belong to any tech company in the neighborhood. But the work here requires a reminder of the physical world. In one corner sits a climate-controlled vivarium that houses two poison dart frogs, Phyllobates terribilis. In the Colombian rainforest, these frogs are lethal; their skin secretes batrachotoxin, a neurotoxin so potent it can stop a human heart. But here, they are harmless. Their toxicity is borrowed, sequestered from a specific diet of beetles and ants they eat in the wild. Denied those beetles, they are benign.

What’s true of the frogs is true of pharmaceuticals: toxicity is not a fixed property. It’s a relationship between a substance and a context.

The founders of Axiom don’t look like toxicologists. Brandon White is a seven-foot-tall software engineer with a background in machine learning from early Uber. His co-founder, Alex Beatson, is a Princeton PhD who once built a spreadsheet to calculate the net present value of his job offers; the model told him to go into high-frequency trading, but he ignored the math to focus on applying machine learning to the natural sciences.

The team includes biologists from Stanford and data scientists from Citadel, and various defectors from pharma R&D. Together, they share a diagnosis: the AI drug discovery field spent a decade obsessing over “discovery” - finding molecules that bind to proteins. But discovery was never the bottleneck. The bottleneck is prediction: knowing what a molecule will do once it’s inside a human body.

Why AI for Bio Has Failed (So Far)

Suppose you want to double your number of bestsellers. You hire a consultant, and they suggest that since every book requires pages, the solution is to mass-produce blank notebooks.

An editor would correctly identify this as a category error: you are solving the easy logistics problem to avoid the hard creative problem. But for the last ten years, this is essentially the thesis statement of the entire techbio sector. They built a really, really efficient paper mill.

That realization was thick in the air when I visited Axiom’s office. Ruxandra Teslo’s autopsy of AI drug discovery was circulating through the sector. The piece was brutal. Billions of dollars had been raised on a premise that turned out to be wrong, and Teslo had the receipts.

The premise went something like this: Drug discovery is slow because humans are slow. If we could just automate the process of finding molecules that bind to proteins, we could churn out cures the way Amazon churns out packages. Companies like Recursion, BenevolentAI, Atomwise, and Exscientia raised enormous sums on this theory. They built robotic labs. They trained neural networks. They generated molecules by the thousands.

The trouble is that pharma was already drowning in molecules. Warehouses full of molecules, libraries of targets, filing cabinets of hypotheses nobody had gotten around to testing. What they lacked was any reliable way of knowing which molecules would work inside a human body.

The mills worked beautifully; their output was prodigious. But because the industry focused on volume (stationery) rather than validity (writing), the results were nigh disastrous. In the past few years alone, BenevolentAI’s lead candidate failed in Phase 2, and Recursion’s drug for cerebral cavernous malformation showed safety and did nothing else detectable. Between five and eight billion dollars in market value evaporated as the industry remembered, once again, that a molecule which binds to a target in a tube has a long way to travel before it becomes a medicine.

The generous interpretation is that these companies were solving the wrong problem. The less generous interpretation is that they were solving the easy problem, because the easy problem is easier to sell to investors.

In 2025, a fleet of new and advanced generative models have arrived. They can dream up a hundred thousand novel molecular structures in an afternoon. But invention has become trivially cheap. This is like announcing that, having failed to produce any bestsellers with your paper mill, you have decided to build a bigger paper mill. The expensive part was never the stationery. The expensive part - the “translation gap” - is knowing which of those hundred thousand molecules will help instead of harm. It remains as wide as ever.

The Visual Language of Distress

Axiom wants to give drug hunters a flashlight. If a chemist can see why a molecule is toxic - if they can weigh the benefit of a drug against the specific risk of mitochondrial stress or lysosomal swelling - they can design around it. They can fix the flaw before the drug ever leaves the whiteboard.

The foundation of this flashlight is a bet on the “scaling laws” of artificial intelligence. The theory holds that if you feed a model enough data about a drug’s exposure, metabolism, and effect on organs, it will eventually derive the fundamental rules of human safety, just as language models derived the rules of grammar.

“We’re trying to find out if the scaling laws for human toxicity exist,” Beatson says, “and whether we can write them first.”

To apply those laws, the team is building a “reasoning agent” connected to a suite of custom tools and massive reference datasets specifically designed for human safety and exposure. The ambition is to move beyond a simple red-light/green-light for toxicity and create a model that acts as a warning system for toxicity in human trials. By parsing the entire corpus of Axiom’s proprietary data - from exposure to metabolism to organ biology to human clinical outcomes - the model constructs a structured reasoning trace, comparing the new candidate to tens of thousands of well-studied historical drugs from Axiom’s experimental dataset; in order to walk the drug hunter step by step through the why behind a prediction.

To feed these models, the team had to industrialize biology overnight. Producing the necessary training data required running eight distinct experimental modalities across thousands of molecules - an effort so massive that vendors, used to the polite pacing of academic research, had never seen anything like it.

The validity of Axiom’s method is perhaps best viewed through the lens of a forensic reconstruction.

The team points to BMS-986020 as a pivotal example of how its reasoning model could save programs before it’s too late. This molecule was an antagonist of lysophosphatidic acid receptor 1 (LPA1) - developed to treat pulmonary fibrosis. In Phase 2 trials, it showed efficacy, but in 2016 it was terminated due to causing hepatotoxicity in some patients.

In a blinded simulation, Axiom shows BMS-986020 to its reasoning model. It has no prior knowledge of its identity.

Working solely from Axiom’s internal assay data, the model traced the drug's exposure and metabolic path de novo. It successfully identified the mechanism of toxicity that human researchers had missed, cited relevant clinical comparators, and outlined the specific steps required to confirm the signal. Impressive indeed.

Had this capability been available during the drug’s development, the toxicity concerns could have been addressed before BMS spent tens of millions of dollars on clinical trials.

Latent Signals

Before any of this could work in silico, someone had to keep the cells alive in order to generate the data for the models. Primary hepatocytes - cells taken directly from a human donor - are notoriously fragile. Removed from the body, they panic. They lose their enzymes; they forget their function. Katherine Titterton, Axiom’s founding biologist, spent weeks coaxing these cells to accept their new reality, refining the delicate recipe of their automated protocol until she and the Axiom team could keep them stable and functioning long enough to measure a drug’s effect.

With the hepatocytes finally domesticated, the interrogation could begin. At scale, Axiom exposed these delicate cells to thousands of molecules, staining them with dyes that target specific organelles. Hoechst stain turns the nucleus a vivid blue. MitoTracker makes the mitochondria glow. The result is a technicolor map of the cell’s internal machinery. The membrane, cytoskeleton, and endoplasmic reticulum appear in sharp relief, distinct against the black void.

This effort culminated in a library of ten million images showing cells in various states of damage. To the human eye, these images are beautiful, abstract art. To the predictive models Axiom has built, they are training data. Neural networks analyze these images, looking for “phenotypic fingerprints” to learn - subtle changes in the cell’s shape and texture that signal trouble - learning a library of warning signs they can use to judge the safety of novel molecules.

Titterton shows me a cluster of dots on a map of this data. Chemically, the drugs here look nothing alike. But biologically, the images reveal they are doing the exact same thing: the cells look pocked and lunar, their interiors riddled with holes.

These holes are vacuoles. The cells are undergoing autophagy - literally “self-eating.” Standard tests would mark these cells as ‘alive’ because their membranes haven’t ruptured yet. But the damage is already done. They’re going to die. Their AI can see it; and conventional toxicology assays cannot.

But vacuoles are textbook. What about the failures nobody has categorized? To catch what human eyes miss, the team developed a ‘bioactivity algorithm’—a neural network designed to notice what human researchers wouldn’t think to look for.

Traditional toxicology tests look for a single smoking gun. This system measures something finer - small changes in the cell’s texture and shape that occur at low concentrations, before a human researcher would notice anything wrong.

“I have a feeling that there are many ‘unknown unknowns’ that lie beneath,” says Nishkrit Desai, one of Axiom’s machine learning engineers.

Nadeem Karmali, a data scientist who previously worked at Citadel, echoes this sentiment. He sees Axiom’s future through the lens of quantitative finance. He argues that the pharmaceutical industry is currently where Wall Street was forty years ago: awash in data it couldn’t interpret. Back then, early quants learned to predict market volatility by aggregating “weak” signals - disparate, noisy inputs like weather patterns or credit card swipes - that seemed useless individually but were predictive when layered together.

Axiom is applying this logic to biology. A slight change in cell shape here, a minor metabolic shift there - on their own, these are weak signals. But when you aggregate them across a drug’s entire lifecycle - accounting for exposure, metabolism, and organ biology - they build a composite picture of human risk.

Karmali acknowledges that this composite may not be perfect from day one, but he argues that the shift in methodology is what matters.

“Early quantitative finance models were wrong but useful,” he tells me. “They created epistemological bedrock. Even imperfect mechanistic understanding changes how you approach problems.”

To reach that bedrock, the team had to redesign the very architecture of their lab models. Standard liver cells in a dish form a flat, lonely layer that barely resembles a real organ. Axiom’s solution resembles something like a “flattened spheroid” - human liver tissue pressed into layers just enough so a microscope can peer across multiple layers of different cells.

Crucially, this isn’t just a monoculture of hepatocytes. It is a microscopic ecosystem, populated by the hepatocyte’s natural neighbors: Kupffer cells that act as immune sentinels, stromal cells for support, and endothelial cells that line the blood vessels. This complexity allows the cells to survive for weeks at a time, revealing the “slow-burn” toxicities that simpler tests miss. But even a perfect model of the liver is useless if you don’t understand how the drug gets there. A drug is a traveler: it enters the body (exposure), gets broken down into new molecules (metabolism), and finally interacts with the tissue (response). Axiom’s data maps every step of this journey.

Axiom’s platform uses all this data to calculate the human “therapeutic index” - the vital safety margin that dictates a drug’s fate. This is the measured distance between the dose that heals you and the dose that harms you. By quantifying this gap across the drug’s entire lifecycle, the system provides a precise estimate of risk, along with a mechanistic narrative which explains the “why” rather than a mysterious red flag.

The Long Game

For decades, pharmaceutical safety has worked like this: we feed drugs to rats and dogs until we find the dose that kills them, then we work backward to guess what might be safe for humans.

History suggests that biology is not nostalgic. In the 1970s, testing drugs for bacterial toxins meant injecting them into rabbits and waiting for a fever. Then came the LAL test, which used the copper-rich blue blood of the horseshoe crab to detect the same toxins with greater precision. And so the rabbits were retired.

Axiom is betting that AI is the next LAL.

To see why that bet might pay off, you have to go to Phoenix, Arizona, where the American College of Toxicology held its annual meeting. Axiom’s booth looks like it wandered in from a different conference. I watch the team pitch a toxicologist from a major pharma company. She stands with her arms crossed, lanyard dangling - but she’s here, at the booth, which means something is already not working for her. She admits she has a molecule giving “worrisome signals.” Her internal testing cycle takes a month. When the team explains they can provide high-dimensional data that actually explains the ‘why’, she starts asking questions. How many compounds? What endpoints? How robust?

This is the conversation Axiom was built for. The toxicologist doesn’t need to be sold on the problem. She lives the problem. What she needs is a more accurate answer she can trust.

In early 2026, Axiom will complete blinded studies with several of the world’s largest pharmaceutical companies. The predictions are on the table. If they’re right - if the platform can reliably predict human exposure and flag human toxicity before trials begin - the implications are hard to overstate. Fewer failed drugs. Fewer patients enrolled in trials for medicines that were never going to work. A clearer signal, sooner, about which molecules to back.

Now they wait. In the office in South Park, nobody’s biting their nails.

You know what’s a fun way to spend a morning? Calculating whether a fictional chemistry teacher’s cancer would be treatable with modern targeted therapy and whether his employer health plan would cover it. I have done this. Let me tell you what I learned.

The basic facts, if you never watched Breaking Bad: A high school chemistry teacher gets lung cancer, has inadequate insurance, cooks meth to pay for treatment and leave money for his family, becomes increasingly murderous drug kingpin, etc. The financial crisis is the inciting incident. Without it - no cancer bills, no blue meth, and no “I am the one who knocks.”

But it’s been 17 years since the show first aired, and cancer therapy has come a long way since. Things have gotten dramatically better since 2008. And re: teacher health insurance -- it was already pretty good in 2008, and it has arguably gotten more standardized and predictable since then, even if not necessarily more generous.

OK, here we go.

The Oncology

In the show, Walter White is diagnosed with stage IIIA non-small-cell lung adenocarcinoma. In 2008, this was essentially a death sentence with palliative care. The five-year survival rate was maybe 15-20% (1, 2, 3). You’d get some chemotherapy and radiation, feel terrible, and probably die within two years.

But in 2025, Walter would immediately get next-generation sequencing of his tumor. Of the population of 50-year-old never-smokers with lung adenocarcinoma, roughly ~30-40% have EGFR mutations (1, 2) another ~10% have ALK rearrangements (1, 2), and maybe 10-15% have other “targetable drivers” (ROS1, RET, MET, etc.).1

Let’s say Walter tests positive for an EGFR mutation, which is the single most likely scenario. His treatment would be:

1. Concurrent chemoradiation (same as 2008, terrible but manageable)

2. Then 80mg of osimertinib (brand name Tagrisso) once daily, potentially for years

With this course of treatment, his prognosis would be much better than what was available to him in 2008! The LAURA trial, which led to FDA approval in September 2024, showed a median progression-free survival of 39.1 months on osimertinib versus 5.6 months on placebo. That’s a hazard ratio of 0.16. Overall survival data are still maturing, but the trend is strongly positive. The five-year survival for Walter’s profile could plausibly be on the order of 50-60%, versus 10-15% in 2008.

Even if he’s driver-negative, he’d get durvalumab immunotherapy after chemoradiation, which pushes five-year survival from about 33% to 43%.2

So: Walter would go from “you will almost certainly die within two years” to “you have a serious cancer but a realistic chance of seeing your kids grow up.” This is a different show.

The Insurance

In the show, Walter has an Health Maintenance Organization (HMO) plan through Albuquerque Public Schools. When Skyler finds a “top-rated oncologist,” the doctor is out of network. The HMO won’t cover it. The billing office wants $5,000 upfront. Walter balks, then pays with meth money.

Here is what people misremember: The $5,000 is not his deductible. It’s a deposit for an out-of-network doctor that his HMO already declined to cover. Walter chose to go outside his network, probably because he thought he was dying and wanted “the best.”

What would his actual in-network coverage have looked like in 2008? For a large public employer with an HMO:

• 80% of enrollees had no general annual deductible for single coverage

• Among those with deductibles, the average was $307 for large firms

• Teacher unions typically negotiated better-than-average benefits

So Walter’s in-network deductible was probably $0-500, not $5,000.

In 2025, Albuquerque Public Schools offers an EPO through Blue Cross Blue Shield of New Mexico with:

• $1,000 annual deductible (single)

• $5,000 annual out-of-pocket maximum for medical (single)

• $3,000 annual out-of-pocket maximum for prescription drugs (single)

• Separate Express Scripts pharmacy benefit

Chemoradiation is billed through the medical benefit: 20% coinsurance after deductible, but once he hits the $5,000 OOP max, everything else is free that year.

Osimertinib would be a specialty drug under the pharmacy benefit. It costs about $70,000-100,000+ per year at list price. But Walter would pay:

• Monthly copay of ~$125-200 (specialty tier)

• Until he hits the $3,000 annual Rx OOP max

• After which: $0

Many employer plans also have manufacturer copay assistance programs that reduce the effective member cost even below the stated copay, while still counting the spending toward the OOP maximum.3

The Bill

Year 1 (diagnosis, chemoradiation, start targeted therapy):

• Medical OOP max: $5,000

• Pharmacy OOP max: $3,000

• Total: $8,000

Years 2-3 (ongoing osimertinib):

• Surveillance imaging and checkups probably don’t hit the medical OOP max

• Pharmacy OOP max: $3,000/year

• Total: ~$3,000-4,000 per year

Three-year total: roughly $14,000-20,000 in out-of-pocket costs, excluding premiums.

So Would He Cook Meth?

Now let’s talk about what Walter actually needed the money for. He makes $43,700 a year teaching chemistry, plus car wash wages. He has a $107,000 mortgage, a $30,000 home equity line, a son with cerebral palsy, and a baby on the way. In the episode “Seven Thirty-Seven,” he sits down and calculates his family’s needs: pay off the house ($137,000), college for both kids (~$400,000), living expenses after he’s gone ($200,000+). Total: $737,000.

So the question isn’t “can he afford $14,000 in cancer bills?” It’s more like, “can he leave three-quarters of a million dollars to his family?” And the answer to that is… not legally, no.

But on the narrower question -- can he actually afford his cancer treatment? -- a teacher making $43,700/year, with access to credit, home equity, and family, can find $14,000-20,000 over three years. It would be stressful. He’d carry credit card debt. Maybe they’d skip Flynn’s college fund contributions for a while, or sell the Aztek early (addition by subtraction). But “we need $15,000 over three years for medical bills” does not naturally lead to “therefore I will manufacture methamphetamine.”

The show’s original pitch was: dying man with huge medical bills turns to crime. In 2025, he’s probably not dying, and the bills are manageable.

But was it ever really about the money?

The show’s genius is that it gives Walter a sympathetic inciting incident --cancer, family, bills -- and then slowly reveals this was never about the money. It’s about pride! Resentment! The life he thinks he should have had! His former friends offer to pay for everything in Season 1, and he refuses. He keeps cooking long after he has “enough.” When Skyler asks how much is enough, he says “more.”

Vince Gilligan has said Walter’s arc is “Mr. Chips to Scarface.” The cancer is the catalyst, but it’s *not* the cause.

The Pitch Meeting (in 2025)

So here’s your prestige TV remake:

Walter gets stage IIIA lung adenocarcinoma, EGFR-positive. His doctor tells him:

“This is serious, but with osimertinib after chemoradiation, we’re seeing patients in your situation live five, ten years or more. Insurance will cover it - you’ll have some out-of-pocket costs, probably a few thousand dollars a year.”

Walter goes home. Does he:

(A) Feel relief, accept the treatment, continue teaching chemistry, become a survivor, end credits, no show

(B) Feel rage that his life’s work amounts to a few thousand dollars he doesn’t have, remember the Nobel Prize his research contributed to, recall his former friends are billionaires, see an opportunity in the drug trade that has nothing to do with hospital bills, and start cooking meth for reasons he doesn’t fully admit to himself

The honest answer is that the 2025 version would just be a different show. The original Breaking Bad used cancer-driven desperation as the premise. In 2025, Gilligan would need to do more work to explain why a man with a serious-but-manageable chronic illness and capped healthcare costs would decide to risk everything. Walter’s situation, if it happened in 2025, would be less Greek tragedy and more character study.

Which… to be fair… is what it always was. The cancer and the bills were never really the point. They were just the excuse Walter gave himself, and us.

But try pitching that to AMC: “It’s about a chemistry teacher with good insurance who cooks meth because he’s sad.”

Doesn’t quite have the same ring to it.

Not medical or financial advice. Do not cook methamphetamine. Do get your lung nodules checked. Osimertinib is approved by the FDA for unresectable stage III EGFR-mutated NSCLC after chemoradiation based on the LAURA trial. The views expressed here are my own and not those of any employer, although honestly who else would claim them.

In September 2021, Bristol Myers Squibb discontinued development of pegbelfermin, a PEGylated version of a hormone called FGF21, after spending years and probably hundreds of millions of dollars testing it in patients with liver disease. The drug reduced 5-7 percentage points more than placebo and improved various biomarkers of liver damage. But in the trial that mattered, 24% of treated patients had fibrosis improvement versus 31% of placebo patients, which is not what you want. BMS said it would “pursue external opportunities” for the asset, which is corporate-speak for “we’re done here, maybe someone else wants to try.”

In May 2025, GSK paid $1.2 billion cash for efimosfermin from Boston Pharmaceuticals, a once-monthly FGF21 analog. Four months later, Roche paid $2.4 billion for 89bio and its pegozafermin, also FGF21. Three weeks after that, Novo Nordisk1 paid $4.7 billion for Akero Therapeutics and efruxifermin, also FGF21. In five months, large pharmaceutical companies deployed more than $8 billion to acquire what are, fundamentally, slightly different derivatives of the same hormone that BMS had walked away from in 2021.

This raises some questions. The efficient market hypothesis suggests that asset prices should reflect all available information. So either: (1) BMS was wrong in 2021 and left billions on the table, or (2) something changed between 2021 and 2025 that made these assets suddenly worth $8 billion, or (3) the acquirers in 2025 are overpaying and will regret this, or (4) these explanations each contain partial truth that reveals how drug development actually works.

Spoiler: it’s mostly option 4.

A Solution Looking for a Problem

Fibroblast growth factor 21, better known as FGF21, is a protein hormone, about 181 amino acids long, that your liver makes when you’re fasting or metabolically stressed. It tells your fat tissue to burn more fat, your liver to be less insulin-resistant, and your brain to maybe stop eating so many carbs. In 2000, scientists at Eli Lilly discovered that if you give extra FGF21 to diabetic monkeys, they get healthier - better blood sugar, lower triglycerides, weight loss.

FGF21 has a half-life in human blood of approximately 90 minutes. Your kidneys clear it out fast, and various proteases degrade it even faster. If you want to use it as a drug, you’d need to inject it constantly. In early human trials, FGF21 analogs improved cholesterol but didn’t lower blood sugar or cause weight loss as dramatically as everyone hoped. By 2013, Lilly had tested an engineered variant in obese diabetic patients. It worked on lipids, but you had to inject it daily. Moreover - it didn’t have a statistically meaningful effect on blood glucose.

So Lilly shelved FGF21 for diabetes. The opportunity cost was too high. FGF21 became what venture capitalists call “a solution looking for a problem.”

But several companies kept tinkering with the molecule in their research labs (we’ll get to this later). This is a common pattern in biotech: the first company to try something often fails, but they generate data that helps the second company succeed.

The NASH Gold Rush and Subsequent Graveyard

Around 2015, a bunch of smart people simultaneously realized that non-alcoholic steatohepatitis (NASH) - fatty liver disease that progresses to inflammation and scarring - was going to be huge. The logic: obesity and diabetes are rising globally, around 5% of adults in developed countries have NASH, it can progress to cirrhosis and liver failure, and there are zero approved treatments. Analysts projected the NASH market at $35-40 billion by 2030.

2016 was peak NASH fever, with companies paying over $1 billion for Phase 2 assets with mixed data. BMS, having licensed pegbelfermin from Ambrx, pivoted it from diabetes to NASH. As we discussed earlier - FGF21 reduces liver fat, increases adiponectin (an anti-inflammatory hormone), and improves insulin sensitivity, which made the mechanistic rationale more than solid.

But NASH drug development is uniquely difficult:

Slow, variable disease: NASH takes decades to progress. To prove your drug prevents bad outcomes, you’d need a 10-year trial. So regulators like the FDA now accept surrogate endpoints (fibrosis improvement on biopsy), creating uncertainty about whether this translates to actual clinical benefit.

Multifactorial biology: NASH isn’t one thing. It’s metabolic dysfunction plus inflammation plus fibrosis. You might need to hit multiple pathways.

High placebo effect: In NASH trials, 10-20% of placebo patients show fibrosis improvement, probably because they’re enrolled in a trial, get counseling, and lose weight.

Between 2018 and 2021, most NASH drugs failed. Gilead’s selonsertib, Novartis/Conatus’s emricasan, Genfit’s elafibranor - all Phase 3 failures. Intercept’s obeticholic acid got rejected by the FDA despite modest fibrosis improvement. By mid-2020, investor sentiment on NASH had soured. Intercept’s stock fell 93% from its peak. Biotech analysts were writing gloomy things like “NASH has become a graveyard of failures.”

Pegbelfermin: Close But No Cigar

Into this environment, BMS reported results for pegbelfermin in 2021. Phase 2a data from 2018 (16 weeks) had shown promise: pegbelfermin reduced liver fat by about 5-7 percentage points more than placebo, decreased liver enzyme markers, and increased adiponectin 2-fold. Safety looked good.

The Phase 2b trials (FALCON 1 and FALCON 2, 48 weeks, 2019-2021) tested pegbelfermin in patients with advanced fibrosis (F3) and compensated cirrhosis (F4). The primary endpoint was at least one stage of fibrosis improvement with no worsening of NASH.

Results: Pegbelfermin did not beat placebo. In FALCON 1 (F3 patients), approximately 24% of pegbelfermin treated patients had fibrosis improvement versus 14% on placebo. Not statistically significant. In FALCON 2 (F4 patients), a similar story - no benefit. BMS consequently discontinued the program.

The Triumph of Incrementalism

While BMS was winding down pegbelfermin, three smaller companies - Akero, 89bio, and Boston Pharmaceuticals - were advancing their own FGF21 programs. All companies were founded around the same period of 2015 - 2018. raising modest Series A rounds (tens of millions, not hundreds). All three were working on second or third-generation FGF21 analogs for NASH as their flagship programs.

Akero’s efruxifermin (EFX): An Fc-FGF21 fusion protein originally developed at Amgen, with the stabilizing mutations including Pro171Gly. Half-life: ~75-85 hours. Dosing: weekly.

Akero ran a Phase 2b trial (HARMONY, 2020-2022) in patients with moderate fibrosis (F2-F3). Dose: 50 mg subcutaneously, once weekly, for 24 weeks.

At 24 weeks, efruxifermin achieved approximately 37% NASH resolution versus 9% on placebo (a 28 percentage point difference); and in a 96-week open-label extension, 75% of patients on EFX had fibrosis improvement, including many with at least two stages of regression.

Even more strikingly, in cirrhotic patients (F4), 29% had cirrhosis reversal to F3 or lower vs 12% placebo - the first time anyone had shown clinical evidence of cirrhosis reversal in a drug trial.

89bio’s pegozafermin: A PEGylated FGF21 analog originally developed at Teva, with the glycoPEG approach2 and similar stabilizing mutations including Pro171Gly. Half-life: ~55-100 hours, enabling once-weekly or every-two-weeks dosing.

89bio ran Phase 2 trials in NASH (ENLIVEN, 2022-2023) with F2-F3 patients.

Pegozafermin was notably better tolerated than efruxifermin, with lower nausea and diarrhea rates (~9-21% vs ~21%), possibly because the every-two-weeks dosing created a flatter pharmacokinetic profile.

Boston Pharmaceuticals’ efimosfermin: An Fc-FGF21 fusion protein originally developed at Novartis’ NIBR and later in-licensed by Boston Pharmaceuticals. It incorporates stabilizing substitutions in the FGF21 core and is engineered for extended exposure, allowing once-monthly subcutaneous dosing.

Boston Pharmaceuticals ran a randomized Phase 2 study in patients with biopsy-confirmed NASH and stage F2–F3 fibrosis. After 24 weeks, 45% of treated patients achieved at least one-stage fibrosis improvement versus 21% on placebo; 68% achieved NASH resolution without fibrosis worsening versus 29% on placebo. The drug was well tolerated, with a low rate of treatment-related gastrointestinal events and minimal discontinuations.

Efimosfermin’s monthly dosing profile gives it a potential convenience advantage over weekly or bi-weekly FGF21 analogs - though the Phase 2 dataset remains smaller than that of Akero or 89bio.

Small Improvements Compound

The molecular differences between these drugs are actually pretty small - a few mutations and improved PEG chemistry. But those small changes translated into meaningfully better clinical outcomes.

The difference between “doesn’t work” and “works really well” came down to maybe 3 to 5 mutations and better PEGylation chemistry. This is a general lesson in drug development: marginal improvements in molecules can have non-marginal effects on clinical outcomes. And those marginal improvements often come from learning what didn’t work before. Pegbelfermin generated data that informed the design of pegozafermin and efruxifermin. BMS didn’t capture the value of that learning, but the industry did.

Resmetirom Changes the Game

In December 2022, while Akero and 89bio were presenting their Phase 2 data, another company - Madrigal Pharmaceuticals - announced that its NASH drug, resmetirom, had succeeded in Phase 3.

Resmetirom is a thyroid hormone receptor-β (THR-β) agonist - not related to FGF21 at all. The Phase 3 trial (MAESTRO-NASH, ~2,000 patients, 52 weeks) met both co-primary endpoints:

• NASH resolution with no worsening of fibrosis: 26% vs 9.7% placebo

• Fibrosis improvement: 24% vs 14% placebo

In March 2024, the FDA approved resmetirom (brand name: Rezdiffra) as the first drug specifically for NASH with moderate-to-advanced fibrosis.

Why does this matter for FGF21 analogs?

Regulatory precedent: Resmetirom’s approval validated the FDA’s willingness to accept histological surrogate endpoints as a basis for conditional approval. This de-risked other NASH programs.

Commercial proof-of-concept: Resmetirom’s launch demonstrated a real market. Payers are covering it, doctors are prescribing it, patients are taking it. Revenue is ramping up (Madrigal is projected to gross over $500M in sales for this year - in only its second on the market).

Competitive context: Resmetirom’s placebo-adjusted fibrosis improvement rate (~10%) set a benchmark. Efruxifermin’s 28% and pegozafermin’s 27% looked better. Suddenly, FGF21 analogs weren’t speculative science projects - they were potential best-in-class drugs entering a validated market.

From a deal-making perspective, resmetirom’s approval in early 2024 was the starting gun. If you’re a big pharma company with no NASH asset, you’re looking at a situation where the market exists, FGF21 analogs have better Phase 2 data than resmetirom had, there are exactly three viable FGF21 programs available, they’re all small companies, and if you don’t buy one now, someone else will.

This is how bidding wars start.

The 2025 Feeding Frenzy

Deal #1: GSK licenses from Boston Pharma (May 2025)

GSK paid $1.2 billion upfront ($2.0B total with milestones) for efimosfermin, an Fc-FGF21 fusion originally from Novartis’ NIBR, similar to efruxifermin but with once-monthly dosing. Monthly dosing is attractive for a chronic disease like NASH - more convenient for patients, might improve adherence. Boston ran a Phase 2 trial showing fibrosis improvement rates comparable to efruxifermin (~25%, placebo adjusted) with good safety.

GSK gets strategic entry into metabolic liver disease (they had no presence), a Phase 3-ready asset, and potential dosing advantage (12x/year instead of 52x/year). The $1.2B upfront is less than what Roche and Novo paid, but efimosfermin is arguably less de-risked with a smaller Phase 2 dataset.

Deal #2: Roche buys 89bio (September 2025)

Roche historically dominated hepatitis C, then lost it when Gilead’s direct-acting antivirals cured hep C in 8-12 weeks. By 2022, Roche was looking for new growth drivers in liver disease.

89bio was an obvious target. Pegozafermin showed strong Phase 2 data in NASH (27% fibrosis improvement) and severe hypertriglyceridemia (57% TG reduction). The dual indication strategy means pegozafermin could address both NASH and a significant cardiovascular risk factor, expanding the commercial opportunity. Every-two-weeks dosing might be better tolerated than weekly.

Roche paid $2.4 billion upfront ($3.5B total with milestones) - the $14.50-per-share cash offer represented about a 52% premium to the 60-day VWAP.

Deal #3: Novo Nordisk buys Akero (October 2025)

Novo is the global leader in diabetes and obesity (semaglutide/Ozempic/Wegovy). They’ve been printing money from GLP-1 agonists. But semaglutide is great at NASH resolution (via weight loss) while not significantly improving fibrosis on its own. In a 72-week Phase 2 trial, semaglutide achieved ~60% NASH resolution but fibrosis improvement was not significantly better than placebo.

Novo’s strategic answer: pair semaglutide (for metabolic/weight) with an FGF21 analog (for fibrosis).

To date, Akero has had the most impressive fibrosis data in the field: 21% net improvement at 24 weeks, and a staggering 49% at 96 weeks - the first evidence of cirrhosis reversal among the FGF21s. Novo’s CEO stated publicly he was “super excited” about FGF21 analogs as “cornerstone therapy, alone or together with semaglutide.”

On October 9, 2025, Novo announced the acquisition: $4.7 billion cash plus a $6 CVR per share (~$500 million) - a total potential value of $5.2 billion. The $54-per-share cash offer equates to ~19% over a 30-day VWAP (likely lower than Roche’s premium due to run-up / speculation before deal announcement).

The combination opportunity is where it gets interesting. If efruxifermin (fibrosis driver) plus semaglutide (metabolic driver) becomes standard of care for metabolic liver disease:

• Semaglutide for obesity/T2D: ~$13,000/year

• Efruxifermin for fibrosis: ~$20,000/year

• Total: ~$33,000/year per patient

Now Novo owns both drugs, capturing the entire $33K. Even with just 500,000 patients, that’s $15 billion in annual revenue. There’s also a defensive element: if Novo hadn’t bought Akero, someone else would have, then partnered with Lilly or another GLP-1 maker to create a competitive combo.

So… What Actually Changed Between 2021 and 2025?

BMS walked away from pegbelfermin in 2021. Three and a half years later, functionally similar molecules are worth $8 billion. What changed?

1. The molecules actually got better (incremental innovation)

Efruxifermin, pegozafermin, and efimosfermin are better engineered molecules - better protease resistance, better PK, better dosing. The molecular improvements are incremental, but their clinical impact is substantial. If pegbelfermin was worth $0 in 2021 and pegozafermin is worth $3.5B in 2025, you’re implicitly valuing a few mutations and 30-40 hours of extra half-life at $3.5 billion.

That seems extreme, which suggests a more nuanced explanation: pegbelfermin wasn’t worth $0 in 2021. It had value - maybe $500M-$1B - but BMS didn’t want to deploy the capital and risk to test it further (in a more specific patient population/at a different dose/in a combination/etc), and no other company was willing to buy it at a price that made sense for BMS.

2. Regulatory and commercial de-risking (resmetirom)

Before resmetirom’s approval in March 2024, NASH was a speculative indication. No one knew for sure if the FDA would approve drugs based on histological surrogates, or if payers would cover them. Resmetirom eliminated most of that risk.

A rough calculation: Say in 2021, the probability of a NASH drug getting approved was ~30%. In 2025, post-resmetirom, it’s ~70%. If peak sales are $4B:

• 2021: 30% * $4B = $1.2B risk-adjusted NPV

• 2025: 70% * $4B = $2.8B risk-adjusted NPV

That’s a $1.6B increase just from de-risking.

3. Superior clinical data changed the probability distribution

Pegbelfermin’s Phase 2b: 24% vs 31% fibrosis improvement (not significant). Even if you believed FGF21 could work, you’d rationally be skeptical about pegbelfermin specifically.

Efruxifermin’s Phase 2b: 4% vs 19% (highly significant). The magnitude of effect (30 percentage point difference) suggests a robust treatment effect unlikely to disappear in Phase 3. Similarly, pegozafermin’s 27% vs 7% is convincing.

Better data leads to higher probability of success leads to higher valuation.

4. Competitive dynamics and scarcity

By late 2024, there were exactly three credible FGF21 programs available for acquisition. Once GSK bought Boston in May 2025, there were two. Once Roche bought 89bio in September, there was one. Novo grabbed it in October. Plausibly scarcity dynamics at play, given the timing of it all.

5. The combination therapy narrative

In 2021, combination therapy for NASH was a nice idea but unproven. By 2025, it’s becoming consensus. GLP-1 agonists address metabolic drivers but not fibrosis. FGF21 analogs address fibrosis but don’t cause dramatic weight loss. Together, they’re complementary.

Novo’s acquisition makes sense only if you believe in combos. Efruxifermin alone might be a $3-4B product. Efruxifermin plus semaglutide together could be a $10-15B franchise.

6. Market size expansion

In 2021, the addressable NASH population was ~5-10 million patients in the US (F2-F4). By 2025, with safe effective drugs, you might treat F1 patients to prevent progression, doubling the addressable population. Pegozafermin works in severe hypertriglyceridemia (another 500K patients).

If the addressable market is 2-3x bigger than previously thought, peak sales increase proportionally, and so does the acquisition price.

The Efficient Market Hypothesis, Revisited

The EMH says asset prices reflect all available information. In a strong-form EMH world, pegbelfermin’s value in 2021 should have been ~$0 if it truly didn’t work, and efruxifermin’s value should have been ~$3-5B if it was going to succeed.

Obviously, that’s not what happened. In 2021, pegbelfermin was discontinued (implied value $0) and efruxifermin was worth maybe $500M (Akero’s market cap). By 2025, efruxifermin is worth $5.2B. Most of this value crystallized in a very short window after all the uncertain factors from 2021 resolved positively.

This is not efficient market behavior in the strong sense. This is more like a phase transition: the market was in a “NASH is too hard, FGF21 doesn’t work” equilibrium from 2018-2021, then abruptly shifted to a “NASH is solvable, FGF21 is the answer” equilibrium in 2023-2025. The companies that bought in after the transition paid full price. BMS, which sold out before the transition, got nothing.

By mid-2021, a diligent investor could have identified the mispricing. The mechanistic upgrades were sitting there in public filings: second-generation FGF21 analogs had FAP-resistance mutations (P171G) and Fc-fusion that fixed the exact cleavage and half-life problems that doomed pegbelfermin. And there was actual human data - efruxifermin’s BALANCED trial showed large liver-fat reductions and histology improvements, while 89bio’s pegozafermin independently did the same thing, which meant this was real biology and not just one lucky molecule.

Better yet, there was a playbook. Published papers had linked >= 30% PDFF reduction to histologic response, so you could translate “fat goes down at 12 weeks” into probabilistic expectations for “fibrosis improves at 52 weeks.” The FDA had already published a draft guidance suggesting that histology endpoints were acceptable for accelerated approval back in 2018. The regulatory path existed.

And the indication was about to get validated anyway. Resmetirom - a completely different mechanism - had good Phase 2 data and was in Phase 3, which meant NASH was going to be a real drug category soon regardless of what happened to FGF21. Meanwhile everyone was freaking out because pegbelfermin failed in November 2021, but that was a first-gen construct without the fixes. It told you nothing about the better-engineered molecules that already had positive data.

All the pieces were there. The market just hadn’t put them together yet. Most investors anchored on recent failures and didn’t differentiate between “first-gen analog failed” and “entire class is doomed.” This created the mispricing that the 2025 feeding frenzy eventually corrected.

Biotech markets are not efficient in real-time. They’re efficient in retrospect. Information takes time to diffuse, narratives take time to shift, and cognitive biases distort valuations.

Smart investors and pharma companies can exploit this, but it requires deep scientific understanding (knowing that Pro-171 mutations matter, that Fc-fusion extends half-life), contrarian thinking (being willing to bet on NASH when everyone else had given up after pegbelfermin), and patience (waiting 3-5 years for clinical data to accumulate and the market to come around). Few possess all three - which is precisely why the mispricing exists.

The FGF21 story shows that in biotech, value is not created smoothly or fairly. It accrues to those who persist through the “nobody cares” phase, who iterate when others quit, and who are positioned correctly when the narrative flips.

For 20 years, nobody wanted FGF21. Then, suddenly, everyone did. That’s the story.

Patent law rests on a simple covenant: inventors reveal their secrets, and society grants them temporary monopolies in return. But some companies want the monopoly without the showing. They want the treasure. They don’t want to draw the map.

In 2014, Amgen had developed evolocumab—a protein comprising 1,328 amino acids arranged with such precision that changing even one could eliminate its function entirely. This antibody binds to PCSK9, a protein that destroys the liver’s cholesterol-clearing receptors, and block its activity completely.

Amgen filed patents describing evolocumab in exhaustive detail. Twenty-five additional antibodies followed—all synthesized, all tested, all real. Then they claimed ownership of millions more they had never made.

That claim would soon be tested. Three thousand miles away, Regeneron had developed an entirely different antibody called alirocumab. Different sequence, different structure, different discovery method. It blocked the same protein.

The FDA blessed both drugs within twenty-eight days that summer of 2015—a bureaucratic miracle that should have marked the triumph of competitive innovation. Instead, Amgen was making the opening moves to an enormous legal assault——one that had begun the prior autumn. Nearly a decade later, nine Supreme Court justices would determine whether building a mousetrap grants you dominion over every possible way to catch a mouse.

Two Paths to the Same Summit

To understand what Amgen was claiming, we need to venture briefly into the cellular processes where this story unfolds.

Picture the liver cell as a recycling facility where LDL receptors serve as loading docks, constantly pulling cholesterol particles from the bloodstream for processing and disposal. PCSK9 functions as a quality control mechanism in this system. Its job—refined over millions of years of evolution—is to bind these receptors and mark them for destruction. When food was scarce and humans faced frequent starvation, this made evolutionary sense. PCSK9 helped conserve every molecule of cholesterol during lean times.

But evolution optimizes for survival to reproductive age, not for the convenience of modern medicine. In a world of drive-throughs and desk jobs, PCSK9’s cholesterol-conserving function has become a liability, contributing to the plaques that trigger heart attacks and strokes.

The protein’s importance emerged through one of biology’s elegant accidents. In the early 2000s, researchers had found genetic lottery winners—a French-Canadian family with naturally inactive PCSK9 who maintained cholesterol levels below 50 mg/dL and remarkably clear arteries well into old age.

This natural experiment provided the kind of proof that pharmaceutical executives dream about: blocking PCSK9 could prevent cardiovascular disease safely and dramatically.

Amgen was quick to capitalize: by 2007, they had developed evolocumab, an antibody against PCSK9. But while their scientists perfected the drug, their patent attorneys crafted a strategy of breathtaking scope. The patents covered any antibody that would bind to specific PCSK9 regions and block its function—defined not by biological architecture but by biological effect.

This created a fundamental problem. Amgen had synthesized just twenty-six antibodies and provided detailed information for each. Yet their patents claimed rights to potentially millions of different molecules—a clear violation of patent law’s core requirement that inventors describe their inventions sufficiently for others to reproduce them.

The inadequacy was glaring. Amgen’s guidance amounted to research assignments rather than manufacturing instructions. Their “roadmap” described standard practices already available to any researcher. Their “conservative substitution” methods provided no reliable way to predict which modifications would work.

This strategy was about to face its first real test. Three thousand miles away in Tarrytown, Regeneron had independently developed a different PCSK9 antibody called alirocumab. Alirocumab was developed using an entirely different approach. Instead of screening synthetic candidates, Regeneron had genetically modified mice to produce fully human antibodies in response to immunization with the PCSK9 protein.

Regeneron’s independent discovery exemplified the crux of how Amgen’s patent strategy was flawed. Developed using completely different technology, alirocumab shared no structural features with evolocumab beyond basic antibody architecture. Yet because it bound roughly the same PCSK9 regions, it fell within Amgen’s expansive claims.

Amgen had built one road to the summit and claimed ownership of the entire mountain. Now they discovered someone else had been climbing from the other side.

From Delaware to the Federal Circuit

The first battle erupted in Wilmington, Delaware, in March 2016. For a single week, expert witnesses attempted to explain protein folding and molecular binding to twelve ordinary citizens. It was like asking a jury to navigate a space mission based on rocket science they were learning in real time.

Amgen portrayed themselves as pioneers who had provided sufficient guidance for others to develop competing antibodies. They emphasized their enormous investment—billions over nearly a decade. Without broad protection, they argued, companies would abandon such research entirely.

Sanofi and Regeneron argued the claims lacked adequate written description and enablement. Their experts explained that antibody discovery is unpredictable—you must make and test candidates to know where they bind. Many different antibodies could meet Amgen’s claims while having vastly different structures, yet the listed sequences were insufficient to represent this full scope. Real-world evidence contradicted Amgen’s enablement theory——if their disclosure truly taught the art, why did Regeneron require years of independent research and proprietary platform development to reach the same therapeutic target?

In a stunning upset, the jury delivered complete victory for Amgen. Judge Sue Robinson’s subsequent ruling proved even more devastating: a permanent injunction ordering Sanofi and Regeneron to cease all sales of alirocumab over the lifetime of the Amgen patents. The injunction would have effectively created a complete monopoly, leaving patients with a single treatment option at whatever price Amgen chose to charge.

But Amgen’s victory proved short-lived. Just months later, the Federal Circuit granted an emergency stay in February 2017, and by October, the appellate court had delivered a dramatic reversal.

The difference lay in technical sophistication. Where the jury trial had stumbled through complex patent law, the Federal Circuit approached the case with precision, identifying a fundamental error in the jury instructions. The trial judge had asked jurors whether Amgen’s patents enabled some antibodies within their claims—the wrong question entirely. The real issue was whether they enabled the full breadth of what Amgen sought to monopolize.

The February 2019 retrial featured the same evidence but corrected legal standards. More damaging to Amgen’s case, their own experts now testified that modifying individual amino acids frequently eliminated an antibody’s function—undermining any claim that knowing a few examples could predict millions of functional variants.

The second jury reached a mixed verdict, but it was Judge Richard Andrews who delivered a decisive blow in August 2019. In an thirty-four-page analysis, he systematically invalidated all of Amgen’s asserted patent claims.

Most damaging to Amgen’s position, Andrews found that their own experimental data contradicted claims of adequate disclosure. As it turned out, Amgen had screened thousands of antibody candidates with failure rates exceeding ninety percent. If Amgen itself—with unlimited resources and years of experience—had failed in the vast majority of their attempts, how could their patents possibly enable others to generate millions of claimed antibodies?

Two years later, the Federal Circuit’s February 2021 decision definitively rejected Amgen’s final appeal. Every federal judge who had examined the enablement question in detail had reached the same conclusion: Amgen’s patents claimed far more than they had disclosed or enabled.

Hail Mary at The Supreme Court

Amgen’s petition for Supreme Court review represented a final attempt to reshape biotechnology patent law fundamentally. The company argued that strict enablement requirements would discourage investment in high-risk research areas where breakthrough innovations require enormous resources and face uncertain outcomes.

The Court’s decision to hear the case surprised observers who expected the justices to decline review of what appeared to be a technical patent dispute between pharmaceutical companies. The acceptance signaled recognition that fundamental questions about innovation policy and patent scope were at stake.

As the case approached the Supreme Court, major pharmaceutical firms began choosing sides. The battle lines resembled Napoleonic Europe—great powers aligning according to strategic interest rather than natural affinity.

The Amgen Coalition formed around broad patent rights for pioneering discoveries. AbbVie warned that strict enablement “chills investment in new discoveries.” GlaxoSmithKline argued that innovators faced an impossible trap: “Either she discloses her secrets for a narrow patent... or else her broad patent is invalidated.”

The Anti-Amgen League proved equally formidable. Pfizer led the opposition, arguing that patents “like Amgen’s violate the patent bargain by allowing patentees to obtain a monopoly on products without disclosing how to make them.” Johnson & Johnson, AstraZeneca, Genentech, and Eli Lilly joined the core alliance. These companies asserted that their long-term interests lay in preventing any firm from claiming entire therapeutic territories based on minimal contributions.

The legal question turned on enablement under 35 U.S.C. § 112(a): had Amgen described their invention in sufficient detail to enable a person skilled in the art to make and use it? Courts apply the Wands factors—considering claim breadth, predictability, working examples, and experimentation required. The Supreme Court would decide whether the Federal Circuit correctly found Amgen’s disclosure inadequate for the scope they claimed.

During oral arguments, Justice Neil Gorsuch focused on patent law’s historical development and core principles. He questioned whether Amgen’s functional claiming approach was consistent with centuries of precedent requiring patents to teach how to make inventions rather than merely describing desired results.

Justice Elena Kagan explored the practical implications of Amgen’s position, asking why the company had not actually synthesized all four hundred antibodies it claimed if the process was as routine as their counsel suggested. Justices Sonya Sotomayor and Ketanji Brown Jackson pressed Amgen’s counsel on the mathematical relationship between disclosure and claimed scope, questioning how twenty-six examples could possibly enable millions of different molecules.

Defeat at Waterloo

The Court killed Amgen’s case in May 2023. Nine justices - no dissent. The message was clear. Justice Gorsuch’s opinion for a unanimous Court grounded the decision in patent law’s essential bargain: inventors receive temporary monopolies in exchange for disclosing their inventions sufficiently to advance human knowledge.

This bargain requires that patent claims be commensurate with disclosure—inventors cannot claim more than they have enabled others to make and use. Gorsuch traced this principle through centuries of American patent law, citing cases involving telegraphs, light bulbs, and other foundational technologies where courts had rejected attempts to claim broad functional monopolies without corresponding disclosure.

The telegraph case O’Reilly v. Morse proved particularly instructive. Samuel Morse had attempted to claim all methods of using electromagnetism for long-distance communication—far broader than the specific telegraph system he had actually invented and disclosed. The Supreme Court rejected this expansive claim while upholding narrower patents on Morse’s specific apparatus.

Justice Gorsuch found these historical precedents directly applicable to Amgen’s situation. Like Morse, Amgen was seeking to “monopolize an entire class of things defined by their function” while providing concrete guidance for only a small fraction of that class.

Most memorably, the Court articulated the principle that “the more one claims, the more one must enable.” This elegant formulation captured patent law’s fundamental requirement that broad claims must be supported by correspondingly broad disclosure—you cannot claim the entire forest while mapping only a single tree.

Applied to Amgen’s patents, this principle was devastating. The unanimous nature of the ruling—with all nine justices agreeing despite their different judicial philosophies—demonstrated the strength of the legal principles involved and the weakness of Amgen’s position.

Aftermath

Despite winning every appeal and securing a unanimous Supreme Court victory, Sanofi achieved a devastating financial loss through the simple expedient of delay.

Their legal triumph masked a commercial catastrophe that reveals why rational executives pursue litigation even expecting ultimate defeat. During the critical launch years of 2016-2017, legal uncertainty clouded alirocumab’s market position while Amgen captured advantages that would compound over time1. In 2016, evolocumab generated $141 million in global sales versus alirocumab’s $116 million globally—a modest difference reflecting physicians’ caution about both revolutionary drugs. But by 2017, with a permanent injunction granted though stayed pending appeal, the gap widened dramatically. In 2019, evolocumab reached $661 million in global sales while alirocumab managed only ~$300 million.

Why invest in training staff and developing treatment protocols for a drug that might disappear from the market? By 2023, as the case reached the Supreme Court, the commercial disparity had become enormous. Evolocumab generated $2.2 billion globally while alirocumab managed approximately $740 million—a gap approaching $1.5 billion annually.

Their strategy wasn’t merely about delay, however. Amgen sought complete exclusion, and the January 2017 permanent injunction proved total victory was legally plausible. Using conservative assumptions, permanent exclusion would have generated roughly $336 million per year over an eight-year patent term. Even with only a fifteen percent probability of sustaining exclusion through appeals, this option value contributed approximately $270 million to the litigation’s expected value. Against litigation costs of perhaps $20 million, the financial logic was overwhelming2.

But the competitive market demonstrated benefits that transcended individual company profits. Both drugs launched with list prices exceeding $14,000 annually—costs that severely limited patient access despite revolutionary efficacy. Competition changed everything. Under sustained pressure, Amgen announced a permanent sixty percent U.S. price reduction to approximately $5,850 annually in 2018. Sanofi quickly matched this U.S. pricing.

These reductions led to dramatically improved insurance coverage and reduced patient cost-sharing. By 2024, most major Part D plans covered either drug, enabling broader access to breakthrough therapy. Competition also spurred continued innovation; Novartis entered with inclisiran, offering twice-yearly injections instead of monthly treatments. Other companies began exploring gene editing approaches for potentially one-time cures.

This therapeutic diversity would have taken longer to emerge if Amgen had their way. By 2024, the combined PCSK9 inhibitor market approached $3.7 billion globally.

For Amgen, the antitrust consequences proved more tangible in financial consequences than the patent defeat. Regeneron alleged that Amgen executives coordinated to eliminate alirocumab’s market position “by hook or crook” after litigation failed, implementing bundling schemes that increased costs for pharmacy benefit managers selecting alirocumab over evolocumab. In May 2025, a federal jury awarded Regeneron $135 million in compensatory damages plus $271 million in punitive damages—over $400 million total.

The verdict represented war reparations––only perhaps too small a sum and too late a time––for Amgen’s failed attempt to monopolize the market through both patent and anticompetitive strategies.

Beyond the PCSK9 Patent War

We’ve spent considerable time dissecting Amgen’s failed legal strategy, but here’s the uncomfortable truth: if you were sitting in those Thousand Oaks boardrooms, you probably would have made the same call. The NPV mathematics we just scrutinized made the litigation inevitable. Even with a fifteen percent chance of sustaining a permanent injunction, the expected value exceeded two hundred million dollars against litigation costs of perhaps seven to eight figures. Odds are, they don’t even regret what they did.

But Amgen deserves credit beyond the cold financial calculus. When they committed hundreds of millions to PCSK9 inhibitors, the target remained genuinely speculative. While other companies recognized the opportunity, Amgen executed where they hesitated3. They ran the trials that proved PCSK9 inhibition could safely reduce cardiovascular events. That kind of pioneering work deserves substantial reward.

But empirical evidence reveals why blocking follow-on competition carries enormous costs. A USC Schaeffer Center analysis published last year found that follow-on drugs earn the largest market share in more than half of classes studied. New approaches appear. Follow-on competition compresses the search time for better therapies: better safety profiles emerge. More convenient dosing arrives. The efficacy ceiling grows taller. New indications are discovered and new uses for other unmet needs are discovered more quickly.

Consider what actually happened versus what Amgen sought. In reality: both drugs launched at fourteen thousand dollars, competition cut prices to fifty-eight hundred, and usage jumped from half a percent to over three percent of eligible patients. New RNA-based approaches emerged with twice-yearly dosing. Under Amgen’s target monopoly: prices would have remained near fourteen thousand dollars indefinitely, fewer than one percent of patients would have received treatment, and alternative approaches would have faced years of delay. Crude modeling suggests this could have prevented a gain of ~550,000 life-years4 over a decade:

The Supreme Court rejected Amgen’s overreach through the enablement doctrine: you must teach what you claim. The Court understood that allowing target-wide monopolies based on minimal disclosure would transform biological mechanisms into winner-take-all territory, collapsing innovation into patent races rather than scientific competition.

This exposes the core policy tension: rewarding genuine pioneers while preserving the competition that benefits patients. Solving it requires preventing patent overreach while actively promoting breakthrough innovation.

For preventing overreach, tiered exclusivity periods for FDA biosimilar approvals could serve as an automatic check against monopolistic behavior when new biologics enter the market. Rather than granting twelve years of market protection to all biologics regardless of entry order, a tiered system would give pioneers the full twelve years while first followers receive eleven years, second followers ten years, declining to a six-year floor5. This creates pricing pressure from progressively shorter exclusivity windows—companies developing follow-ons must offer genuine added value to justify positive returns on shorter exclusivity periods, while pioneers face earlier competitive pressure that incentivizes proactive price cuts rather than indefinite monopoly pricing.

A net price growth cap represents a separate powerful mechanism: freezing net price growth for all biologics during their first five years post-approval6. This could prevent coordinated price increases that undermine price competition, even when multiple products exist.

For promoting innovation, tax-based incentives could offer a cleaner approach than extended exclusivity periods. Patent boxes——already implemented successfully in countries like the UK and Ireland——provide reduced corporate tax rates on intellectual property income. Applying this concept specifically to first-in-class biologics could offer rates of ten percent instead of twenty-one percent on qualifying profits for seven years. This could substantially boost early cash flows when pioneers need capital most, without affecting pricing or delaying competition.

Super-deductions allowing enhanced write-offs on late-stage development costs provide another front-loaded incentive. Rather than gambling on extended market exclusivity, companies could claim 150% deductions on qualified clinical trial and manufacturing expenses in their first year post-approval—immediate tax relief that rewards successful execution of risky projects.

Additional targeted mechanisms could include temporary prior-authorization relief for genuine first-in-class therapies and delayed Medicare price negotiation timelines that acknowledge the greater risks pioneers face7.

These approaches hold promise because they address the root problem: current patent law provides identical protection regardless of genuine contribution, creating incentives for companies like Amgen to pursue defensive intellectual property litigation. By front-loading rewards for authentic risk-taking while preserving competitive dynamics, we eliminate the economic logic behind target-wide patent strategies.

Future pioneers will need to earn their kingdoms rather than simply declaring them. That may be exactly as it should be. After all, the combination of innovation incentives and competitive dynamics has produced an unprecedented expansion of human health and longevity. The challenge is preserving both elements through policy design that recognizes economic realities while defending principles that have served us well for centuries.

The other customers at SuperPharm were beginning to stare.

During my recent stay in Israel, I developed what can only be described as the world's dullest obsession: methodically photographing medicine shelves at SuperPharm (think Israeli CVS, but with more arguing about prices). I had been photographing medicine boxes for the better part of half an hour, picking up each package, examining it for a particular logo, then carefully documenting the label while maintaining what I hoped was the casual demeanor of someone who definitely wasn't conducting industrial espionage.

I was hunting for a drug called "Optalgin" - the ubiquitous Israeli painkiller - because I'd just finished reading about a man who turned dishwashing into a generic drugs giant, and I wanted to see if his products were still on the shelves. This is the kind of thing that happens when you read business biographies for fun - you develop weird obsessions and convince yourself that hunting for fifty-year-old aspirin brands constitutes legitimate research.

Yossi Goldstein’s "Eli Hurvitz and the Creation of Teva Pharmaceuticals" is ostensibly the story of how a kibbutznik-turned-dishwasher built one of the world's largest generic drug companies. But it's really a case study in a thing even more interesting - what happens when someone has an unusually high tolerance for acting on incomplete information.

Most business biographies follow a familiar template: visionary sees opportunity, overcomes obstacles, builds empire, retires wealthy. Hurvitz's story fits this pattern superficially, but the details are weird enough to make you wonder whether successful entrepreneurship is less about having good ideas and more about having a fundamentally different relationship with uncertainty.

How Growing Up During National Formation Calibrates Your Risk Tolerance Differently Than Normal

The book's account of Hurvitz's upbringing reads like someone took every possible Israeli founding myth and decided to see if they could all happen to the same guy.

His parents met in what may be the Israeli-est way possible. his father caught malaria while draining swamps in the Hula Valley. The fever was so severe that, as the biography delicately puts it, "one day, feverish and disoriented, Zvi scrambled up a tall eucalyptus tree and refused to come down." One of the spectators watching this fever-induced tree climbing was Zippora, who "quickly fell in love with the sick young man."

This is apparently how pharmaceutical dynasties begin.

By the time young Eli reached adolescence, Israel was fighting for independence and he was running clandestine radio operations from his bathroom, where Haganah radio equipment was "constantly being shuttled from place to place" to avoid detection. At 16, he lied about his age to join the Haganah because he wanted to fight alongside his classmates - a decision that would prove formative in ways that extend far beyond youthful patriotism.

Later, he helped found Kibbutz Tel Katzir near the Galilee, which involved farming next to the Syrian border where snipers would take potshots at agricultural workers. Hurvitz's solution to being shot at while plowing was characteristically cavalier. That is, to jump off the moving tractor and run alongside it, steering with one hand while using the tractor as a shield.

"If your steering was off," he later recalled, "you had no choice but to jump back onto the tractor. This was an uncomfortable situation, as changing directions in the unwieldy vehicle required stopping, and it was clear that the Syrians would fire on you in the process. But what else could you do? You couldn't leave the tractor there."

Reading this, you start to understand how someone might develop an unusual relationship with risk assessment. If you've spent your teenage years dodging sniper fire while steering farm equipment, conventional business risks probably seem manageable by comparison.

But by the early 1950s, kibbutz idealism was wearing thin. Friends were leaving for the city, collectivist economics were proving frustrating, and his wife Dalia's heart condition provided the excuse they needed to escape to the capitalist world. When Hurvitz approached his father-in-law for a job at Assia Laboratories, he was offered a comfortable administrative position - the kind of role befitting an economics graduate and family member.

His response was to politely decline and ask if he could wash dishes instead.

When Choosing Information Access Over Status Signals Turns Out to Be Surprisingly Effective

This seems insane until you understand the reasoning. Hurvitz had correctly intuited that washing laboratory glassware would give him access to every aspect of the company's operations in a way that a desk job never could. While handling the equipment, he could observe production processes, understand material flows, and discover inefficiencies that management couldn't see from their offices.

More importantly, he understood a nuance about organizational dynamics that many people miss. Authority flows to whoever understands the system best, and not whoever has the fanciest title. By positioning himself at the center of laboratory operations, he could learn everything while appearing non-threatening to existing power structures.

The strategy worked spectacularly. Within months, Hurvitz had identified that Assia was profitable despite having no clear understanding of what anything cost to produce. Management was running a pharmaceutical company on pure intuition, like a restaurant that never checks food costs.

When they asked him to develop a pricing methodology, his response revealed the mindset that would define his career.

"I would sit down, take everything I learned about pricing, and try to construct a method capable of accurately computing the cost."

Notice the confidence embedded in that statement - not "I'll try to figure this out" but "I'll construct a method." The assumption that complex problems have solutions if you're willing to build them from scratch.

This pattern - accepting short-term disadvantage for long-term positioning - shows up repeatedly throughout his time at Teva:

ELI: Hey, why aren't we doing [insert audacious business scheme]?

MANAGEMENT: That sounds risky/impossible/insane...

ELI: Too bad. I already started doing it

MANAGEMENT: Aw man! Aw shucks! Ya got us again, Eli!

His philosophy, in his own words, was deceptively even more simple:

"Authority is not given, authority is taken... Responsibility is not divided. There is no such thing as: 'I'll share the responsibility with you.' That's just nonsense. Either I take responsibility, or you do."

That Time Eli Solved Currency Devaluation by Trading Pharmaceuticals for Nuts (And Other Shenanagins)

Eli's first glimpse of what we might now call "thinking outside the box" came when Turkish currency devaluation made pharmaceutical exports unprofitable. Management wanted to abandon the market entirely. Hurvitz had a different idea: if Turkish money was worthless, why get paid in Turkish money?

He engineered an elaborate three-country barter scheme that reads like an anecdote from a different era of international commerce: Assia would trade pharmaceuticals to Turkey for nuts, then sell the nuts to America through a Greek middleman who happened to be pro-Israel (because the Middle East in the 1950s was small enough that everyone knew everyone's political affiliations).

"I was convinced that we could not continue exporting on such terms. I proposed a barter transaction that enabled us to use the system's folly to our advantage."

Instead of accepting the system's constraints, he found a way to profit from its inefficiencies.

The nut arbitrage generated more profit than a straightforward sale would have, becoming "the most profitable deal in the company's history at the time." But the real value wasn't the immediate profit - it was proving that supposedly intractable problems often have creative solutions if you're willing to ignore conventional wisdom about how business "should" work.

Another wild scheme of Eli’s that Goldstein highlights is his adventures of selling drugs in post-colonial Africa. When Hurvitz, at the tender age of twenty four, proposed to Assia’s board about developing pharmaceutical sales in Africa in the 1960s, the objections were entirely reasonable. African countries had limited purchasing power, nightmarish logistics, and uncertain regulatory environments. Management's skepticism made perfect sense.

Hurvitz's response was to book a flight to Nigeria before getting final approval.

What makes it instructive is what happened once he arrived. Instead of working through established British distributors who had been operating there for decades, Hurvitz rented vans and drove into remote areas to sell medicines directly to local pharmacists.

This revealed a remarkable and valuable business secret. British companies were taking a year to deliver what Assia could deliver in a week. When Hurvitz's colleague promised one-week delivery, the local pharmacist's reaction was "You are like God!"

The success came from discovering that established companies were providing spectacularly poor service despite having every conceivable advantage. Within a few years, Assia controlled over 50% of Nigeria's pharmaceutical market through mobile pharmacy vans - a distribution model that nobody else had thought to try.

The broader insight is this: if your competitors take a year to deliver what you can deliver in a week, you will win. The fact that established British companies had somehow missed this basic principle suggests either spectacular incompetence or that colonial business practices weren't optimized for customer satisfaction.

How to Execute Israel's First Hostile Takeover When Your Collateral Is a Two-Room Apartment

By age 27, Hurvitz had become Assia's most important executive despite holding no official title. And despite his early successes in his first years at Assia, Israel's tiny domestic market was rapidly becoming a constraint. Pharmaceutical companies had to expand aggressively through acquisitions and exports, or risk being acquired themselves.

The obvious target was Teva Pharmaceutical Industries, which had better products than Assia, and this drove Hurvitz quietly crazy.

Teva had been founded in the 1930s by Gunther Friedlander and his aunt Elsa Kuver, German-Jewish refugees who'd built it into one of Israel's more successful pharmaceutical companies despite what would become obvious management problems. Although they had superior products and better market positioning than Assia, Teva's profits were less than one-tenth of Assia's. The company hadn't paid dividends in years, employees weren't always paid on time, and the Jerusalem plant was deteriorating.

Yet Friedlander refused all merger discussions because he viewed Teva not as "a tradable pharmaceutical company that may or may not be profitable", but instead as "an idea, a dream, and a vision."

Hurvitz's solution was to engineer one of Israel's first major hostile corporate takeovers, which required navigating complex political and financial relationships in a country where everyone knew everyone else's business. The book's account of this process reads like a comedy of errors that somehow worked.

The breakthrough came when Hurvitz convinced Alfred Feuchtwanger, Friedlander's banker relative, to sell his one-third stake for above-market prices. But Hurvitz still needed a bank guarantee for one million Israeli pounds by end of day, or political pressure would kill the deal.

When Bank Leumi refused to help, Hurvitz noticed something useful about Israeli business geography: the Industrial Development Bank was just two floors above the Export Bank in the same building. Rather than travel across town to find financing, he simply went downstairs.

"Zalman," he told Export Bank's Zalman Shoval, "I have a one of a kind story to tell you. If you join me, I'll build a small business and you'll be able to claim a great deal of credit. If you don't, we'll try elsewhere."

Shoval's decision to provide the guarantee despite Hurvitz's net worth consisting entirely of a two-room apartment reveals a fascinating quirk about 1960s Israeli banking: major financial decisions were made based on character assessment rather than sophisticated risk analysis. The entire acquisition hinged on one young banker's gut feeling about whether Hurvitz seemed trustworthy.

Acquiring Teva meant dealing with 220 striking employees who were convinced that Tel Aviv-based Assia would shut down their Jerusalem facility. When advisors warned Hurvitz not to face the striking workers gathered outside the bank, he wilfully ignored their pleas: "Tomorrow they will be working for me. I'm walking out the front door."

What followed was probably the most Israeli corporate negotiation in world history, with Hurvitz standing on a Jerusalem street, surrounded by dozens of worried employees, calmly fielding questions about job security while passersby wondered what was happening.

When one employee was particularly confrontational, Hurvitz's responded resolutely:

"Don't tell me your name. I don't want to remember it. Remember one thing: you will never be my boss, but it is 100% certain that I will be your boss, so behave accordingly."

"They looked as if they were going to faint when I said that," he later recalled.

The workers asked practical questions. Would he promise not to fire anyone? No, but he'd work with their committee to identify necessary changes and provide generous severance. Would he open a company preschool?

"You don't have a preschool today, so why are you asking me for one? You can ask me if I would be willing to consider the needs of the employees and open a preschool. We'll look into the matter and we'll open a preschool if possible. If it is the right thing for us to do, we'll open one. It depends on how many hours you work."

When the meeting ended, the workers had signed an agreement to return to work. Hurvitz had executed a hostile takeover simply by being more reasonable and practical than anyone expected.

How the Arab Economic Boycott Accidentally Created the World's Best Generic Drug Company

With Teva acquired, Hurvitz controlled the foundation of what would become a sophisticated operation built around exploiting intellectual property loopholes.

The Arab world’s boycott of Israel since its independence had created an unintended consequence. Western pharmaceutical companies often didn't bother patenting their drugs in Israel to avoid complicating relationships with Arab customers. This meant Israeli companies could legally manufacture "generic" versions of drugs still under patent everywhere else in the world.

The Nitrovin case illustrates how this worked. When Assia started manufacturing the drug because of "improper patent registration," American Cyanamid's Israeli attorney called Hurvitz at midnight in a panic. Instead of apologizing, Hurvitz proposed that American Cyanamid make Assia their global supplier since Assia could manufacture the drug more cheaply than the original developer.

American Cyanamid agreed, provided Assia could deliver 50 kilograms within two months as proof of concept. This was ambitious since Assia had never produced even one kilogram commercially, but they delivered on schedule.

Then there's the Penbritin story, which demonstrates the hilarious complexity of Israeli patent law. When British pharmaceutical giant Beecham refused to market their leading antibiotic in Israel (to avoid Arab boycott complications), Hurvitz sued them for a "compulsory license."

Israeli law allowed companies to manufacture patented drugs if they could prove the patent holder was refusing to serve Israeli markets for non-commercial reasons. If you possessed knowledge to manufacture a life-saving drug, but refused to make it available in Israel for political reasons, courts could compel licensing in exchange for reasonable royalties.

Assia won. Hurvitz's post-victory negotiation with Beecham reveals his approach to these situations:

"Your packaging has a reputation in Israel. We won't change the packaging, but we will change the name a bit. Your product is called Penibrin. We'll call ours Penbritin so that the public understands that it is the same medication."

This pattern - finding legal ways to manufacture drugs unavailable in Israel due to boycott politics - became Teva's core competency. For decades, while competitors focused on traditional R&D, Teva accumulated reverse-engineering expertise that nobody else thought was valuable - until American drug policy changed everything.

The payoff came with the Hatch-Waxman Act of 1984, which streamlined generic drug approvals in America. Suddenly, Teva was perfectly positioned. While other companies waited for patents to expire then scrambled to develop generic formulations from scratch, Teva already had decades of chemistry knowledge. They'd been legally copying drugs since the 1960s and had mastered the synthesis processes.

More importantly, they'd learned to challenge patents systematically. In the nabumetone case, Teva's researchers discovered that GlaxoSmithKline's patent was invalid because the active ingredient had been discovered in 1973, almost a decade before GSK filed their patent. Teva developed a generic, won FDA approval, received six months of market exclusivity, and when GSK sued, won in appeals court.

The deeper insight here is that generic manufacturing wasn't actually a commodity business - it was a scale business disguised as a commodity business. Each individual generic drug was commoditized, but managing portfolios of hundreds of generic products across multiple regulatory environments required operational sophistication that other companies couldn't replicate.

The Arab boycott meant to strangle Israeli companies had accidentally created the world's most sophisticated generic drug manufacturer.

The Multiple Sclerosis Drug That Nobody Could Draw the Chemical Structure Of (And How It Got FDA Approval Anyway)

The deal that truly transformed Teva came from scientists who were trying to give laboratory animals multiple sclerosis and accidentally discovered a treatment instead.

In the 1960s, researchers at the Weizmann Institute led by Michael Sela were studying multiple sclerosis by creating MS-like conditions in lab animals using a synthetic polymer called "Cop-1." Their theory was this: if you could reliably cause MS symptoms in healthy animals, you could study the disease mechanism and test potential treatments.

Instead, to their complete bewilderment, Cop-1 prevented MS symptoms entirely.

This was pharmaceutical serendipity of the highest order - they were trying to cause a disease and accidentally discovered a breakthrough treatment of it. The mainstream research approach focused on stopping immune systems from attacking myelin sheaths around nerve cells. Sela's team had a different idea that was "so simplistic in concept that the entire establishment ridiculed it": create a "decoy target" that would distract immune cells from attacking real nerve tissue.

After 16 years of animal testing, they had proof that Cop-1 could delay and sometimes suppress MS symptoms. Even more mysteriously, the drug seemed to provide transferable immunity - treated animals could somehow pass protection to untreated animals, which nobody could explain.

The clinical trial results were remarkable. In the double-blind study of 48 MS patients, 56% of those receiving Cop-1 experienced no attacks over two years, compared to only 26% in the placebo group. The drug was effective and had essentially zero side effects - which is almost unheard of in pharmaceutical development.

After Sela presented these results at Hurvitz's home one evening - complete with slide show over coffee - Hurvitz made the decision that would define the rest of his career. Despite "substantial opposition" from his board, who were understandably skeptical about betting the company on a drug whose molecular structure was unknown, he called it "an opportunity of a lifetime for Teva."

There was just one problem: nobody could figure out what Cop-1 actually was. Unlike every drug previously approved by the FDA, "it was impossible to draw a picture depicting the chemical structure of Cop-1." The synthetic mixture consisted of molecules of various lengths, and every attempt to identify a single molecular structure failed.

This created an unprecedented regulatory problem. The FDA's approval process depends on something called Chemical Manufacturing Controls (CMC) - basically proving you know exactly what your drug is and can manufacture it consistently. When you can't even draw your molecule, this becomes philosophically challenging. Every major pharmaceutical company that examined Cop-1 concluded it was "unmanufacturable as a drug and unapprovable by the FDA."

The FDA approval process required unprecedented creativity. Since normal quality control methods couldn't work without knowing the molecular structure, Teva had to invent entirely new approaches to manufacturing validation. They essentially had to convince the FDA to approve a drug based on its effects rather than its chemistry; which is like asking a restaurant inspector to approve a dish without being allowed to examine the recipe, ingredients, or cooking process - just the final taste. The gambit worked; and on June 19, 1996, the FDA advisory committee unanimously recommended approval.

When Copaxone launched in April 1997, Hurvitz had cautiously projected sales might reach $200 million annually. By 2009, it was generating $3 billion per year - Teva's most profitable product and the most successful drug ever developed in Israel, administered to over 200,000 MS patients worldwide.

What All This Pharmaceutical Stuff Actually Tells Us About How Things Get Built (A Meditation That Will Almost Certainly Devolve Into Inspirational Platitudes About Courage)

By the time Hurvitz stepped down as CEO in the early 2000s, Teva had become the world's largest generic drug manufacturer, with operations in 60 countries. From a small Israeli company that couldn't always pay its employees on time, he'd built a pharmaceutical giant manufacturing over 1,000 different generic drugs while simultaneously developing breakthrough treatments like Copaxone - a dual capability almost unprecedented in pharmaceuticals. When he finally retired, he'd transformed a dishwashing job into a $15 billion corporation and proven that a small country under economic boycott could build a company sophisticated enough to outmaneuver the world's largest pharmaceutical corporations.

Goldstein's account of Eli Hurvitz’s life has one particular takeaway that’s sat with me since I finished reading, which is that exceptional business success often comes from consistently doing obvious things that other people avoid because they're difficult, uncomfortable, or uncertain. Hurvitz's achievements weren't exactly the result of secret knowledge - but instead had compounded from his consistent choosing action over analysis.

Granted, the book’s reading of Hurvitz is in a success story dialect tinged with what we might call "prophetic perfect tense" - every decision framed as obviously correct, every risk as calculated genius. Goldstein himself worried about writing "hymns of praise" for a "less flawless protagonist" - then proceeded to do exactly that, as reviewers noted. We don't hear about pharmaceutical executives who made similar bets and lost everything.

But what makes Hurvitz’s story compelling - the kind of thing that makes you put down whatever you’re reading and sit quietly for a while - starts with all our elaborate theories about entrepreneurial excellence. We’ve built mythologies around “agency” and “reality distortion fields” and “disruptive thinking,” sophisticated frameworks to explain why some people change the world and others don’t. These frameworks are really just ways of avoiding what we already know.

When you strip away all the business school analysis, what remains is profound - Eli Hurvitz was exceptionally brave. The rare kind of brave that fixes what's broken in the world, even when the work isn't sexy. A man with no technical background washed laboratory glassware until he understood how medicines were made. Washed. With his hands, in soapy water, until the knowledge soaked into him like light through glass. He drove into Nigerian villages to ask pharmacists what they actually needed. He stood before 220 frightened workers whose livelihoods hung on his words. For fifty years he chose solving problems over promoting himself, as if there were no other way to live. Reading his story reminds me that all our theories about leadership are just elaborate ways of avoiding one truth we can barely name - the world belongs to the brave.

In 2002, Mark Fishman walked into a glass building in Cambridge with an unusual assignment: to turn the Swiss pharmaceutical company, Novartis, into the world’s greatest therapeutics research firm. More unusually still, Fishman was - at least on paper - precisely the wrong man for the job.

The Harvard cardiologist had spent his career studying zebrafish hearts and teaching medical students. He had no pharmaceutical experience and no business training. And yet, Daniel Vasella - the physician-turned-CEO who had overseen the merger of Ciba-Geigy and Sandoz to form Novartis1 back in 1996 - had just handed Fishman billions of dollars to reignite the company’s internal drug development programs.

The timing was inauspicious. Fishman was recruited at a moment when pharmaceutical R&D productivity was halving every nine years. In the early 2000s, a dollar of research produced only a fraction of the drugs it generated in 1950. The pharmaceutical industry at large was adapting by acquiring innovative drugs rather than discovering them in-house. Pfizer was purchasing companies left and right. Merck was cutting research budgets. Even Roche, with its legendary research heritage, was turning to external partnerships. The consensus was absolute: internal R&D was finished.

But Fishman didn’t see it that way.

What emerged from his unlikely hire over the next fourteen years would systematically violate many principles of modern pharmaceutical management. But the Novartis Institutes for Biomedical Research (NIBR) would achieve something the pharmaceutical industry had begun to consider a fantasy: Under Fishman’s tenure, 65 percent of the company’s new drug approvals came from internal development. Many of these drugs would go on to earn the company tens of billions in revenue. And then, in 2016, Novartis began dismantling it.

This is the story of an academic cardiologist and a CEO who showed that curiosity‑driven research can rival the best work in pharma, and why even that success could not shield their institute from unforgiving market forces.

The Bronze Age Collapse of Pharma

When Daniel Vasella announced in 2001 that Novartis would create the largest corporate research organization in the industry, the timing couldn’t have been worse.

The late 1990s brought a crisis of confidence in pharmaceutical safety, effects that continued into the early 2000s. Twelve prescription drugs, or roughly 5 percent of all marketed medicines, vanished from pharmacy shelves between 1997 and 2001. Most were withdrawn due to safety concerns. The popular “fen-phen” weight-loss combo, for example, was found to damage heart valves, thus ending the first weight-loss drug craze.

Then, in September 1999, eighteen-year-old Jesse Gelsinger died during a gene therapy trial, the first person publicly identified to have died from an experimental gene treatment. His death shook regulators so much that the once-hyped gene therapy sector collapsed. The fallout continued for decades.

As bad as this was, nothing quite compared to Vioxx. When Merck withdrew their blockbuster painkiller in 2004, an estimated 20 million Americans had already taken it. But studies had linked the medication to 88,000 heart attacks and 38,000 deaths. Congressional hearings and thousands of lawsuits followed, creating what industry analysts called a “regulatory ratchet effect,” where a pharmaceutical failure leads to stricter requirements that rarely loosen later on.

These failures shifted how companies prioritized their research and development programs. Scientists became less inclined to take “courageous” bets. Risk-taking gave way to risk aversion as companies instituted extra safety checkpoints and killed higher-stakes projects earlier. Meanwhile, the industry faced what researchers dubbed the “Better than the Beatles” problem. Since most common diseases already had effective, cheap generic treatments, companies were forced to move into tougher, uncharted disease areas with inherently higher failure rates.

The industry’s response was predictable and consequential. It chose to consolidate and externalize. Rather than fix their R&D organizations, companies combined them or abandoned internal discovery altogether; instead looking toward venture-funded biotech companies to take on early research risks, with pharma running expensive later-stage Phase III trials with drug candidates that seemed likely to succeed.

This cautious approach had become standard by the time Vasella decided to hire Fishman and give him billions to pursue basic biological research in-house with minimal commercial oversight.

The Candy Factory Coup

Mark Fishman was a curious choice to lead Novartis’ R&D arm. The Harvard Medical School professor had published many elegant papers on cardiac genetics, but few people outside academia ever read them. While he had no business training, no pharmaceutical experience, and no obvious qualifications for running a multi-billion-dollar research operation, he did have genuine scientific curiosity. While industry veterans knew all the reasons why ambitious projects wouldn’t work, Fishman had no presumption they were “impossible”. His academic background meant he thought in terms of biological mechanisms rather than market segments, and to value scientific problems above profit margins.

So why Fishman, then? Vasella's choice to poach him was rooted in his own medical training. At the time, he himself was the only physician leading a major pharmaceutical company. Where business-minded executives saw the Human Genome Project's flood of new targets as a management challenge requiring cost controls, Vasella saw a once-in-a-generation scientific opportunity that demanded the opposite approach. His bet was that only an immersive, talent-first strategy could convert the genomic revolution into breakthrough medicines - a commitment that would require patient capital and faith in science over spreadsheets.

Hiring Fishman was only part of Novartis’ decision to double down on curiosity-driven science, though. In 2002, Vasella also decided to move Novartis’ global research headquarters from Basel, Switzerland, to Cambridge, Massachusetts. No European pharmaceutical giant had ever abandoned their home turf quite like this. Vasella was betting that breakthrough innovation required immersion in a richer biotech ecosystem, even if that meant severing traditional business relationships.

Fishman’s new institute occupied the old New England Confectionery Company factory in Kendall Square near MIT. Where millions of chalky wafers once rolled off production lines, 900 newly hired scientists set up their research benches. “We have to go where the talent is,” said Vasella. “Cambridge is a pool of scientific talent not found elsewhere in the world.”

From here, Vasella instructed Fishman to invent a research culture that borrowed the best from both industry and academia. NIBR would operate independently of Novartis’ marketing department, research priorities would not be dictated by sales teams, and projects would be selected on their potential to “change the practice of medicine,” regardless of commercial outlook.

When asked about research strategy, Fishman sketched out a 2x2 chart with “unmet medical need” on one axis and “mechanistic understanding” on the other. Its sweet spot lay in the upper right: Novartis would develop drugs with clear biological mechanisms for desperate patients.

“What wasn’t on the chart?” asked Fishman. “Money… we were the only group that didn’t assess projects based on market potential.”

NIBR explicitly rejected the financial reductionism of tracking efficiency metrics, calculating financial returns, and killing projects that didn’t promise huge profits. This structural foundation would prove critical as Novartis began rejecting the fundamental orthodoxies of modern pharmaceutical management.

The Four Heresies of NIBR

Four organizational principles crystallized from NIBR's culture under Fishman: approaches that flew in the face of everything the industry had learned from its disasters. Each principle - nay, heresy - addressed a specific failure mode of crisis-era pharmaceutical management. And together, they created a reproducible system for breakthrough innovation.

Heresy 1: Fast Proof-of-Concept in Extreme Phenotypes

The first was to deliver fast proof-of-concepts for extreme phenotypes.

Call it smart drug development if you must, though it functioned more like a scientific cheat code. The desperate and the rare, it turned out, are biology's most honest witnesses - and they could validate mechanisms with shocking speed.

Fishman’s approach towards canakinumab illustrates this radical philosophy. Canakinumab is an antibody that targets IL-1β, a master inflammatory switch. Rheumatoid arthritis beckoned: 1.3 million patients, established market, clear path to blockbuster status. Any pharmaceutical executive could have mapped that strategy in their sleep; and most would have.

Instead, Fishman’s team turned to Muckle-Wells syndrome, discovered in 1962 and found in only four hundred patients worldwide - what most would consider a commercial footnote. But these patients offered something priceless: a pure test of IL-1β’s importance. Their daily fevers came from a genetic mutation that continuously floods their systems with the protein. Block IL-1β here, and the antibody’s binding would be unmistakable; and so Novartis ran clinical trials, dosing patients suffering from Muckle-Wells syndrome with canakinumab.

The first patient's fever broke in a day. All patients responded with shocking immediacy - fevers that had burned daily for decades simply switched off, as if someone had finally found the thermostat in a house that had been sweltering since childhood. One dose. 24 hours. Proof-of-concept achieved.

This rapid validation became the foundation for confidently testing the same mechanism across multiple inflammatory conditions: systemic juvenile idiopathic arthritis, gout, and eventually atherosclerosis. But the ultimate validation came with CANTOS - a massive cardiovascular prevention trial enrolling 10,000 patients with prior history of cardiovascular disease. Four years into the study, Fishman got a call from up above: "This better work." It did. The combined risk of heart attack, stroke, or cardiovascular death dropped by 15%. Then came a surprise nobody had predicted: lung cancer incidence plummeted by 67%. What began as a 24-hour proof-of-concept in 400 patients had revealed fundamental inflammatory mechanisms underlying diseases affecting millions.

Heresy 2: Follow Pathways, Not Disease Categories

The second heresy followed naturally: organize around biological pathways, not market categories.

While the pharmaceutical industry had structured itself around market categories - cardiovascular, oncology, neurology - NIBR began to organize around biology itself, following the ancient molecular pathways that connect seemingly disparate diseases.

Consider the wandering history of fingolimod, or FTY720, a synthetic analog of myriocin originally isolated from the fungus Isaria sinclairii. Its mechanism is both elegant and counterintuitive. This drug interacts with lymphocytes, the immune system’s foot soldiers, and forces them to remain sequestered in the lymph nodes. The trapped lymphocytes, unable to circulate through the bloodstream, stop crossing into tissues where they might cause harm.

Fingolimod’s original indication was kidney transplantation, where the goal was to prevent organ rejection by temporarily knocking out the immune system’s surveillance apparatus. But as often happens in drug development, the results weren’t as expected. The kidney program failed, though not because the mechanism was wrong; but because transplant rejection was not the right disease to showcase lymphocyte sequestration. Transplant patients already receive powerful immunosuppressive cocktails, leaving little room for fingolimod's unique mechanism to demonstrate additional benefit.

Yet, rather than abandon the pathway entirely like most other pharmas would, NIBR made good on its second heresy by asking a completely different question: where else might wayward immune cells cause problems?

The answer came from an unexpected direction: multiple sclerosis, a disease that exists at the intersection of immunology and neurology. In patients with multiple sclerosis, T-cells cross the blood-brain barrier and attack myelin, the insulation surrounding nerve fibers. The result is progressive neurological damage as the immune system attacks the central nervous system.

If fingolimod could prevent immune cells from circulating through the bloodstream… could it prevent them from entering the brain?

As it turned out - yes. When Gilenya (fingolimod’s commercial name) was approved by the FDA in 2010, it became the first oral therapy for multiple sclerosis, transforming a failed transplant drug into a three-billion-dollar medicine. Fingolimod’s success verified that biological pathways rather than market categories should determine how pharmaceutical companies think about disease and treatment. While competitors’ research-arm design made pathway-following discoveries organizationally challenging, NIBR minimized company silos and enabled researchers to ask: “Where else does this biological mechanism cause problems?”

Heresy 3: Embrace Academics - Don't Compete

The third heresy challenged the industry's relationship with academia itself.

Most pharmaceutical companies viewed universities as potential threats or irrelevant ivory towers, maintaining arm's-length licensing relationships.

NIBR's academic culture went beyond hiring professors; it required rebuilding pharma's relationship with knowledge creation itself. While competitors guarded research behind corporate walls, NIBR encouraged scientists to publish prolifically, present at conferences, and maintain deep university collaborations.

NIBR's ability to move from biological insight to clinical validation with such confidence stemmed partly from their unusual organizational structure: the same scientists who designed the discovery program shepherded their molecules through first-in-human studies. Unlike the traditional pharmaceutical model where compounds are "thrown over the wall" from research to development, NIBR integrated translational medicine physicians into discovery teams from day one. These physician-scientists remained with their programs through early clinical trials, preserving institutional memory and ensuring that critical biological insights didn't get lost in translation. When canakinumab moved into human testing, the researchers who understood its mechanism at the molecular level were also the same ones designing clinical protocols for it.

NIBR scientists published in Nature, Cell, and Science at rates comparable to leading academic institutions. The institute’s publication record even became a recruiting tool, because it proved that joining Novartis didn’t mean abandoning scientific ambition.

This openness extended to the most unconventional research areas, such as gerontology. Most competitors avoided aging research as being too basic, too risky, and too long-term. NIBR, however, saw its potential to unlock multiple therapeutic areas. As unsexy as it is, everyone ages. Joan Mannick, a physician-scientist who joined NIBR to study immune aging, showed the institute's willingness to tackle such unconventional research areas.

This same philosophy of embracing overlooked opportunities would prove crucial in another area entirely. Carl June, an immunologist at the University of Pennsylvania, was pioneering CAR-T cell therapy - a revolutionary technique for genetically reprogramming a patient's own immune cells into cancer-killing machines. Rather than a standard license, Novartis and Penn created a deep co-development alliance and built the Novartis-Penn Center for Advanced Cellular Therapeutics on Penn’s campus, a joint facility staffed by Penn and Novartis scientists that accelerated CAR-T research and manufacturing.

The partnership that emerged was impressive in its depth and integration. June's team worked alongside NIBR scientists as they refined CAR-T manufacturing and dosing protocols, eventually leading to Kymriah, the first approved cell therapy. And when resistance mutations inevitably emerged, the academic-industry teams worked together to understand their mechanisms and develop next-generation approaches.

This deep academic integration eliminated the "valley of death" that typically exists between discovery and development. Because by keeping the scientists who understood the biology involved in clinical design, NIBR ensured that crucial insights weren't lost in translation.

Heresy 4: Don’t Build The Wheel From Scratch

NIBR’s fourth and final heresy was to refuse to be scared off by research areas already extensively investigated or tainted by previous setbacks. While competitors focused on de novo drug discovery within predictable development cycles, NIBR systematically built upon research foundations laid decades earlier.

NIBR’s long-term approach built on decades of blood pressure research. Scientists had discovered that the body controls circulation through a hormone cascade involving angiotensin, a stress hormone that constricts blood vessels and raises pressure. When ACE inhibitors - drugs that block angiotensin production - emerged in the 1980s, they helped heart failure patients, but weren’t enough. Half still died within five years.

The last major innovation attempt had been omapatrilat, which tried a promising dual approach: block an enzyme called neprilysin to boost natriuretic peptides (heart‑protective hormones that help the kidney shed salt) while simultaneously blocking the harmful angiotensin pathway. But as the drug also elevated bradykinin, a molecule that can cause life-threatening throat swelling, the FDA rejected it in 2002.

NIBR saw an opportunity in this failure. Instead of abandoning the dual approach entirely, they spent five years redesigning around it. Omapatrilat’s throat swelling problem came from how it blocked angiotensin, so NIBR paired their neprilysin inhibitor with valsartan - their already-approved blood pressure drug. This eliminated the bradykinin problem while preserving the dual benefits.

The resulting combination drug - LCZ696, later named Entresto - faced the hardest possible benchmark. It had to go head-to-head against enalapril, the gold standard ACE inhibitor. This trial, dubbed PARADIGM-HF, was stopped early because Entresto’s benefits were so overwhelming that continuing would have been unethical.

LCZ696 reduced the primary composite endpoint by 20 percent compared to enalapril. All-cause mortality dropped by 16 percent. But the timeline had been a long one. By the time Entresto was approved in July 2015, 28 years had passed from valsartan’s first synthesis. By 2024, it had grown to a $7.8 billion franchise.

While competitors started fresh with each program, NIBR’s fourth heresy compelled them to treat their entire research history as cumulative capital. They recognized that breakthrough medicines emerge by patiently and deliberately building upon decades of biological understanding.

NIBR’s Scorecard

NIBR generated remarkable results: 65% of Novartis’ new drugs came from internal development (versus 20% at Pfizer), with a 16.7% FDA approval rate ranking 4th among major R&D spenders. Four NIBR drugs - Gilenya, Cosentyx, Entresto, and Affinitor - have generated $108 billion in lifetime sales, powering Novartis’ climb from 7th place in 2004 to 2nd place globally by 2014.

While NIBR’s innovations consistently opened entirely new biological territories, competitors that implemented the more conservative “lessons learned” approach saw declining returns. AstraZeneca adopted explicit NPV hurdles and cut its pipeline by over 40 percent. GSK created “kill committees” that terminated over 35 percent of discovery projects based on ROI calculations. These financially driven approaches yielded exactly what economic theory predicts: incremental improvements and risk aversion.

To put this in perspective: the combined income from those four drugs - Gilenya, Cosentyx, Entresto, and Affinitor - were rivaling the entire annual revenues of mature pharmaceutical companies like Moderna ($18B), Regeneron ($12B), or Biogen ($10.9B). Vasella's $250 million bet on a Cambridge candy factory had created what amounted to multiple Fortune 500 pharmaceutical companies worth of revenue from a single research institute.

NIBR had seemingly solved the fundamental paradox of pharmaceutical R&D: how to systematically generate breakthrough innovation within a large organization2. Its four principles appeared to offer a reproducible system for doing what competitors deemed impossible. And for over a decade, its success seemed unshakeable.

But the same market forces that had driven the industry toward externalization were still at work, growing stronger with each quarterly earnings call. Financial pressure from investors was escalating. The end, when it came, would prove that even the most successful innovation models cannot survive indefinitely in a system optimized for short-term returns.

When the Center Could Not Hold

In March 2016, Mark Fishman stepped down as President of NIBR after thirteen years, passing its leadership to Harvard chemical biologist, Jay Bradner. Fishman’s departure left a philosophical vacuum that proved impossible to fill. He hadn’t only been NIBR’s founding father, but also its conscience, championing a biology-first covenant that had sustained the organization through commercial pressures.

Yet the financial reality was becoming impossible to ignore. NIBR’s annual operating costs had ballooned to $4 billion - a sum that could fund entire national science foundations. What had once seemed like visionary investment now looked like profligate spending to shareholders demanding quarterly returns. A McKinsey analysis released earlier this year even suggested that companies pursuing “external innovation” delivered three to eight times higher total shareholder return per invested dollar compared to those maintaining internal research3.

NIBR had expanded globally during its golden years, with specialized facilities in Shanghai, Singapore, and California. But this network began contracting in 2016 as Novartis closed sites and consolidated operations. Press releases spoke of “critical mass” and “operational efficiency” - corporate euphemisms for spreading too thin. Key researcher departures too increased steadily during this period, too. Senior scientists left with their institutional knowledge, many joining Cambridge biotechnology companies (1, 2, 3, 4).

Even NIBR’s most successful drugs faced growing competition. Cosentyx, the leading psoriasis treatment, was challenged by newer competitors offering improved efficacy. Lilly’s ixekizumab and UCB’s bimekizumab were gaining market share as dermatologists found them more effective. Meanwhile, Gilenya - the pioneering oral MS therapy - was being displaced by Bristol Myers Squibb’s Zeposia and J&J’s Ponvory, drugs that eliminated the cardiac monitoring requirements that made Gilenya cumbersome to prescribe. What were once flagship franchises now resembled warships being picked apart by torpedo strikes. Lifecycle management was turning into damage control.

In the Fishman era, programs were evaluated primarily on biological rationale and mechanistic clarity. Under increasing financial pressure, these criteria evolved to include market size, competitive landscape, and peak sales projections. Programs now needed to promise blockbuster revenues to survive.

But here's some cruel irony: chasing blockbuster markets moved NIBR away from the extreme phenotype strategy that made their early successes possible, and devastation ensued. Serelaxin, a heart failure hormone that had shown early promise, collapsed in Phase III, costing Novartis $200 million. Fevipiprant, an asthma drug targeting the CRTh2 receptor, died in 2019 after years of investment. Most devastating was CNP520, an Alzheimer's drug that didn't merely fail - it appeared to accelerate the cognitive decline it was meant to prevent. Even Ilaris, despite CANTOS success, faced FDA rejection for cardiovascular indications due to infection risk and high cost. By 2019, NIBR was shuttering clinical programs at an unprecedented pace, with twenty-one candidates meeting their end in a single year.

When Fiona Marshall, a veteran pharmaceutical executive from Merck, took over from Bradner in late 2022, she inherited an organization resembling a Swiss watch dropped from considerable height. Marshall’s first act was symbolic but telling: "Novartis Institutes of Biomedical Research" plural became "Novartis Biomedical Research" singular - a linguistic neutron bomb vaporizing nearly two decades of autonomy.

At the 2023 STAT Future Summit, she explained that NIBR would focus on “projects likely to yield commercially successful drugs … We want that alignment.” The word “alignment” weighed heavily on whether a program had a clear, near‑term commercial path. In other words, research would get green‑lit only if the development and marketing arms could already see how to turn it into a profitable, approvable drug - which meant the replacement of Fishman’s biology-first covenant with the commercial considerations that would have killed programs like Entresto before they began. In a separate 2023 interview, Marshall stressed that the new NIBR would not any more explore the “cool thing” that a scientist might find, but work on “alignment” with development strategy. Missing from this vision was any semblance of the culture that Fishman had started twenty years before, and with it, confirmation that financial pressures had finally reshaped the entire pharmaceutical sector.

Internal R&D: An Endangered Species

Pharmaceutical companies have discovered something more profitable than discovering drugs: not discovering them at all.

Between 2016 and 2020, fourteen of the world’s largest pharmaceutical companies spent $577 billion on share buybacks and dividends versus $521 billion on R&D - a $56 billion preference for financial engineering over actual engineering. By July 2024, even Novartis’ new CEO Vas Narasimhan would tell investors plainly: “We’d rather use our capital to buy back our own shares … we still have $10 billion in our ongoing buyback program.”

This can be interpreted as pharma companies eating tomorrow’s seed corn. Every dollar diverted from research is a therapy that won’t be discovered, a biological insight that won’t be pursued, and a patient population that won’t be served.

The industry’s response has been to outsource innovation. Since 2018, emerging biopharma companies have led 73 percent of late-stage clinical programs and account for 72 percent of new FDA approvals. Big Pharma has essentially become a licensing and marketing operation, rather than a discovery engine.

But this strategy may be too clever by half. If buying innovation is so much more efficient, why does anyone need internal R&D? Because internal R&D provides something irreplaceable: institutional memory (which targets failed due to toxicity?), scientific judgment (without active researchers, how do business development teams evaluate whether biotech data is genuinely promising?), and long-term perspective (biotechs need to exit within their funding cycles, regardless of optimal development timelines).

Without institutions like NIBR, the industry increasingly focuses on proven mechanisms rather than breakthrough discovery. Pharma companies lose research capabilities, biotechs optimize for quick acquisition, and true innovation becomes economically risky.

Indeed, what we have seen is that pharmaceutical innovation requires inefficiency. It requires funding ten programs to achieve one success. It requires scientists to pursue hunches that MBA-trained portfolio managers would kill. It requires the kind of patient, curious, often wasteful research that public markets punish but humanity desperately needs.

The glass building endures in Cambridge, now a monument to deliberate amnesia. The scientists who created the impossible have scattered to biotechnology companies, academic institutions, and consulting firms, carrying institutional memory that the industry has chosen to forget.

The lesson of this story ought not to be that NIBR’s model failed; but that even proven innovation approaches can’t survive the relentless pressure of quarterly earnings expectations. Fishman’s four heretical principles generated tens of billions in therapies and remain as valid today as they were twenty years ago. The industry has chosen predictable returns over uncertain breakthroughs; quarterly results over long-term impact.

What dies with institutions like NIBR is the capacity to solve problems we don't yet understand. Every quarter that passes without biology-first research is a generation of therapies that will never exist, patients who will never be treated, insights that will never be pursued.

The twenty-year experiment of NIBR is over. We documented every success, analyzed every breakthrough, and then systematically dismantled what we had learned. The question isn't whether we learned anything from it - we did - but whether we're content to ignore those lessons in favor of the comfortable mediocrity of managing decline.

The choice, as always, is ours. The patients are waiting.

Acknowledgements: A special thanks to Niko McCarthy, Xander Balwit, and Saloni Dattani for reviewing earlier drafts.

This is how I found myself on an Arkia Airlines redeye in July sitting next to a Navy reservist who codes for some Tel Aviv startup between his monthly Gaza patrol shifts, and he’s giving me restaurant recommendations while recounting war stories like I would my college years, and I’m thinking this is my first glimpse of a country where normal doesn’t mean what I thought it meant. The teenagers behind us are chattering about American summer camps—the reverse exodus, Israelis heading to the Catskills while I’m flying toward their miracle—and this kid won’t stop asking me about everything from Accutane’s mechanism of action to whether Americans really learn languages as badly as everyone says.

The thing about traveling to a country at war is that life insists on being ordinary. In Jerusalem I met Aryeh Yonatan and Rafi at Mahane Yehuda where vendors sell pomegranates in seventeen languages and the air smells like fresh bread and exhaust fumes, and Aryeh tells us he lost his beautiful green jacket at this bar three months ago, the one with the pixelated Peaky Blinders artwork that looks like it was designed by someone’s drunk cousin. So naturally I ask if he’s ever tried asking for it back—he hasn’t—and he walks up to the gorgeous barista and gets it immediately, then loses it again thirty minutes later when we’re out clubbing. I saved it, wore it for one photograph where I look like I’m borrowing someone else’s life, which maybe I was.

At the boureka stand this guy spent ten minutes explaining in patient Hebrew that sesame seeds mean cheese, peppers mean potato, and when understanding finally dawned across my face he kissed my forehead like I was his slow but beloved grandson learning the world’s most important lesson. This is what I mean about ordinary life: a tank driver sits across from me in a kitschy Tel Aviv bar for American expats, aged twenty-two with those thousand-yard spaces between his jokes, showing me videos of accidentally fender-bendering his tank into another kid’s tank, telling me about dogs in Gaza that have learned to eat dead bodies, about commanders barely old enough to vote, about pulling out of a war they might not win, with hostages still wasting away in tunnels that only exist to imprison them as bargaining chips made flesh. He rescued a puppy but had to give it away to an Israeli family. Between stories he sips a Gold Star and shows me photos of his friend escorting the Catholic Patriarch of Jerusalem to pay respects at a bombed church—one guy in full Catholic regalia, the other in combat gear, both posing for the camera like it’s the world’s most surreal photo op.

The Brazilians from the other Taglit group adopted me at the Israel Museum because I was wandering alone and they needed someone to take photos, and I’m speaking Portuguese I don’t know to kids who explain things in English while their guide drones on about pottery shards and ancient coins. One girl looks exactly like Mikey Madison so we create this running joke about pretending she’s actually the actress, which works until she gets tired of me asking for autographs. The Russian techies are reddit-nerdy, the French kids obsessed with oldies, the British ones complete assholes, and our token Israelis join halfway through: one laid-back and intelligent, another timid and carrying October 7th in her pockets, one who tells Europeans she’s from Malta rather than deal with their assumptions, and another who looks like a Swedish DJ and whose parents are venture capitalists and supermodels but who turns out to be the most down-to-earth of all of us, vaping his way through the Promised Land with startling grace.

Friday night in Jerusalem the sirens go off and we descend into bomb shelters like it’s just another part of Shabbat dinner, and I’m thinking this is not how I imagined my first trip outside America would go. The Houthis sent rockets that got intercepted before they could deliver their message, and most people barely look up from their conversations because this is what resilience actually looks like—not heroic speeches but ordinary people refusing to let terror interrupt their hummus, and I’m sitting there trying to process that I’m in an actual bomb shelter while my friends back home are probably arguing about parking spots in the Mission.

Jets scramble overhead at the Dead Sea, racing toward Yemen, and I’m floating in water so salty I can’t sink, reading war news on my phone while biblical mountains turn black under their shadow.

At Yad Vashem the children’s memorial destroys me completely. There’s this video loop of young voices singing Hatikvah before they learned what hopelessness looked like, these sweet innocent sounds rising in the darkness while their faces glow on screens like ghosts, and I’m crying alone while tour groups shuffle past because no one else seems affected and the guide maintains that professional distance between tragedy and tourism. It’s always the children that break me, not the blood or violence but these tiny voices singing hope songs they’d never live to finish. The dates on military headstones at Mount Herzl read like countdown clocks: 2006, 2005, 2004—boys younger than me, younger than my brother, buried in soil they died defending.

Shalev stands before us at the Nova site carrying October 7th in his eyes like shrapnel, describing how he hid under a Bedouin farmer’s house while Hamas terrorists searched for survivors. “Where are the naked Jews?” he heard them calling—he wasn’t wearing a shirt when he escaped—and his words carry the weight of those who’ve gained memories they wish they never had. His black eyes briefly lock with mine, and I see that they don’t belong to a twentysomething but instead a Holocaust survivor, his body rejuvenated, with sixty years of aging to go until his testimony becomes croaked whisper. The sound of controlled explosions echoes across fields where kids once danced to electronic music under desert stars, and now it’s a memorial to joy interrupted, to futures cut short by ancient hatred.

Five shekels buys me a glimpse through binoculars at Gaza, smoke rising from places that used to have names, used to have families, and this elderly Russian guy tells me I should join the IDF. I wonder what my soft San Francisco tech bubble life has prepared me for this terrible landscape, and there’s this strange vertigo of standing at the edge of a war that’s happening right there, close enough to see the smoke, close enough that the old man thinks I could walk into it.

In Sderot, right next to the border, people go about their business as if rockets aren’t a daily possibility. Markets open, children play, lovers hold hands, because this too is being Israeli: refusing to let fear become the organizing principle of existence.

The cats in Israel are incredibly friendly and I pet many of them, hoping I don’t get fleas. At the Kotel I meet a kid from the Five Towns who went to HANC and knows someone from home—the diaspora folding back on itself in impossible loops. Two older religious American guys armed with enormous rifles chit-chat while pigeons coo overhead, and when I joke about “Kfar Rockaway” they chuckle like I’ve told them the best joke in years. In Yafo I become an unofficial photographer for an Israeli-Taiwanese couple, my Hebrew and Mandarin tangling together like DNA strands while I try to direct their poses, language becoming this three-way dance of translation and miscommunication and sudden perfect understanding. At Masada I bump into a girl from high school at the bonfire—the world compressing to the size of a candle flame—and we’re sitting on the same mountaintop where Zealots chose death over surrender, warming our hands over flames that could have been burning for two thousand years.

In this country chapstick is clear lipstick and Ethiopian soldiers serve alongside Ashkenazi reservists without anyone batting an eye because minor differences in minhag dissolve into irrelevance when survival of Am Yisrael trumps everything else. Hostage posters paper every surface—trees, benches, billboards, touchscreens—faces of the disappeared haunting every corner with their insistent presence, yellow ribbons fluttering from antennas like some desperate semaphore. A ballistic missile impact site in downtown Tel Aviv sits like a broken tooth among apartment buildings, and pedestrians walk past as if urban warfare were just another fact of life, like traffic or inflation or the price of avocados.

I’m not only bringing back to San Francisco the new Hebrew slang rolling around my mouth like treasure (though there’s plenty of that too). I’ll bring back with me actual faces: the barista who returned a lost jacket, the vendor who kissed my forehead when language barriers finally fell, the twenty-two-year-old tank driver showing me puppy photos from a war zone.

And perhaps forever burned in my memory is that moment in the children’s memorial at Yad Vashem, crying alone in the darkness while those sweet voices sang Hatikvah on an endless loop, feeling the crushing weight of all that innocence snuffed out before it could bloom. I stood there surrounded by the faces of children who would never grow up, never fall in love, never learn Hebrew or argue about politics or rescue puppies from war zones, and for a moment the hopelessness was absolute.

But then I think about the eyes of the timid girl and Shalev and the tank driver—all these young people who’ve been forced to grow old too fast, who carry themselves with the gravity of those who’ve looked directly into the worst of humanity and somehow emerged more human, not less. In their faces, worn by sirens and rocket fire and things twenty-two-year-olds shouldn’t have to know, I’ve glimpsed the cruelest paradox: that sometimes the only way to honor the dead is to become more alive. That those tiny voices in the darkness weren’t singing a lament—they were singing instructions.

There are two examples of American justice that never fail to warm my heart. The first is how O.J. Simpson walked free after a little light murder. The second is how Hims & Hers will undoubtedly walk free after theirs - though in fairness to the Juice, at least he didn't claim to be democratizing justice while brandishing the knife.

Hims & Hers is the apex predator of the insecure millennial. If you look at their branding - the serif fonts, the muted "millennial beige" color palette, the cactus-green bottles - it’s all designed to bypass the part of your brain that associates medicine with *sickness*. In the old days (and by old days, I mean, like, 1998), if you had erectile dysfunction or male pattern baldness, you had to undergo the humiliating ritual of the In-Person Appointment. You had to sit on the crinkly paper. You had to make eye contact with a guy named Dr. Lipshitz and admit that your body was failing you. It was awful, but there was a kind of moral friction to it. It was *real*.

But today, Hims removes that friction, and turns the patient into a "member" and the treatment into a "lifestyle hack." To see what I mean - just take a look at the company's Super Bowl commercial in early 2025 - titled "Sick of the System". Between the beer ads and the crypto pitches, Hims positioned itself as David against Big Pharma's Goliath, dramatically blaming "Big Pharma's price-gouging" for making effective weight-loss drugs unaffordable while promoting their own cheaper compounded semaglutide. Within weeks, this self-appointed enemy of pharmaceutical greed would partner with Novo Nordisk, the very Danish giant behind the thousand-dollar-a-month Wegovy injections they had just finished condemning.

Their partnership lasted exactly two months. Which, in fairness to both parties, is longer than most celebrity marriages and roughly equivalent to the lifespan of a mayfly (though considerably less dignified than either).

What happened in those eight weeks reveals something essential about the kind of company Hims has become.

It turns out that while Hims was shaking hands in the boardroom, they were simultaneously selling what Novo described as “illegitimate, knockoff versions” of Novo’s own flagship drug out the back door. And when Novo pointed this out - noting that the mass-compounding was supposed to stop - Hims essentially shrugged - pffft - and so the deal collapsed.

"We had an agreement that the mass compounding would stop and unfortunately it didn't," a Novo VP explained at the time. "That's why we ended the partnership."

This, my friends, is a perfect crystallization of Hims’ style of corporate duplicity: promising a Healthcare Revolution while profiting from the very system they claimed to oppose.

In Which We Learn That Adding Vitamin B12 to Anything Makes It "Personalized Medicine"

To understand the money at play here - which is why Hims is so motivated to keep screwing customers over - you have to understand the “Compounding Exemption.”

You see: in a sane world, compounding is for edge cases. A patient allergic to the dye! A child who needs a liquid version of a solid pill! The FDA allows pharmacists to mix these custom batches. It is a compassionate loophole.

But Hims takes the concept of personalized compounding and abuses it at industrial scale.

For example - by adding a token amount of Vitamin B12 to semaglutide, Hims can call it a “compounded” drug that is legally a unique, personalized prescription, - but functionally acts a a way to mass-produce a patent-protected drug without a single glance from the FDA.

And they are hardly alone in this exploitation of regulatory good faith. Companies like Eden are marketing sermorelin - another peptide hormone - as fitness enhancers with bold taglines like "Cardio + Strength" and promises that the compound "may support HGH production." Never mind that sermorelin's original FDA approval was withdrawn because the manufacturer simply stopped selling it in 2008...

The Ketchup-and-Mustard School of Erectile Dysfunction Treatment

Perhaps a more telling aspect of the Hims empire lies in their approach to sexual dysfunction - specifically, their "Hard Mints," chewable tablets combining both sildenafil and tadalafil (the active ingredients in Viagra and Cialis). To me, this is basically the pharmaceutical equivalent of putting both ketchup and mustard on a hot dog and calling it “gourmet”. You can’t just slap these together to make a better acting drug!

What makes this particularly grotesque is its resemblance to the infamous "Rhino" pills that haunted gas station counters in the early 2000s. Those black-market supplements secretly contained both sildenafil and tadalafil - and poor guys not knowing any better took these and ended up in emergency rooms. The agency repeatedly flagged products like "Rhino SE7EN" for containing undisclosed pharmaceutical ingredients, noting the dangers especially for men on nitrates or with heart conditions.

Hims has essentially taken this discredited gas-station formula, added a dash of vitamin B12 for "personalization," and called it a day. It’s a remarkably shoddy job at making themselves look legitimate, frankly.

The company's own blog warns against combining Viagra and Cialis due to risks including "sudden drops in blood pressure," even as they market products that do exactly that.

To me, this contradiction - simultaneously cautioning against and profiting from the same practice - would be remarkable… if it were not otherwise so characteristic of the entire enterprise.

How to Extract $3,588 from Someone Who Just Wants Help

The genius of Hims lies in understanding that consumers will pay almost any premium to avoid the humiliation of discussing erectile dysfunction or hair loss with an actual human being. They have identified a market inefficiency in desperation, and built an empire around it. Their telehealth consultations are brief by design, their prescriptions are near-automatic, because the human interaction between “I want Viagra!” and “My Viagra arrived in the mail! Yipee!” has been minimized.

This becomes even clearer when examining their pricing structure. The drugs Hims prescribes are, in most cases, generic medications that have been available for decades. Sildenafil (the active ingredient in Viagra) costs roughly $2-4 per pill through traditional pharmacies like Amazon Pharmacy or GoodRx - sometimes even less with insurance. Finasteride for hair loss runs about $10-15 per month as a generic, and can cost as little as $2 per month with a GoodRx coupon.

Yet Hims is getting away with charging $79 per month for "personalized kits" of these same drugs, all the while locking customers into ten-month advance payments. Their own website admits that finasteride "usually costs between $20 and $60" depending on where you buy(!) then pegs their own price at $22 per month - dramatically more expensive than alternatives.

But who's counting when you're disrupting the healthcare-industrial complex one follicle at a time?

It doesn’t take a long time trawling through various subreddits to discover a myriad of customer complaints about Hims - like people being charged $300-400 immediately after brief online questionnaires, or getting prescriptions "approved in 1 minute" with no live doctor interaction - which is either remarkably efficient healthcare or remarkably efficient fraud, depending on your perspective. One Reddit user recounts here: "Didn't talk to a single doctor and was charged $395!!! … Approved in 1 min by checking some boxes and then charged within 5 min." And another spent $3,588 on a weight-loss subscription only to discover the drugs made them violently ill. When they sought a refund, they learned what many customers learn too late: that convenience and customer service are not the same thing.

But the subscription traps are where the real Extraction occurs. Customers complain of being locked into year-long commitments they can't escape, like hotel California but with erectile dysfunction pills. Better Business Bureau complaints reveal complaints by customers who try to pause subscriptions for six months only to have Hims automatically resume billing without warning, charging $85 "out of the blue." Others discovered they had been auto-enrolled in recurring shipments without notification.

When they try to cancel immediately - because apparently "immediately" is a foreign concept in Subscriptionland - Hims refuses refunds because the product has already shipped.

(Ironically, Amazon itself offers many of these same medications at a fraction of the cost, with actual pharmacists available for consultation and no year-long subscription traps - but Amazon doesn't market shame as a premium service)

A Brief Digression on the Commodification of Side Effects

Hims also sells "oral weight loss kits" with no GLP-1 in them, but these might be even worse in a way. What makes them particularly grotesque is their shotgun approach to pharmacology: rather than prescribing one medication and monitoring its effects, Hims is combining three or four different drugs into cocktails that have never been tested together - what they call "personalized kits" that can "include a combination of bupropion, metformin, topiramate, vitamin B12, and naltrexone," taken once or twice daily.

While each medication is sometimes used individually for weight management, or in known FDA-approved pairings like bupropion plus naltrexone (Contrave), Hims literally just puts them all into a horse pill. One user described being prescribed a triple regimen: bupropion XL every morning, plus a naltrexone + B12 tablet each morning, with metformin to be added later. The patient experienced severe side effects within hours: "massive headaches" followed by repeated vomiting for hours. They were so sick they had to stop and consult the provider, who then advised re-introducing the drugs one by one more gradually.

(BTW: while a single generic pill might cost a few dollars, a "personalized kit" of multiple medications can command $79 per month, paid ten months in advance)

How to Source Your Pharmaceuticals Like a Wish.com Order

The paper trail behind Hims' $165-per-month weight-loss shots reveals a supply chain designed around regulatory arbitrage, and a troubling one at that. A broader analysis of 2,465 GLP-1 shipments by the Partnership for Safe Medicines found that nearly 10 percent came from unregistered factories - with the plurality of them traced to Chinese peptide manufacturers operating outside FDA oversight. Despite this, customs officials still cleared 80 percent of these unregistered semaglutide shipments anyway, creating a green corridor for synthetic powder that costs a fraction of Novo Nordisk's FDA-approved, yeast-derived semaglutide.

Novo Nordisk’s own filed complaint to the FDA underscores why that matters. LC‑MS on a compounded‑drug sample supplied by “a large tele‑health platform” 1 detected sequence‑deleted peptide impurities and an unknown 0.11 % peak - defects that raise immunogenicity risk and do not appear in Novo’s semaglutide(!)

Perplexingly, FAERS data makes compounded semaglutide appear 100x safer than FDA-approved versions - 719 adverse events per million prescriptions for Wegovy versus just 7 for compounded shots2.

This obviously reflects a broken reporting system for compounded drugs. Why? Because FDA-approved drugs carry mandatory adverse event tracking. On the other hand, compounded versions operate in a reporting shadow zone where 503B pharmacies have no obligation to monitor what happens after patients inject their products.

This cost-cutting explains how Hims undercuts Wegovy's $1,000+ monthly price tag, but the safety trade-offs are mounting. FDA records show over 13,000 vials recalled for sterility failures at 503B facilities, and BPI Labs - one of Hims' contracted pharmacies - now operates under an FDA Warning Letter for refusing to recall an unapproved product.

In Which Our Heroes Achieve Peak Disruption by Making Medicine Worse

To be clear, these are not objections to treating erectile dysfunction, hair loss, or obesity. I believe that real medical conditions which cause genuine suffering deserve effective, affordable, accessible treatment.

Nor do I have Luddite objections to loosening direct-to-consumer medical access - in theory, such expansion represents a net good: more people treated, and fewer bureaucratic hoops, less institutional inertia. My main problem is that Hims represents the worst possible way to provide this kind of care: in a sanctimonious, slippery, ethics-as-marketing-until-it-becomes-inconvenient kind of way.

They have a certain smarmy self-regard that proves hard to pin down but impossible to ignore. They are not evil, exactly, no, They are just hollow, and worse: pleased with themselves about it.

Like Upton Sinclair's meatpacking plants, companies like Hims have taken something essential - in this case, the trust between regulator and regulated that makes modern medicine possible - and corrupted it for profit. The only difference is that instead of adulterating our food, they are adulterating our pharmaceuticals, and instead of hiding behind industrial secrecy, they are hiding behind the complexity of modern drug regulation.

But the fundamental dynamic remains the same: companies gaming a system built on good faith, regulators playing catch-up to bad actors, and consumers paying the price for both the corruption and the cleanup.

Dr. Fukuyama, when you plant the word "against" adjacent to the phrase "life extension," you've earned an "F" in Longevity Strawman Arguments, Volume 1. The project of longevity is ethically imperative and economically rational; opposing it requires selective amnesia about medicine's entire record.

Fukuyama's case has two pillar: physiological impossibility and sociopolitical sclerosis. But in my view, both crumble on inspection.

*cracks knuckles*

Biological Objections

The Whack-a-Mole Misconception

In longevity discourse, there is a classic objection: aging is complex, so targeting individual diseases is futile, akin to playing whack-a-mole at a carnival.

But I find there are two problems with this argument:

First, we're already doing it, and it rocks. Statins have slashed heart attack deaths. Finasteride and tamoxifen prevent age-related cancers. GLP-1s seem to hit obesity, diabetes, and cardiovascular risk in one swing. Every whack can buy healthy years. Your conclusion of "therefore don't try" simply doesn't follow.

Second, the moles share a warren: whack one and three neighbors duck. Obesity is more than a poor lifestyle choice, because it multiplies risk for dementia, heart disease, and cancer. Atherosclerosis happens everywhere and is largely preventable by keeping LDL low over decades. Plus - mouse studies show synergy: the combination of rapamycin with either acarbose or trametinib extends lifespan more than any of the three drugs do alone.

The real-world compression of morbidity is already happening by the way. Mannick's mTOR inhibitor trials showed significant reductions in respiratory tract infections among adults 65+ taking rapamycin-like drugs. Human centenarian cohorts consistently show compressed disability periods - they live longer and stay functional longer. Whether we solve aging through root causes or targeted interventions is an implementation detail. Refusing seatbelts because you'd still need airbags would be absurd; so is refusing proven interventions because aging is complex.

Sociocultural Objections

The Cognitive Stasis Scare

Your second argument - that longer lives mean calcified thinking - fails on multiple fronts. Why? Because:

Neuroplasticity is real. The brain remains adaptable well into our seventies. Cognitive decline rates among 70-somethings have fallen roughly 15% per decade since the 1990s. History is littered with late-life intellectual pivots: Wittgenstein reversed his entire philosophy mid-career. Kant published his major works in his fifties. Grace Hopper invented COBOL at 53. I can go on.

You're seeing selection bias. Flexible elders blend in, and rigid ones stick out - so rigidity looks universal when it isn't.

Moreover, plenty of ideas that drive our world today are ancient. Liberal democracy takes its genesis from ancient Athens. These ideas, though ancient, evolved through living minds - not replacement.

The "immortal dictator" variant of this argument - that tyrants will oppress for millennia - applies equally to any powerful technology. Reductio ad absurdum: ban penicillin while you're at it. The paper and pen enabled propaganda; cars enabled blitzkrieg. We ought not to reject transformative technologies because bad actors might misuse them.

Immigration (and Other) Boomerangs

Fukuyama forecasts that hordes of caregivers imported to tend frail natives. But following that argument: if healthspan rises, then the care gap shrinks. And even if we do welcome immigrants, that influx historically fuels innovation, not stagnation. To me, this is a win-win, not zero-sum.

The Generational-Change Fallacy

The 25-year "turning" model freezes people's beliefs at 25 and claims social progress advances one funeral at a time. Data say otherwise though. Views on marriage equality and cannabis have shifted across living cohorts without mass die-offs. Longer lives simply lengthen the stretch of "formative" experience.

Overlooked Dividends

Compound expertise: seasoned engineers, surgeons, and entrepreneurs are force multipliers. A 60-year career can give you multiple lab-to-market cycles instead of one.

Cheaper healthcare: preventing disease beats treating it, and the compound returns on education, training, and relationship-building could be enormous over extended lifespans.

Innovation runway: more time means more shots at breakthrough discoveries and deeper accumulated wisdom.

Summing Up

Basically, Fukuyama's syllogism boils down to:

• Change is necessary

• Death creates change

• Therefore, death is necessary

But by that logic, we'd still accept smallpox as the price of social dynamism. The real question is how to stretch healthy life while keeping societies adaptive. And that's a design problem - not a philosophical roadblock!

Longevity offers even the most rigid among us a chance to revise their priors while still drawing breath - surely the free market of ideas should welcome that opportunity.

So, to put it briefly: Dr. Fukuyama, "against life extension" really means for avoidable disease and wasted human potential. And I'll take the opposite side of that trade every time.

The Salesforce Tower shoulders up through the city like a blue-glass tombstone, but only at first glance. Step nearer, past the sidewalk steam, the acrid espresso breath of Market Street, and its skin behaves more like a mood ring, sipping sunrise and exhaling a dim corporate bruise. Commuters spill out of BART portals in the half-light, still blinking. The tower drinks light and gives back nothing.

Then there’s me. I slip past the Salesforce Tower in those gunmetal pre-dawn hours when the city finally shows its unpowdered face. Street sweepers sluice yesterday’s dreams into the gutters while tents under the overpasses unzip, their blue tarps fluttering like broken wings. Commute buses groan by, windows fogged with the weary faces of people hired to fatten someone else’s fortune. I trudge south toward a warehouse pretending to be a lab. The roll-up door shudders open, and I’m greeted by the pilgrim smells of bleach, agar, and a -80 freezer exhaling frost like a beaten dragon. Pipettes click, centrifuges keen, photons pinball through liquid chromophores.

This is supposed to be where the outcasts wash up. Those of us who couldn’t fit anywhere else. I came here believing San Francisco was still the place where the strange and stubborn could matter. But I got here to find the city locked in a fever that apparently never breaks. Every generation gets its own version. Gold rush, dot-com boom, crypto winter, AI summer. Each one promising to change everything while changing nothing that matters. At least the original prospectors were digging for something real.

The biotech labs cluster south of the city, exiled by rent and relevance. We work in converted warehouses while the tower people work in temples of glass and steel. Our experiments take years to show results; their code ships by lunch and shows revenue by dinner. We sequence genomes while they sequester ARR.

The VCs ruffle our hair at networking events. “Biotech! How important! So noble!” Then they go fund another app to help people avoid making eye contact with their delivery drivers. They’ll give us just enough money to keep the lights on if we promise to say “AI-powered” somewhere in our pitch deck, but the real money, the stupid money, the tower money, all flows to software.

I’m starting to understand why. Software scales like kudzu and biology moves like redwoods. Software fails fast and pivots faster; biology fails slow and usually just fails.

At least other cities are honest about what they are. New York doesn’t pretend Wall Street is saving the world. It just admits it’s there to make money. There’s something almost refreshing about that kind of straightforward greed.

But San Francisco can’t help itself. It has to dress every money grab in world-changing rhetoric. The tower doesn’t say “we help companies extract more revenue from customers.” It says “we’re democratizing customer relationships.” Every rent-seeker calls themselves a revolutionary, and every middleman insists they’re cutting out the middleman.

The people in the tower, and they really are just people, some of them younger than me, making ten times what the PhD grads in my lab make, they’ve figured out the secret to this economy. Don’t create anything new: just position yourself between existing things and charge a toll. Don’t solve problems: create platforms where other people solve problems and take a cut.

They call themselves builders, but they build nothing. They’re tollbooth operators charging admission to roads they didn’t pave. DoorDash between hungry people and food, taking its cut. Tinder monetizes desire. The sick and the cure, well, that’s where they’ve graciously allowed us to keep working, for now. Though I’m sure someone’s building the “Uber for clinical trials” as I write this.

Living here as a biotech person means living with a specific kind of cognitive dissonance. Your work matters more and pays less. You’re saving lives while they’re optimizing ad targeting, but guess who can afford the city? You’re doing science while they’re doing arbitrage, but guess whose company gets the headlines?

There are people here I couldn’t find anywhere else. Brilliant, obsessed, slightly unhinged people who dream bigger than makes sense. The woman in the lab next door who’s teaching bacteria to eat plastic tried MIT first, but they thought she was too weird. The guy down at the incubator who swears he’s going to prevent most cancers would die of boredom in San Diego.

We end up at the same dive bars in Mission Bay after our experiments inevitably fail, and we talk about leaving. Moving to Boston where biotech is taken seriously. Moving somewhere with cheaper rent and lower expectations.

But we never actually leave. Because despite the tower casting its shadow over everything, despite being second-class citizens in the kingdom of software, this is still the only city crazy enough to let us try to cure death. The same delusion that builds monuments to customer relationship management also funds moonshots at mortality. The same fever that creates fake problems sometimes accidentally funds solutions to real ones.

But the fog always lifts. And there’s the tower again, blue and gleaming and smugly confident, perfectly erect while the rest of us scramble for funding.

Sometimes I wonder if we’re all just waiting for the Big One. Not because we want destruction, but because we want an excuse to start over. To build a city where the tallest structure might house a particle accelerator or a research hospital instead of a CRM company.

But earthquakes don’t reset cultures, just buildings. And this culture has been running a fever for so long it doesn’t remember what normal feels like.

Still, I stay. The work is actually starting to show promise. My friend just closed a funding round and bought drinks for all of us, and for one night we felt like we might actually matter. Somewhere in this city of platforms and profit margins, there are still people trying to solve problems that will outlast the next funding cycle.

Every morning I walk past that tower and wonder: What if we actually cure something? What if we figure out how to make human life longer, healthier, more meaningful? What monument would they build for that?

What color would those LEDs glow?

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Dear Mr. Kennedy,

Picture, if you will, a nation-sized coronary artery: plaque laid down year after year like bureaucratic memos - the lumen of public health narrowing with every missed opportunity.

Two days ago, your shop at HHS unfurled the shiny new Request for Information - your 10-to-1 deregulation gauntlet thrown at the feet of every rule that ever gathered dust in the Federal Register. Amid the gewgaws and heavy machinery of federal health policy there sits a single, absurdly obvious lever: reclassify a low-dose statin (say, atorvastatin 10 mg or rosuvastatin 5 mg) from Rx-only to true, Walmart-checkout-aisle OTC. Pull it, and you do more for cardiovascular prevention than a decade of slogan-heavy wellness campaigns.

1. Causality carved in stone tablets

• Every mmol/L that low-density lipoprotein is forced downward chops the risk of myocardial infarction or stroke by roughly 22 percent - the conclusion of the Cholesterol Treatment Trialists’ 170 000-patient meta-analysis:

• Mother Nature herself runs a permanent, double-blind trial: people born with loss-of-function variants in PCSK9 or ANGPTL3 cruise through life with LDLs in the 20 - 40 mg/dL range and enjoy 30-plus-percent cuts in coronary risk without obvious downside (1, 2, 3, 4).

  

When biology, randomized evidence, and genetics all hum the same tune… policy should probably dance.

2. Safety so boring it is practically soporific

Serious muscle injury from statins occurs in <0.1% of users; hepatotoxicity is an order of magnitude rarer. For context, you’re free to purchase orlistat - a drug whose calling card is oily rectal incontinence - straight from Amazon’s shelves. If we are letting consumers gamble their underwear for a few pounds lost, we can surely trust them with the pill that costs pennies and saves hearts.

3. There is precedent of statins being OTC

The United Kingdom loosed simvastatin 10 mg (Zocor Heart-Pro) onto pharmacy shelves back in 2004. Uptake was modest - partly price, partly faint-hearted marketing - but no safety alarms rang. America can improve on the British half-measure with more potent, generic molecules and a proper consumer-education blitz.

The FDA, by contrast, has kept moving the goalposts for approval of OTC statin use:

Notice the pattern: every rejection centred on consumer competence, not on statin safety (which the panels broadly conceded). The committees fretted that shoppers would misjudge their own 10-year ASCVD risk or forget to see a doctor, ironically the very inertia that keeps millions untreated today.

Tech has already torpedoed those fears, anyway. In 2021-24 AstraZeneca’s web-app TACTiC studies showed >96% concordance between consumer self-selection and clinician judgment for rosuvastatin 5 mg, exactly the “additional condition for non-prescription use” the FDA now invites under its new ACNU rule.

Bottom line: the only things standing between Americans and safe, cheap OTC statins are dusty committee anxieties that pre-date smartphones, and three decades of real-world evidence that statins are among the safest chronic drugs we have.

4. Even a rounding-error uptake pays out in health dividends

Say only one percent of the 130 million U.S. adults aged 40-75 grab an OTC statin. That is 1.3 million new users. If you apply the CTT risk curve to a conservative 10-year ASCVD baseline of 5 percent, you avert ~14,000 heart attacks and strokes. Value each event at a (ludicrously low) 4 QALYs, and you are buying 56,000 quality-adjusted life-years for pocket change1. The cost-per-QALY plunges below the price of a fast-food combo meal2.

5. Natural enough for the supplement aisle

If critics whip out the organic-purist card, remind them that lovastatin was literally purified from red-yeast-rice mold. Statins are fermented corn, just tidied up by medicinal chemistry. The FDA currently bans supplement makers from leaving the active monacolin K fraction in their red-yeast-rice capsules; but your deregulatory pen could fix that contradiction overnight.

My ask is this: bake a statin switch into your inaugural 10-to-1 bundle.

You could - and should - draft guidance that (a) designates low-dose statins as Generally Recognized as Safe and Effective for primary prevention in adults meeting a clear risk threshold, (b) mandates a pharmacist-screened initial sale (à la pseudoephedrine) if you need a training-wheels phase, and (c) sunsets the pharmacist checkpoint after post-market data confirm what two million patient-years already tell us.

You pledged to Make America Healthy Again by scrapping deadweight regs. Here is a regulation that literally clogs arteries and kills quietly. Strike it, and you will create the kind of overnight, measurable public-health win that presidents put on campaign posters - no new technology, no trillion-dollar appropriations… just one less line in the Code of Federal Regulations.

It is low-hanging fruit, Bobby. Let’s pick it before another heart muscle seizes up waiting for a prescription refill.

Sincerely,

A citizen who prefers his arteries wide and his policy wider

Charles River Laboratories is in trouble.

If you’ve been following the FDA’s slow-motion reimagining of how drugs get approved in this country, you’ll know that last week, the agency dropped a seismic update: they’re planning to gradually phase out preclinical animal studies for monoclonal antibody BLAs. Not reduce, nor refine. Phase out - as in, eliminate.

The new guidelines, quietly slipped out in a dense, 11-page roadmap PDF, lay out a path for sponsors to start submitting INDs and BLAs for mAbs without the usual mouse-to-monkey toxicology gauntlet. Instead, developers can lean on organoids, organ-on-chip systems, human-derived cell models, AI simulations - what the FDA is calling “New Approach Methodologies,” or NAMs. And: what Charles River might, internally, call a direct threat to their business model.

Cue the reaction.

Charles River’s stock ($CRL), already dragging under the weight of a sluggish biotech cycle and the lingering stink of a Cambodian primate import scandal (a subplot best filed under Primategate), went into free fall. Like, a bone-fide crash. We’re talking about the kind of sickening vertical drop that gives hedge fund analysts nosebleeds and makes Reddit traders open their Robinhood apps mid-coitus. Twenty percent, gone in a flash. Analysts downgraded. Shareholders balking. Pundits murmuring “existential.” Et cetera.

Why the panic? Because Charles River is animal testing.

We’re talking about a company that, by its own admission, derives something like 80% of its revenue from two business lines: one that literally breeds animals for lab use (RMS, the Research Models & Services division) and one that conducts preclinical studies (DSA, Discovery & Safety Assessment) that have, for most of modern pharmaceutical history, relied on those animals to prove a compound’s worth.

For most of modern pharmaceutical history, Charles River has been the god of rats, full stop. And now, the FDA - the only god that matters more - has begun to question whether rats are needed at all.

Let’s pivot and talk numbers. Because no matter how philosophical we get about the ethics of rat suffering or the beauty of liver organoids - this is a public company. And public companies live and die by margins, multiples, and whether sell-side analysts can look at a 10-K without vomiting.

Before the FDA’s announcement, CRL wasn’t exactly in freefall. It was more like a well-fed prizefighter getting winded in round seven. As per their 2024 10-K, they were already managing damage:

• A moderate-to-heavy debt load, with enterprise value exceeding market cap by $2.5B

• 2024 adjusted EBITDA of ~$570M, with margins around 14%, down from a healthier 17–20% in the pre-scandal years

• A guidance of 4.5–7% revenue decline in 2025, even before the FDA blindsided them with the NAM roadmap

Why this pre-recent news depression? We could blame it on a few converging disasters:

• The Cambodian primate import scandal. A weird, semi-dark episode involving questions about whether Charles River’s non-human primates (NHPs) were actually wild-caught, which led to halted imports, skyrocketing costs, and a whole bunch of canceled studies.

• The biotech downturn. Smaller biopharmas, already struggling with higher interest rates and tighter capital, cut back on their R&D budgets, which hit Charles River’s bread and butter: outsourced preclinical studies.

• General inflationary pressure. Energy, logistics, and lab technician salaries don't pay themselves.

To triage the bleeding, Charles River initiated cost-saving measures and restructuring in late 2024 - essentially streamlining their site network and trimming fat. Management has claimed that these efforts would offset the projected 4.5 - 7% decline in revenue for 2025, even before the FDA pulled out the rug. They suggested profitability would only be “modestly” affected (which is basically corporatespeak for “we’re not panicking yet! please don’t tank our stock!”)

So far, their liquidity and free cash flow have remained solid. They’re not at risk of missing payroll or defaulting on debt (yet). They’ve continued investing - selectively - in AI modeling, microphysiological systems, and even a few tuck-in acquisitions to hedge the NAM transition. So their war chest isn’t bottomless per se, but it’s not empty either.

Alas, Wall Street doesn’t care about “modest” hits: it cares about growth. It cares about durability. And CRL’s valuation metrics have collapsed as a result of perceived structural decline. Just look at how they stack up next to peers:

So: CRL is trading like a distressed asset, because the market is pricing in risk of obsolescence. A ~7.6× EV/EBITDA multiple is what you’d assign to a company with fundamental business model decay. And maybe that’s true. But, importantly, it also means this: if CRL survives the pivot, the multiple has room to double.

Compare that to Wuxi AppTec for example, whose multiples remain buoyant despite geopolitical risk and much more regulatory opacity in China. Or Medpace, which doesn’t touch preclinical at all and is thus being rewarded with premium pricing for the sin of staying downstream. CRL looks cheap - if it’s not marching straight into a structural meat grinder.

To fight this, they’ve been restructuring; cutting costs; consolidating sites. They’ve launched something called AMAP (Alternative Methods Advancement Project), a mildly Orwellian acronym that signaled at least an awareness of the industry’s pivot toward non-animal models: organoids, chips, algorithms, insert other bla bla buzzwords here. In other words, they haven’t been completely blind. They’ve seen this coming. But they also still have millions of rats. And facilities built for rats. And a profit model engineered - genetically, almost - for rats. The main storyline for CRL is still: give us your compound -> we’ll test it on a bunch of rodents and monkeys -> and hand you a packet to submit to FDA.

Now a question worth thinking about is: can they pivot fast enough? Maybe, but not convincingly.

Capex tells the truth. Charles River’s FY24 guidance earmarked $1.05  billion in total capital expenditures.1 Our back-of-the-envelope split:

• $520 M to maintain and expand animal facilities. (translation: keeping the rats alive.)

• $160 M toward NAM infrastructure: organoids, organ-on-chip platforms, AI tox prediction.

• The rest is IT, admin, and other CRO verticals.

That’s ~15% of spend chasing the future, while ~50% is defending the past. Which tells you exactly how this company is thinking about hedging its own obituary.

The FDA’s recent move has truly shoved Charles River into a liminal state: not yet obsolete, but also not yet retooled; and the window to retool is shrinking.

From a biotech-operator perspective, here’s my 2 cents on where NAMs actually stand - and what the FDA’s roadmap really enables:

So what’s left for CRL? My envisioned scenarios:

Three paths, all of which are risky, and only one ending in reinvention.

Each path I have provided a nickname:

• Bear case, or the "Blockbuster of Beagles": NAMs prove out fast, and CRL is left renting VHS tapes of rodent data

• Base case, or the "Dying‑but‑Diverse": Gradual cannibalization., with manufacturing & microbiology softening the arterial bleed

• Bull case, or the "Rodents‑to‑Redux": FDA slows its roll, and CRL rebrands as the Oracle of NAM validation; the rats get severance(!)

  

Valuation-wise, slap 8x/10x/12x EBITDA multiples on those scenario lines, and you land at $55 / $85 / $110 per share. At ~$80 today, the market is effectively saying: “Show me the pivot.”

Right now, CRL is standing at that junction. And the market’s betting they don’t make the turn. But if they do, this might just be one of those rare moments when a company staring down structural obsolescence manages to rewrite its role in the story. Touching, really.

It’s the Business Model, Not The Rats

There’s a version of the future where Charles River still exists, still runs studies, still makes money - but becomes a kind of mid-century curiosity. A legacy provider, in other words. The company that used to breed rats but now mostly consults on how to train your AI model to simulate hepatotoxicity; like a Blockbuster that survived the apocalypse by pivoting to metadata services for Netflix (or a Blackberry who pivots to cyber security from phones). Still here, technically. But not exactly in command.

I don’t think this is some fringe fantasy, because the FDA’s new policy is really about control, if you think about it. And about who defines what counts as evidence in drug development. For decades, Charles River made its money knowing how to generate the kind of data the FDA liked. The necropsies, the dose-response curves, the GLP-compliant rodent mortality tables, etc. That knowledge - down to the language, the formatting, the politics of a submission packet - was their moat! The moat was made of Dead Animals.

But NAMs care about data architecture, human tissue fidelity, and AI-validated predictivity more than cages or legacy processes. And for the first time in its history, Charles River is being asked to compete not with other CROs, but with entirely different species of company. Like bio-AI hybrids, synthetic biology startups, and machine learning platforms with no interest in beagles and no sunk cost in vivariums.

The market sees this, and that’s why CRL’s valuation cratered.

So you end up with this weird, liminal moment: a company with billions in physical assets that may soon be half-relevant, and a bunch of cautious institutional investors trying to figure out if this is terminal decline or mispriced future-forward pivot play.

Because this is an ontological inflection point for them. The reason Charles River exists - their entire corporate cosmology - is being… rewritten.

 Introduction

In 2024, China’s pharmaceutical industry made headlines. To some extent – it was one of the biggest shocks of last year. Once known primarily for generic drugs and contract manufacturing, China is now producing innovative therapies, attracting major investments, and striking high-profile deals with Western pharma – something few expected only a decade ago would happen.

To put in perspective where we are now, consider the following numbers & figures:

• Market value: The market capitalization of Chinese biopharma innovators surged from just $3 billion in 2016 to over $380 billion by mid-2021. Chinese biotech firms have led global IPO charts – 7 of the world’s 10 largest biopharma IPOs from 2018–2020 were by China-based companies. In 2020 alone, 23 Chinese biotechs went public.

• R&D pipeline: China’s share of the global drug innovation pipeline jumped from 4.1% in 2015 to 13.9% in 2020. By 2023, China became the world’s top location for new clinical trials, with 39% of all trials initiated that year including a site in China.

• Major licensing deals: Chinese companies are now regularly out-licensing novel drug candidates to big pharma. The number of such deals more than doubled from 15 in 2019 to 33 in 2023. 

• Blockbuster drugs & FDA approvals: A decade ago, China had few if any globally marketed novel drugs; now Chinese-origin medicines are achieving blockbuster status.

I’ve observed two parallel threads underlying this surprising ascent of China’s pharma ecosystem––on one hand are the slow-burning trends – changes that took years or even decades to bear fruit:

• A pattern of “reverse brain drain” that has brought experienced scientific talent back to China

• An ambitious and highly coordinated national-industrial strategy that has gradually shifted the country’s involvement in the drug development chain from generic drugs to high-value innovation

On the other are the fast-moving trends – recent accelerants that have rapidly propelled China’s capabilities to new heights, which include:

• A drastic regulatory overhaul that accelerated drug approvals and aligned standards with global norms

• Macro-level economic circumstances which incentivized larger-than-average amounts of deal-making between Chinese and Western companies

Main takeaway: China’s pharmaceutical sector from 2015 to 2025 has transitioned from a supporting player to a major leader in drug innovation. The country now hosts world-class R&D hubs, produces novel drugs approved internationally, and is partnering with – or competing against – Western pharma giants. 

Needless to say, global pharma companies can no longer ignore China’s innovation capabilities and market potential; and before we know it, we could very well be hearing in earnings calls, 

“What’s your China strategy?”

Slow Trends

1. A 7,000-mile-long boomerang: the problem of “reverse brain drain”

For decades, the flow of scientific talent followed a predictable pattern—China’s brightest students pursued graduate education in the U.S., often staying to build careers in academia, biotech, and pharma. 

But that dynamic has flipped. According to China’s Ministry of Education, since 1978, 86% of the 6.6 million Chinese students who studied abroad have returned home. The life sciences sector illustrates this shift clearly. In 2000, fewer than 10 US-based Chinese life sciences professionals repatriated to China; by 2021, that number had grown to approximately 600.

So, what’s behind this change?

Two forces are pulling in opposite directions:

1. The U.S. has raised geopolitical and regulatory barriers—visa restrictions, IP crackdowns, and growing suspicion around Chinese scientists in American labs.

2. China has aggressively rolled out incentives—offering top-tier salaries, well-funded research, and leadership roles in its booming biotech and pharmaceutical sectors.

The result? Many of these professionals are choosing to boomerang back home to build their futures in China rather than remaining in the US; as Professor Emeritus at HKUST David Zweig details in a 66-page dossier published last year, the Chinese government has systematically cultivated policies to attract overseas talent while the U.S. has implemented measures that discourage their retention. Zweig highlights that the growing restrictions on Chinese researchers in the U.S., coupled with the expansion of China’s state-backed talent recruitment programs, have accelerated this trend.

1a. How U.S. geopolitical barriers sent Chinese talent packing

Like any compelling story, this one involves espionage—or at least the fear of it. As American foreign policy hardened against Chinese intellectual property theft throughout the 2010s, Chinese scientists working in the U.S. found themselves caught in the crossfire.

Concerns over China-sponsored trade secret theft culminated in the Trump administration’s China Initiative, a Department of Justice-led campaign aimed at identifying, prosecuting, and imprisoning researchers suspected of economic espionage. While the program officially targeted illicit technology transfers, it disproportionately impacted Chinese and Chinese-American scientists, leading to heightened scrutiny, career disruptions, and widespread fear within the academic and research communities.

David Zweig, Professor Emeritus at HKUST, describes the chilling effect this had:

“In part, due to the U.S. Department of Justice’s China Initiative, talent is flowing back to China even as collaboration across the Pacific is declining. Thus, the percentage of Chinese Ph.D.’s in science and engineering who remain in the United States five years after graduation has decreased significantly—from the low 90s in 2012 to 74.0 percent in 2022.”

Beyond direct prosecutions, the China Initiative created an environment of uncertainty, pushing many Chinese researchers to reconsider their future in the U.S. A survey conducted by the University of Arizona and the Committee of 100 in late 2021 captured this growing unease. Of the 1,949 valid responses from scientists and professors:

• 50.7% of Chinese-descent researchers reported feeling considerable fear or anxiety that they were under U.S. government surveillance, compared to 11.7% of non-Chinese-descent researchers

• 42.1% of non-U.S. citizen researchers of Chinese descent indicated that FBI investigations and/or the China Initiative influenced their decision to leave the U.S

• 42.2% of Chinese-descent scientists believed they were being racially profiled by the U.S. government, while only 8.6% of non-Chinese-descent scientists felt the same

Zweig highlights the real-world consequences of this climate of suspicion, writing:

“A Chinese American professor of genetics voiced the greatest concerns: ‘The China Initiative has a significant impact on my research and personal life. I assume all my electronic communications are potentially monitored by the U.S. government. I decided not to collaborate with researchers in China and other foreign countries due to perceived conflicts of interest. I even decline outside research consulting.’”

For many, the calculus became simple: Stay in a country where you’re under suspicion, or return to China, where you’re actively being recruited, welcomed, and funded?

1b. China’s talent recruitment machine has kicked into high gear

As the U.S. put up barriers, China rolled out the red carpet: over the past two decades, the Chinese government has been engineering an aggressive, structured, and highly organized campaign to bring its top-tier talent back home.

At the center of this effort is the Thousand Talents Plan (TTP)—a government initiative launched in 2008 to recruit elite scientists, particularly those with experience in the U.S. and Europe. The program offers:

• Direct financial bonuses to relocate back to China

• Substantial funding and lab space

• Faster career progression

• Ability to lead major national projects

The Chinese government’s carrot-and-stick have been abundant to ensure the program’s success—entire cities were pressured to hit recruitment quotas. Zweig describes the level of mobilization:

“Cities throughout China were pressured to commit publicly to a target number of highly talented returnees they would recruit. Beijing promised to deliver 500 new talents from abroad within a 5-year period, while Guangzhou promised to bring home 300 China-born scientists, academics, and businesspeople.”

While the Thousand Talents Plan is China’s flagship recruitment effort, it is far from the only one. Over the past two decades, China has launched multiple highly structured foreign outreach programs aimed at different categories of overseas Chinese professionals, from academic researchers to industry executives.

Here’s a snapshot of some of the key programs:

Program

Agency

Target

Start Year

Key Benefits

Thousand Talents Plan (TTP)

CLGCTW

Top-tier scientists, executives, and entrepreneurs under 55

2008

3.5M RMB startup funding, 400K RMB/year salary

Changjiang Scholar Program

MOE

Endowed professorships under 45 (or 55 in humanities)

1998

200K RMB/year + housing

Hundred Talents Program (HTP)

CAS

Scientists under 45

1994

>2M RMB research funds, 400K RMB/year

Young Thousand Talents Plan (YTTP)

CLGCTW

Academics under 40 with 3+ years postdoc

2010

Research & salary support

Notice that each of these programs targets a different slice of the overseas Chinese professional population—ensuring that talent is lured back at all career stages.

And why wouldn’t they return? The benefits extend far beyond funding; a study from the Chinese Academy of Sciences (CAS) tracked career progression among returnees vs. local scientists from 2001 to 2004:

Promotion Pace

Returnees (%)

Local Scientists (%)

Very Quick

14.3%

2.4%

Comparatively Quick

22.6%

7.3%

Neither Fast Nor Slow

25.0%

24.4%

Relatively Slow

16.7%

31.7%

Very Slow

14.3%

24.4%

Simply put: returnees rise faster.

China’s pharma industry now has its own brain trust

China’s biggest biotech companies today are stacked with U.S.-trained leaders. A 2020 Boston Consulting Group (BCG) report found that 75% of China’s top biotech talent has at least five years of overseas experience.

When you zoom in on the founders of China’s most valuable biopharma firms, the trend is even clearer:

• BeiGene → Founded by Xiaodong Wang (PhD, University of Texas, former U.S. oncology exec).

• WuXi AppTec → Co-founded by Ge Li (PhD, Columbia, ex-U.S. biotech).

• Hutchison MediPharma → Co-founded by Samantha Du (PhD, University of Cincinnati, ex-Pfizer).

In short: the rapid rise of China’s biotech and pharmaceutical industries is, in part, a direct consequence of reverse brain drain. U.S.-trained scientists and executives now drive China’s most innovative biotech firms––leveraging their Western education and industry experience to build world-class enterprises at home.

2. China has leveraged its manufacturing might on the world stage - to major success

There’s a simple, almost embarrassingly obvious reason why China has catapulted itself to near-parity with the U.S. in drug development: it controls the beating heart of global pharmaceutical manufacturing. China has clearly played the long game here––leveraging its dominance in pharmaceutical ingredient production to bankroll its way up the value chain.

2a. Lessons from China’s manufacturing moat

It’s no secret that the Chinese government has played a monumental role in economically buoying certain domestic industries––no less ones of critical national interest. 

Investments in infrastructure have been key

Infrastructure comes first, of course: the Chinese government has invested heavily in infrastructure such as industrial parks and incubators dedicated to pharma. Dozens of “biomedicine industrial parks” across China provide turnkey facilities, shared equipment, and favorable leasing terms to manufacturers; and state-backed investment funds have poured capital into pharma companies – for instance, the China State Pharmaceutical Investment Fund and various provincial funds invest in capacity expansion projects. In recent years, local governments in major hubs (Shanghai, Beijing, Guangzhou, etc.) have set up multi-billion-yuan funds to support biotech startups and help build manufacturing plants. 

Many Chinese production facilities are large, newly built plants that take advantage of economies of scale and the latest equipment. It’s common for companies to run multiple production lines in parallel and operate round-the-clock with rotating shifts, maximizing output from each plant. Plus, construction and capital costs for factories are lower in China, allowing installation of state-of-the-art machinery at a fraction of the expense in Western countries. 

When possible, do everything in-house

Chinese firms manufacture roughly 1,650 API varieties, accounting for about 30% of global API output. This means Chinese drug manufacturers effectively have local access to nearly all key raw materials and intermediates without relying on slow or expensive imports. Having API suppliers next door shortens lead times for materials delivery and allows just-in-time manufacturing; it also gives companies bargaining power to get cheaper input prices due to the abundance of suppliers. 

In practice - a Chinese generic drug factory can source its chemicals, packaging, and other inputs from domestic producers in a coordinated, efficient manner––slashing the time and cost required to procure inputs. By contrast, a U.S. manufacturer might need to import APIs or components from abroad (often from China itself), adding shipping delays and expense. China’s logistics network further amplifies this advantage – with extensive highways, railways, and major ports, domestic freight is fast and relatively low-cost. 

China’s pharmaceutical manufacturing sector employs ~725,000 workers (vs. ~627,000 in the U.S. ), giving firms flexibility to expand production lines or add new facilities rapidly. This large labor supply––combined with lower wages––lets Chinese manufacturers increase output speed without a linear rise in labor cost; in essence, China can throw more manpower at a project to accelerate timelines and still remain cost-efficient. 

A nation going all-in on subsidizing R&D 

Tax incentives are also important: China’s tax code allows super deductions for R&D expenses (currently 200% deduction for eligible R&D, meaning companies can double-count R&D costs to reduce taxable income), which many pharma companies utilize. 

Pharmaceutical manufacturing enterprises that qualify as “High and New Technology Enterprises” enjoy a reduced 15% corporate income tax rate (versus the standard 25%). There are also VAT rebates or exemptions for certain drug sales and for exported pharmaceuticals. 

In addition, local governments might provide free or discounted land, utilities discounts, or cash rebates for building new manufacturing facilities in their jurisdictions. For example: to attract a major vaccine plant, a city might cover part of the construction cost or offer rent-free space for initial years; these incentives lower the capital and operating costs for Chinese manufacturers, effectively acting as indirect subsidies that boost competitiveness.

2b. The “Teva effect” - from generic drugs to innovative ones

The way China’s pharmaceutical industry is undergoing strategic pivoting bears resemblance to the corporate arc of Teva Pharmaceuticals – the world’s largest generic drug company – which over the past two decades attempted to transform from a pure generics manufacturer into a developer of novel, patented drugs. 

This “Teva effect” refers to the evolution from low-margin generic business to high-value innovation. For Chinese pharma companies, many of which built their fortunes on generics, the 2015–2025 period has been marked by a similar push to invest in R&D, create proprietary medicines, and reduce reliance on commoditized generic sales. 

Wait… what even is the Teva effect?!

Let me explain:

Teva grew to prominence by manufacturing generic drugs at scale, becoming a global leader in off-patent medicines. However, Teva also had a taste of innovation success – most notably with the drug Copaxone (glatiramer acetate) for multiple sclerosis, a novel drug it launched in 1996 that became a blockbuster. Encouraged by this, Teva over time sought to expand its innovative portfolio through acquisitions and internal R&D. 

Around the early 2010s, facing intense price competition in generics and anticipating patent cliffs, Teva’s management began to emphasize a pivot to “specialty” and innovative drugs. In 2011, Teva acquired Cephalon (bringing products and pipelines in oncology and CNS) and later invested in biologics and neurology (developing fremanezumab for migraine, for example); and in 2023, Teva’s new CEO announced a renewed strategy explicitly reallocating resources from generics towards innovative medicines and high-value products. In short: as the company evolved over time, Teva has gradually been able to leverage its global scale and core R&D areas to drive growth––acknowledging that pure generics alone no longer suffice. 

This arc: from booming generics, to growing pains, – to refocusing on innovation – provides a roadmap that many Chinese companies are now following, albeit on a compressed timeline.

Some Chinese examples of the Teva effect

Historically, China’s domestic pharma companies predominantly produced generic copies of Western drugs (often for the local market). However, the Chinese government’s centralized drug procurement program (launched in 2018, also known as “4+7” policy) began sharply undercutting prices of generics via nationwide tendering––effectively eroding profit margins by up to 90%. This volume-based procurement created an existential threat for purely generic-focused companies; they had to innovate, otherwise they would die. 

In effect, they needed to execute their own Teva-like shift, moving up the value chain to become originators, not just copycats. Let’s examine a few leading Chinese companies as case studies:

Jiangsu Hengrui Pharmaceuticals

Hengrui is often cited as a bellwether for China’s pharma innovation drive. Traditionally a maker of cancer generics and anesthesia products, Hengrui began heavily investing in R&D in the 2000s. It received its first innovative drug approval in 2011 (a novel anti-cancer agent), marking the start of a new era. Since then, Hengrui has poured extraordinary resources into drug discovery – over $5 billion invested in R&D cumulatively.

Financially, the strategy is paying off: Hengrui’s revenue from innovative products now eclipses revenue from generics. 

Jiangsu Hansoh Pharmaceuticals

Over the course of its existence, Hansoh has followed a similar trajectory to Hengrui; originally known for psychiatric and diabetes generics, Hansoh ramped up R&D around 2015, developing new drugs for oncology and diabetes. The impact is evident in its financials: in 2019, only ~19% of Hansoh’s revenue came from innovative drugs; by H1 2022, over 52% of revenue was from innovative products. 

Gan & Lee Pharmaceuticals

Gan & Lee is one of China’s leading insulin manufacturers, long producing biosimilar insulins and insulin analogues (such as biosimilar glargine) for the domestic market. 

But when confronted with competition and pricing pressure, Gan & Lee has made a strategic move to develop novel treatments in diabetes and related metabolic diseases––recently, they announced that three of its self-developed innovative drugs – a bi-weekly GLP-1 agonist (GZR18), a once-weekly insulin analog (GZR4), and a first-in-class dual insulin/GLP-1 combo (GZR101) – achieved positive Phase 2 results, outperforming leading international products in trials. 

Projecting outwards from Teva

Just as Teva faced eroding margins in commoditized generics (especially in the U.S. after 2010), Chinese firms have been hit by margin collapse due to domestic price reforms around 2018–2019. This “survival pressure” has forced companies to seek higher-margin innovative products. 

In doing so, Chinese companies have been able to step out of the purely generic exporter role (where China historically just shipped APIs or generics to other countries) and into the role of innovator-exporter. A notable example: BeiGene’s cancer drug Brukinsa––entirely discovered in China––secured approvals in the U.S., EU, and dozens of countries, with BeiGene setting up its own U.S. salesforce – a major and historical milestone for China’s pharma industry.

Fast Trends

3. Regulatory overhaul and clinical trial expansion

China’s regulatory environment for pharmaceuticals has transformed dramatically since 2015, evolving from a slow and insular system to one that is faster, more transparent, and globally aligned. This regulatory overhaul – spearheaded by the National Medical Products Administration (NMPA, formerly CFDA) – has greatly accelerated drug approval timelines and enabled an explosion of clinical trials, integrating China into global drug development.

3a. Breaking the drug approval backlog

In 2015, China’s drug regulators faced a notorious backlog of drug applications (over 21,000 drug registrations pending review). Approval processes were painfully slow – a new medicine could take 5–7 years to get through Chinese trials and reviews, often lagging far behind the U.S. or EU (“drug lag”). 

But beginning in August 2015, the government launched comprehensive reforms to tackle these issues. A key early step was a one-time campaign to clear the backlog, which saw regulators and companies withdraw or fast-track thousands of pending generics applications to focus resources on higher-quality and innovative drugs. 

Over the next few years, NMPA hired and trained far more reviewers: the staff of the Center for Drug Evaluation (CDE) grew from only ~100 in 2015 to about 1,000 reviewers by 2020. This tenfold increase in manpower allowed the review speed to dramatically improve: by the he average CDE review time for a new drug dropped from ~900 days to ~300 days(!) by 2019. By 2020, new regulations stipulated standard review timelines of 200 working days (approx. 9 months) for normal new drug applications, with priority reviews targeted as low as 70–130 working days in certain case. For the first time––these changes made China’s drug review cycle directly comparable to that of FDA/EMA.

3b. Joining the regulatory world stage

An enormous milestone in China’s regulatory upgrade was joining the International Council for Harmonisation (ICH) in 2017. By becoming an official member of ICH, China committed to adopting international Good Clinical Practice (GCP) and technical guidelines; bringing China in line with U.S., EU, and Japan norms. Deputy Commissioner Xu Jinghe noted in 2021 that China had “accelerated the integration of its drug regulatory policies… with international rules and practices,” emphasizing science-based regulation and keeping up with ICH’s cutting-edge developments.

This global alignment not only boosts international confidence in drugs tested/approved in China but also allows Chinese trial data to be used in approvals abroad. For example––as China’s GCP became ICH-compliant––data from Chinese patient cohorts could be accepted by the FDA in multinational trials. In 2019, the FDA approved a Chinese-origin cancer drug (Brigatinib for ALK+ lung cancer) partly based on trials that included Chinese sites. Such developments were virtually unheard of prior to 2015!

The 2015-2018 era of regulatory overhaul also introduced mechanisms to encourage innovation. Notably –– in 2020, the NMPA launched a Breakthrough Therapy Designation (BTD) system akin to the FDA’s, in order to give promising therapies enhanced support and swifter review; since then, dozens of breakthrough designations have since been granted to both foreign and domestic drugs (over 130 by 2021), particularly in oncology.

Culminating in 2021, China had approved a record number of new drugs––many of them first-in-class in China. Local innovative drugs benefited as well – e.g., China’s first homegrown PD-1 cancer immunotherapy was approved in 2018 only 9 months after its NDA filing, under priority review, at a speed that surprised many industry observers.

3c. Less regulations → more clinical trials

As regulatory barriers have fallen, China has quickly seen an explosion in clinical trial activity. The number of trials (especially for innovative drugs) grew exponentially, turning China into a global clinical research hub. According to GlobalData, China accounted for 24.7% of all clinical trials worldwide in 2020 – up from an average of ~12% over the prior decade. And this momentum kept building: between 2019 and 2023, about 31% of all new clinical trials initiated globally were in China. In absolute terms – trial starts in China rose 46% from 2019 to 2023 even as the global total declined by 7%. By 2023, China overtook the U.S. in number of trial initiations; nearly 4 in 10 new trials globally had a site in China that year. This is a remarkable change from a decade ago when China was an afterthought in most multinational studies.

Several factors contributed to this trial boom:

Regulatory encouragement of local trials

The 2015 reforms removed bottlenecks for trial approval; the NMPA abolished a long-standing requirement that each trial had to get a specific approval letter (“implicit approval” was introduced – if regulators don’t object within 60 days, a trial can proceed). This 60-day IND approval mechanism, adopted in 2017, vastly speeded up trial starts. Consequently, the number of domestic trial initiations surged. In 2023, the CDE (Center for Drug Evaluation) accepted 2,244 new investigational drug (IND) applications for innovative drugs and vaccines – a 32% increase over the prior year. 

Opening to global sponsors

China made it easier for foreign companies to include China in global trials or run trials directly. After joining ICH, many global pharma companies began adding Chinese sites to Phase III trials for major drugs, knowing the data could support simultaneous China approval. By 2022–2023, virtually every multinational pharma had dozens of trials in China, often in partnership with local biotech or hospitals. That said, Chinese sponsors still dominate; one analysis notes that while domestic companies run the majority of trials in China, the top 20 big pharmas still tend to include Chinese sites in a minority of their trials (likely for strategic assets in oncology, etc.). 

Patient population and speed of enrollment

China offers the world’s largest pool of treatment-naïve patients, which can make recruitment for trials faster, especially in oncology or rare genetic diseases where Western pools are saturated or slow. Companies have been able to enroll Chinese cohorts very rapidly for certain cancer trials. This has led to situations where Chinese trial data has been pivotal in global filings (e.g., Zai Lab’s tumor drug niraparib included substantial Chinese clinical trial data for FDA approval). By contributing patients, China is becoming a “must-have” in trial strategy to accelerate timelines. An IQVIA report in 2023 highlighted China’s shorter patient enrollment durations compared to global averages in many indications – an attractive factor for sponsors.

4. Facing an economic downturn, Chinese pharma companies have needed to do deals to survive

Over the past three years, China’s economy has experienced a marked slowdown and several financial headwinds. GDP growth decelerated sharply – for example, 2021’s post-pandemic rebound of 8.4% gave way to only 3.0% growth in 2022, one of the weakest performances in decades. This slowdown was driven by stringent zero-COVID policies (and their abrupt end), a property sector slump, and weakened consumer spending, which together created a bumpy economic environment.

Interestingly - a notable consequence of the capital crunch is a surge in licensing and M&A deals in the Chinese pharmaceutical sector: unable to rely on frothy stock markets, many pharma and biotech firms have now turned to business development transactions to generate cash and sustain R&D. In 2023, China saw an unprecedented wave of deal-making: approximately 240 life-science licensing deals were reported, an increase of almost 50% compared to 2021. This includes around 70 outbound licensing agreements where Chinese companies licensed out drug candidates or technologies to foreign partners, with disclosed aggregate deal values exceeding $35 billion (including milestone payments). In fact––for the first time ever––Chinese biopharma companies raised more capital via such partnering deals than through IPOs; initial license fees alone totaled about ¥26.8 billion (~$3.7 billion) in 2023, far surpassing IPO proceeds in the sector.

Below are some of the most notable deals from 2023–2025:

GSK and Hansoh Pharma (2023)

British pharma giant GlaxoSmithKline struck two major licensing deals with Jiangsu Hansoh in late 2023 to bolster its oncology pipeline with antibody-drug conjugates (ADCs) discovered in China. 

In October 2023, GSK licensed Hansoh’s B7-H4 ADC (HS-20089) for a reported $85 million upfront and up to ~$1.06 billion in milestones. Just two months later, in December 2023, GSK inked a second agreement for Hansoh’s B7-H3 ADC (HS-20093), paying $185 million upfront and committing to up to $1.525 billion in milestone payments. These deals (total potential ~$2.7B) give GSK ex-China rights to promising cancer therapies developed by Hansoh. 

Merck and Hansoh Pharma (2024)

In Dec 2024, Merck & Co. entered a global license with Hansoh for HS-10535, an oral GLP-1 receptor agonist for metabolic diseases. Merck paid $112 million upfront, and Hansoh is eligible for up to $1.9 billion in development and commercialization milestones. 

AstraZeneca and Eccogene (2023)

In November 2023, AstraZeneca raised the stakes in the obesity drug race by licensing an experimental oral GLP-1 agonist from Shanghai-based Eccogene. AZ agreed to pay $185 million upfront and up to $1.825 billion in milestones for global rights to Eccogene’s molecule (known as ECC5004). 

Roche and Carmot (2023)

In a blockbuster move in Dec 2023, Roche acquired Carmot Therapeutics for $2.7 billion upfront. Carmot was a U.S. based company, but it had China ties (its lead asset CT-388 for obesity is a GLP-1/GIP dual agonist and it collaborated with Chinese researchers). 

Takeda and HUTCHMED (2023)

In January 2023, Takeda licensed ex-China rights to fruquintinib––a novel VEGFR inhibitor for colorectal cancer from Chinese pharma HUTCHMED––for $400 million upfront and up to $730 million in milestones (total $1.13 billion). 

This bet paid off – in September 2023, the FDA approved fruquintinib (brand name Qinlock) for colorectal cancer, validating the drug’s global potential and making it one of the first China-discovered small molecules to be approved in the US. 

Innovent/Junshi/LianBio (2020–2023)

A flurry of deals around Chinese immunotherapy: 

• In 2020, Eli Lilly paid $200M upfront (total >$15B) to enter a licensing agreement with Innovent on a PD-L1 antibody (sintilimab) for ex-China rights (which sadly didn’t last for long, due to an infamously scrupulous and pedantic rebuff by the FDA)

• In 2021, AbbVie paid $180M upfront (total $2B) for rights to I-Mab’s CD47 monoclonal antibody (an immuno-oncology therapy)

• In 2023, Bristol Myers Squibb paid $350M upfront to LianBio for rights to mavacamten (a cardiovascular drug) in China/Asia – which was interestingly a reverse-direction deal (i.e. taking Western innovation into China via a Chinese company).

Conclusion

For much of modern history, major new drugs and medical breakthroughs came from Western (or Japanese) companies and academia. China’s rapid progress is altering that balance. By contributing ~14% of the global drug pipeline by 2020 (and likely a higher percentage by EOY 2025), China has become a key source of innovation. Western pharmaceutical companies now routinely scout Chinese research for licensing opportunities, as detailed above. This means the center of gravity in drug innovation is shifting to a more multipolar world. U.S. and European firms that used to compete mainly with each other now must also compete or collaborate with rising Chinese firms.

One immediate implication is price competition and market expansion: as Chinese companies bring drugs to market (in China and abroad), they often do so at lower price points––undercutting Western drugs. For example, China’s domestic PD-1 immunotherapies are sold at a fraction of the cost of Merck’s Keytruda in China, forcing down prices and expanding access. If Chinese companies manage to get these drugs approved overseas, they could introduce more price competition in markets like Southeast Asia, Latin America, or even Europe. Consequently, Western firms will need to adapt strategies – possibly by accelerating their own innovation cycles or finding ways to differentiate their products beyond price. In some cases, Western companies have preemptively partnered––like Novartis with BeiGene on PD-1, effectively to avoid competing against this wave.

Despite the largely collaborative tone in science, the U.S.-China strategic rivalry of the 2020s does seem like it it is set to spill into biotech; just recently, Trump announced that he’ll be imposing 25% tariffs on foreign-imported pharmaceuticals, a not-so-covert way of punishing China for its manufacturing might. If relations worsen, it’s not hard to imagine a bifurcated pharmaceutical world––one where China (perhaps with allied countries) has its own parallel drug development and approval system somewhat separate from the West. In such a scenario, we might see a world not too dissimilar from our own in the past decade––Chinese companies focusing on serving China and emerging markets with innovative drugs tailored to those populations; while Western companies focus on U.S./EU/Japan. There might be less cross-licensing, with each side would commercialize its own innovations within its bloc. Patients would ultimately get access to most drugs, but possibly with delays in each direction (like Western drugs in China or Chinese drugs in the West might face barriers). Some signs of this: the FDA has yet to approve some Chinese drugs that are already proven effective in China (though slowly this is changing). If decoupling happened, that gap could widen.

However, the costs of such duplication are high: the pharmaceutical industry benefits greatly from global scale – larger trials, bigger markets to recoup R&D, and so on. A decoupled scenario could slow innovation (by reducing collaboration and cross-pollination of ideas) and raise costs (by requiring separate R&D pathways). It could also limit patients’ timely access to therapies available elsewhere. Thus, while possible if geopolitics severely deteriorate, a full decoupling in pharma is not in most stakeholders’ interest. 

The hope, is of course that this won’t happen. If managed well, China’s rise in pharma could herald a new golden age of drug discovery with multi-center innovation driving down disease burdens worldwide. The next few years will be crucial in setting the tone – whether through more joint successes or through rivalry – and that will determine how the story unfolds through 2030 and beyond.

Proposal 1. Establish a U.S. equivalent of Australia’s Clinical Trial Notification (CTN) scheme

Adopting a Clinical Trial Notification (CTN) model—where ethics committees approve protocols and the FDA is simply notified—could dramatically cut startup times while maintaining safety oversight.

Rationale:
The FDA's current IND approval process significantly slows the initiation of early-stage trials, leading to higher costs and delays in bringing new therapies to patients. 

Supporting Evidence:

• Australia's CTN model expedites Phase 1 trial starts within 6–12 weeks, compared to months-long FDA IND reviews.

• Lower regulatory burden reduces Phase 1 trial costs to $1–2M in Australia vs. $3–4M+ in the U.S., aided by a 43.5% R&D tax rebate.

Proposal 2. Expand Project Orbis and appeal 21 CFR 312.120 to get more Phase III trials accepted by FDA

Greater use of international trial standards (ICH E5/E17) and collaboration could reduce redundancy – e.g. FDA’s acceptance of EU or Japan Phase III results.

Rationale:

The FDA can approve drugs based on overseas trials (per 21 CFR 312.120), but requires that trials meet FDA’s quality standards and represent U.S. populations; Project Orbis, launched by the FDA in 2019, provides a framework for concurrent review of oncology drugs by the U.S., EU, UK, Japan, Canada, Australia and others. 

Supporting Evidence:

• 21 CFR 312.120:

  • A notable case of 21 CFR 312.120 overstepping a drug approval was an immunotherapy (sintilimab) tested entirely in China: despite a positive trial, FDA advisors refused approval due to concerns that the single-country study (with an outdated chemo comparator and homogeneous population) might not generalize to U.S. patients​.

• Project Orbis:

  • Project Orbis has significantly accelerated cancer drug availability: in 2020 alone, Orbis led to 17 new oncology drugs and 32 new indications being approved simultaneously in multiple countries​ 

  • By 2023, FDA had listed 68 Orbis drug approvals with most partner agencies approving those drugs around the same time​. 

Proposal 3. Establish a "Genetic Priority Designation" for drug approval

A formal "Genetic Priority Designation" should be established for therapies with well-supported genetic underpinnings, expediting their review process.

Rationale:
Genetic evidence from GWAS and Mendelian randomization studies provides strong causal links between biological pathways and disease. The FDA should integrate these data more explicitly into accelerated approval pathways, allowing earlier surrogate endpoint approvals for drugs (especially monoclonal antibodies and siRNA/ASOs) targeting genetically validated mechanisms. 

Supporting Evidence:

• PCSK9 inhibitors were approved based on Mendelian randomization data linking LDL to cardiovascular risk 

• Lipoprotein(a) inhibitors received FDA Fast Track designation based on strong genetic data

• FDA used breakthrough therapy for Evkeeza, given the genetic evidence of ANGPTL3 LoF

• Case studies in progress include drugs targeting APOE ε4 for Alzheimer’s (genetics identifies a high-risk subgroup) and INHBE for obesity (loss-of-function MR suggests targeting it might be beneficial).

Proposal 4. Establish a public database of failed and discontinued clinical trials

Sharing non-sensitive failed trial data (preclinical findings, trial outcomes, etc., without revealing proprietary chemistry) could prevent duplicative efforts and guide new research.

Rationale:

Currently, if a company’s IND or NDA fails, most data remains secret, which means other researchers might repeat similar trials in ignorance. For example, if a certain mechanism doesn’t work despite a robust Phase 3 trial, publishing that result (even if negative) allows the scientific community to redirect efforts – saving time and R&D dollars​ (1, 2)

​

Supporting Evidence:

• Analyses suggest that concerns that transparency would harm innovation are unfounded​–on the contrary, cumulative knowledge from both successes and failures drives efficiency in drug discovery. 

Proposal 5. Develop an “Aging Drug Designation”

Grant extended market exclusivity for drugs approved to treat diseases of aging. 

Rationale:

Aging-related diseases present a unique challenge – conditions like Alzheimer’s, osteoarthritis, frailty, and others that affect millions and have huge societal impact. They aren’t “rare,” so the Orphan Act’s market exclusivity incentives don’t apply, and companies can be reluctant to pursue them due to high failure rates. 

Supporting Evidence:

• Since its passing in 1983, the Orphan Drug Act has lead to more than 882 drug approvals for rare diseases with high unmet need. The total number of medication approved prior to the Orphan Drug Act was a paltry list of 38 drugs.

Proposal 6. Penalize patent life of “me too” drugs

Shorten monopoly time for drugs that aren’t novel in mechanism of action; or lack improved dosing regimen, or enhanced safety/tolerability.

Rationale:

The patent and exclusivity system is meant to reward innovation, but it often extends monopolies for drugs that show minimal improvements (“me-too” or “evergreened” drugs). Pharmaceutical companies frequently make slight modifications to existing drugs – e.g. a new isomer, a prodrug, an extended-release formulation, or a new combination – and obtain new patents or FDA exclusivities, blocking generics and prolonging high prices despite little added clinical value. 

Supporting Evidence:

• A classic example of an evergreened drug is esomeprazole (Nexium), the single-isomer form of omeprazole (Prilosec).

  • Nexium was patented and marketed as an improved therapy, but its efficacy was nearly identical to omeprazole; nonetheless, the new patent/exclusivity period let the manufacturer retain market control. 

• Numerous “line extensions” follow this pattern (e.g. escitalopram vs citalopram, controlled-release ADHD stimulants, insulin analog tweaks). 

• Studies by health technology assessors in Europe have found that over half of new drug approvals offer no or only minor additional benefit for patients​.

If you have uniquely powerful but “narrow” leverage in a given domain, you can amplify and transfer it asymmetrically to gain influence beyond your initial constraints.

Example 1: Paul Atreides playing up religious zeal → Galactic emperor

Paul Atreides began with narrow leverage: the Bene Gesserit-implanted prophecy among the Fremen, a small but elite fighting force, and control over Arrakis’ spice trade. Despite being technologically and numerically outgunned, he used these assets to:

• Exploit the Lisan al-Gaib myth to unify and control the Fremen.

• Turn Fremen fanaticism into a powerful political and military force.

• Leverage the galaxy’s spice dependency to bring the Empire to its knees.

Example 2: Trump running a popular TV show → President of the United States

Trump didn’t follow a conventional political path—he transferred his media leverage into political power:

• Real estate mogul → Built financial capital and name recognition.

• Reality TV host → Used mass-market media presence to cultivate nationwide appeal.

• Presidential campaign → Transformed celebrity status into political dominance.

Example 3: Carl Icahn’s minority stake & fear campaigns → De facto control over huge companies

Carl Icahn controlled companies without owning them by leveraging minority stakes and fear of his influence:

• TWA (1985) – Used borrowed money to buy TWA, then sold off assets for profit while leaving the company in debt.

• Apple (2013-2016) – Took a $3.6B stake and pressured Apple into massive stock buybacks, profiting before exiting.

• Netflix (2012) – Invested $321M, pressured Netflix to consider selling, then exited with a $1.6B profit.

Example 4: Napoleon’s artillery expertise → Emperor of France

Napoleon’s narrow technical expertise in artillery became a stepping stone to political and military dominance:

• Mastered artillery tactics, using cannons offensively and repositioning them mid-battle.

• Toulon (1793) – His artillery strategy drove out the British, earning him his first major promotion.

• Italian campaign (1796-1797) – His battlefield success made him the most famous military leader in France.

• Political leverage → 18 Brumaire Coup (1799) – His military credibility allowed him to overthrow the government and become First Consul, later Emperor.

Corollaries of narrow leverage

1. “All money is green” → capital transcends its origins

If you have capital, you can deploy it into new arenas. People don’t care where the money came from—only that you have it.

• Examples:

  • François Pinault (wood trading → luxury empire)

    • Started as a timber trader in France, pivoted into high fashion (Gucci, Balenciaga, YSL) and became a luxury tycoon.

  • Roman Abramovich (Russian oil → Chelsea FC & global influence)

    • Used wealth from post-Soviet oil deals to become a global power player, gaining influence in both sports and politics.

2. “Attention is currency” → visibility can be monetized and weaponized

If you control attention, you control perception—perception then dictates reality; fame doesn’t require expertise, it requires narrative control.

• Examples:

  • Kim Kardashian (reality TV → beauty empire → billionaire)

  • MrBeast (YouTube algorithm mastery → business empire & mainstream deals)

  • Andrew Tate (kickboxing → controversial internet empire)

    • Had a mediocre sports career, but transformed himself into an online cult figure through algorithm hacking and controversy.

3.  “Control the pipes” → owning infrastructure is the ultimate power

The highest leverage comes from controlling access, not just participating. If people depend on your infrastructure, you have permanent leverage.

• Examples:

  • Bloomberg Terminal (owning market data → financial gatekeeping)

    • Every major finance firm relies on Bloomberg’s data terminals, making them essential to the financial world.

  • Epic & Cerner (healthcare data → US medical infrastructure)

    • Control over medical records means they dictate how hospitals and insurers operate.

  • Elon Musk (DOGE use of read-only access to government payment flows)

    • Government agencies often operate with slow-moving bureaucracy; Musk, through read-only access to payment flows, is able to spot underutilized funds or inefficient allocations.

4. “Leverage is a one-way ratchet” → once you have power, it’s easier to get more

Leverage compounds—once you break through, every move gets easier. Gatekeepers apply rules to others, not themselves.

• Examples:

  • Warren Buffett (success in investing → better deal flow → easier future wins)

  • Reed Hastings (Netflix streaming → dictating Hollywood production) 

    • Started by licensing movies, then moved into content creation, now Hollywood depends on Netflix more than vice versa.

5. “Be the bottleneck” → if everything flows through you, you’re unstoppable

If people can’t bypass you, you own the game.

• Examples:

  • Intel (owning the semiconductor pipeline → Dictating computing power for decades)

  • OPEC (oil cartel → holding leverage over global energy markets)

  • Hollywood Agencies (talent pipelines → controlling entertainment industry deals)

  • GitHub (default for software hosting → indirect control over global development)

6. “Elite buy-in is optional” → mass adoption can rival institutional approval

If enough people back you, institutional opposition becomes irrelevant.

• Examples:

  • Cryptocurrency (ignored by banks → now held in hedge fund portfolios)

  • TikTok (dismissed as a toy → now a threat to Instagram & YouTube)

Table of Contents

1. Introduction

2. Past Pharmacological Sarcopenia Plays

   1. Anabolic-androgenic steroids (AAS) & Selective androgen receptor modulators (SARMs)

3. Present Targets

   1. Myostatin inhibitors

   2. APJ receptor agonists

4. Future Targets

   1. PPARδ

   2. Neuromuscular junction (NMJ)-based therapies

Why sarcopenia matters

Sarcopenia is a progressive, chronic age related loss of muscle mass and muscle function. Nearly everyone experiences sarcopenia at some point in their lifetime, but it typically manifests in a clinically significant manner by the seventh decade of life. 

Sarcopenia affects millions of older adults worldwide; while it may begin insidiously, its consequences become increasingly difficult to ignore as mobility, balance, and overall physical resilience decline—often culminating in disability, frailty, and loss of independence; compared with their non sarcopenic counterparts, those with characteristics of sarcopenia––like low muscle mass, strength, or physical function––are more likely to die from any cause. 

In the United States alone, it’s estimated that health complications from adults 60 and older with sarcopenia adds roughly $20 billion to healthcare burden (1, 2). Despite this clear unmet need, there are still no FDA-approved pharmacological therapies for sarcopenia. The only widely accepted intervention for the gradual loss of muscle mass and function with age is the monotone advice of one’s primary care physician: diet and exercise.

Naturally, this stark contrast between the growing unmet need and the lack of effective treatments leads to a key question: why aren’t pharmaceutical companies successfully developing drugs for sarcopenia? In a follow-up piece, we’ll examine the regulatory, commercial, and clinical development barriers that have slowed progress. First, however, it’s important to look at what has been tried thus far. Let’s take a bird’s-eye view of the therapeutic landscape for sarcopenia—past, present, and future.

The past (1950s - mid 2000s)

Anabolic androgenic steroids

This is the androgen receptor. 

The androgen receptor is a hormone binding nuclear receptor that lives in the cytoplasm. When anabolic-androgenic hormones bind to it, it swims into the nucleus and acts as a transcription factor, activating several growth-promoting genes downstream of it. 

Signaling cascade diagram of androgen receptor. Source

Among this variety of androgen responsive genes are a few familiar names that one might recognize from the literature in aging biology: IGF-1R, mTOR, Akt. These genes are heavily implicated in anabolism, meaning cellular growth, proliferation, and survival. By activating these genes, the androgen receptor tells the cells it's located: Grow! Divide! Use Up Energy! 

Anabolic androgenic steroids: the good, the iffy, and the ugly

The good: Anabolic androgenic steroids (AAS), which mimic the activity of native testosterone, are very good at building muscle. Within weeks of continuous administration at supraphysiological levels, their effects on muscle growth become visibly apparent.

Given that AAS are primarily used for hormone replacement or supplementation in a clinical setting, the vast amount of literature on anabolic steroids is under the lens of treating hypogonadal older men; hence, the following data is presented in context of that particular patient population:

These studies show promising results—treatment with anabolic steroids appears to be a highly effective strategy for reversing age-related loss of muscle mass.

The iffy: While anabolic steroids reliably increase muscle mass in sarcopenic individuals, their ability to translate these gains into meaningful and durable improvements in muscle strength is less clear.

Meta-analyses and RCTs suggest modest strength benefits, but these are often confounded by inconsistencies in study quality, heterogeneity in populations (e.g., hypogonadal vs. eugonadal), and the practical significance of observed effects in frail, elderly individuals. 

• Lee (2023): Eugonadal elderly men experienced more modest improvements in physical function compared to hypogonadal men.

• Parahiba (2020): The initially significant effect size of testosterone treatment on handgrip strength (+1.58 kgf [0.17, 3.0]) dropped to a non-significant +0.43 kgf [-2.05, 2.90] after excluding low- to mid-quality studies.

• Burrato (2023): Found no significant difference in handgrip strength between placebo and testosterone therapy in older men over 6–12 months.

• Isidori (2005): Reported no statistically significant differences between testosterone treatment and placebo for strength measures such as handgrip and leg extension.

These findings suggest that anabolic steroids may have limited efficacy in overcoming the complex physiological barriers to functional strength gains in aging individuals, beyond simply increasing muscle mass.

The ugly: Unfortunately, targeting the androgen receptor for sarcopenia with AAS opens a can of worms regarding safety.

Outside of skeletal muscle, the androgen receptor is expressed pretty much everywhere in the human body. And AAS don’t care where they bind to: when they come in contact with the androgen receptor, they bind to it––whether that be in the heart, prostate, or liver. 

Due to their lack of tissue selectivity, AAS are infamous for causing serious off-target side effects.

In men:

• Acceleration in prostate growth and increased risk of prostate cancer

• Shrinkage of testes, erectile dysfunction, & infertility

  • Sex hormones are tied together in a spiderweb of interlinked feedback loops. When men take exogenous androgenic hormones, it causes a cascade of effects - some reversible, some not. Namely, AAS usage acutely suppresses luteinizing hormone, follicle stimulating hormone, and gonadotropin releasing hormone (GnRH).

  • In turn, suppression of GnRH leads to lower testosterone production in the testicles, in turn leading to the effects of male infertility, testicular atrophy, and azoospermia.

• Gynecomastia

  • Not so fun fact: testosterone readily gets turned into estrogen via aromatase - and higher than normal levels of testosterone therefore means higher than normal levels of estrogen. This altered balance between androgens : estrogens associated with AAS usage will sometimes lead to breast development in men. 

• Male pattern baldness & acne 

  • In the cell, an enzyme called 5-alpha reductase metabolizes testosterone into dihydrotestosterone  (DHT). DHT plays a role in the production of sebum (the stuff that makes hair oily and also the stuff in pimples) and hair follicles. When DHT is elevated, it's implicated with those nasty, manly side effects.

In women, AAS unsurprisingly have masculinizing effects, such as:

• facial hair growth

• irreversible deepening of voice

• alteration of menstrual cycle

• clitoromegaly 

Cardiovascular safety of anabolic steroids remains elusive: A large longitudinal study of 5,000 testosterone replacement therapy (TRT) patients with existing cardiovascular disease (CVD) found no association between testosterone use and adverse outcomes like heart failure. However, it’s widely known that abuse of anabolic steroids—using doses exceeding therapeutic levels—has been strongly associated with serious cardiovascular risks. Androgen receptor agonism has been linked to dyslipidemia (increased LDL and decreased HDL), left ventricular hypertrophy (thickening of the heart muscle, which reduces its pumping efficiency), elevated blood pressure, and a heightened risk of blood clots due to overproduction of red blood cells (erythropoiesis). 

Overall, anabolic androgenic steroids (AAS) reliably increase muscle mass in older men—particularly those who are hypogonadal—and have shown modest strength benefits in meta-analyses; but most importantly––because they lack tissue selectivity–– the safety profile of AAS complicates their viability in being used therapeutically for sarcopenia.

SARMs

Unlike anabolic steroids, selective androgen receptor modulators (SARMs) were invented with a promise: to selectively target androgen receptors in muscle and bone tissues while sparing other organs from unwanted AAS related side effects.

Where did SARMs come from?

The development of SARMs begins with its sister class of hormone therapy - the selective estrogen receptor modulator (SERM). SERMs, such as tamoxifen and raloxifene, revolutionized the treatment of hormone-responsive cancers by selectively modulating estrogen receptors in different tissues. Their success spurred researchers to explore similar strategies for other hormone receptors, leading to the development of SARMs.

Their first obvious use case was to be developed for prostate cancer, an androgen receptor sensitive cancer that in previous time had much cruder treatments (similar to breast cancer before the emergence of SERMs). Bicalutamide, discovered & approved for its role in blocking androgen receptors in prostate tissue, proved to be a worthy scaffold for the development of further SARMs. Unlike traditional anabolic steroids, which affect multiple tissues indiscriminately, bicalutamide demonstrated the potential for selective receptor modulation. This selectivity laid the groundwork for designing other synthetic SARMs that could target specific tissues with greater precision.

The interesting aspect of SARMs is that their “selectivity” can be somewhat misleading. SARMs still interact with androgen receptors throughout the body; however, they exploit subtle differences in androgen receptor coregulators that vary between tissues. This enables them to have greater potency in desired tissues such as bone and muscle, while reducing their potency in other tissues like the prostate.

Unlike anabolic steroids, which equally affect muscle and prostate, SARMs increase the therapeutic efficacy for muscle growth via higher affinity for muscle over prostate. Source

All bark and no bite: the failure of SARMs in achieving FDA approval

Early research showed promising results for SARMs in terms of muscle mass increase and bone density improvements in mice (1, 2, 3, 4, 5); but despite initial excitement, SARMs have not yet lived up to their potential in treating sarcopenia. 

Clinical trials have revealed mixed results, with some studies showing modest benefits while others fail to demonstrate significant improvements in muscle function.

Below is a table of compiled efficacy of various SARMs in clinical studies:

As made apparent, SARMs do show promise in potentially increasing lean body mass, but as for increasing muscle function, the clinical evidence is fuzzy.

What is also made apparent is that SARMs are not free of all side effects—at the end of the day, being tissue discriminant is not the same as being truly tissue selective; this is why hormonal changes are still observed with their use, and why they have been explored for use in hormone reliant cancers.  Besides suffering from off-target hormonal effects, some SARMs in clinical trials have had issues with liver safety - having transient raises in liver enzymes (1, 2). Due to these side effects overshadowing their benefit, progress in development & approval of SARMs has been very slow moving.

The present (mid 2000s - now)

Myostatin & activin A inhibitors

Few discoveries in the world of muscle biology have garnered as much excitement as the inhibition of myostatin: a powerful regulator of muscle growth. 

The discovery of myostatin dates back to 1997 when Se-Jin Lee discovered that a previously unknown gene called GDF-8 played a crucial role in regulating muscle growth. Lee discovered that mice lacking this gene exhibited significant muscle hypertrophy, leading to the realization that GDF-8 (better known as myostatin) acts as a powerful inhibitor of muscle development. 

What are myostatin and activin A, and why are they relevant to muscle?

Myostatin and activin A are both members of the TGF-β superfamily, a cluster of proteins highly involved with cell growth and survival, particularly by inhibiting tissue growth. 

In muscle cells, these proteins bind to activin type II receptors (ACVR2A and ACVR2B), which then pair with type I receptors to form a complex. This complex initiates a signaling cascade by phosphorylating SMAD2/3 proteins. Once phosphorylated, SMAD2/3 combine with SMAD4 to form a regulatory complex that translocates to the nucleus and modulates gene expression, suppressing muscle growth and regeneration.

In practical terms, this signaling pathway acts as a “brake” on muscle growth. By limiting myocyte proliferation and hypertrophy, myostatin and activin A help ensure that muscle mass doesn’t grow unchecked. However, in conditions like sarcopenia—where muscle loss is a major issue—blocking this pathway could, theoretically, help remove the brakes and restore muscle mass and function.

Preclinical evidence of blocking the myostatin and/or activin A signaling cascade in mice has been very exciting; it’s shown promise in improving muscle endurance, muscle size + strength, lowers fat mass, and extends lifespan in mice. 

Myostatin genetic KO mice have pronounced muscular phenotype. Source

Due to their promise of growing muscle while avoiding the side effects of anabolic 

steroids, myostatin & activin A inhibitors have seen a surge of interest from pharmaceutical companies: including some of the biggest ones, like Regeneron and Eli Lilly.

So, Where’s My Anti-Myostatin?!

Clinically, anti-myostatins have come in two different flavors thus far:

Antibody-based antagonists

Antibody-based inhibitors are designed to bind specifically to myostatin and/or activin A, preventing it from interacting with the activin type II receptor. 

Ligand traps

Ligand traps are fusion proteins that combine the extracellular domain of the activin type II receptor with a robust immunoglobulin framework, creating a so-called “decoy” receptor; by pretending to be an endogenous receptor to myostatin, ligand traps sequester away myostatin and activin A away from binding to the “true” receptor, kind of like a fishing net!

Receptor Blockades

Receptor blockades like Eli Lilly’s bimagrumab represent another therapeutic approach. These blockades work by inhibiting receptor interactions with ligands while sparing the ligands themselves. This mechanism offers a distinct advantage by reducing the likelihood of off-target side effects that may arise from interfering directly with the ligands.

Clinical-stage anti-myostatins

View enlarged table

Despite the palpable excitement seen in preclinical animal models, myostatin & activin A have not seen as much success in people. 

The reason this could be the case, in part, are the following reasons:

1) The myostatin/activin A has multiple built-in redundancies

As I mentioned above, the myostatin/activin A signaling cascade happens through a heterodimer, i.e. two distinct receptors:

1. Activin receptor type-IIB (ACVR2B)

2. Activin receptor type-IIA (ACVR2A)

Binding to these receptors causes recruitment of one of the following receptors:

3. Activin receptor type-IB (ACVR1B)

4. TGFβ receptor type-I (TGFBR1)

To fully inhibit the signaling cascade, two approaches are possible: block both ACVR2B and ACVR2A, or block the downstream type I receptors, such as ACVR1B and TGFBR1. Each receptor in the pair can compensate for the other, and this has been demonstrated clinically. 

The complexity increases further when considering the redundancy of the ligands themselves. Due to the high homology between myostatin and activin A, they can partially compensate for one another. For example, if myostatin is blocked from binding to one of the four receptors mentioned above using a ligand trap, activin A can step in to activate the receptor—and vice versa. For example, Regeneron’s trevogrumab produced only mild effects because blocking myostatin alone allowed ligands like activin A or GDF11 to continue signaling through ACVR2/B.

This suggests that therapies exclusively targeting myostatin—or more broadly, focusing on a single leaf of this complex signaling cascade tree—are less effective in promoting muscle hypertrophy than they might otherwise be.

And lastly: a finer point that’s often overlooked is the translational difference in myostatin/activin A signaling between species. While myostatin is well-known for its role, it is actually less significant in humans and primates compared to mice. Compared to mice, activin A plays a much more prominent role in regulating muscle growth and homeostasis.

2) Inhibition of myostatin during adulthood is not as powerful as genetic embryonic knockout of myostatin

In humans, muscle hyperplasia – the division and proliferation of myocytes – happens during fetal development, and gradually slows to a standstill in early childhood.  Interestingly, the most compelling preclinical/observational studies showing increased muscle strength have been in genetic myostatin knockouts (1, 2, 3); and given that myostatin plays a role in embryonic development of muscle fibers, it is possible that this is why strength benefits have not been seen as robustly in adults.

Follistatin: a dark horse path to inhibiting myostatin?

Follistatin is an endogenous inhibitor of myostatin and activin A; in preclinical animal models, its overexpression has been shown to increase muscle mass and strength (1, 2, 3, 4), just like inhibiting receptor binding of myostatin and/or activin A can.  Unlike other kinds of myostatin inhibitors––which may only affect one ligand––follistatin’s broader activity could provide a more comprehensive boost to muscle growth by neutralizing multiple inhibitory ligands simultaneously.

Follistatin-derived therapies have reached early clinical trials. Acceleron Pharmaceuticals advanced ACE-083, a locally acting follistatin fusion protein, through multiple studies. While ACE-083 successfully increased the size of targeted muscle groups in both healthy volunteers and patients with rare muscular diseases, it failed to significantly improve muscle function in patients during two Phase 2 trials (1, 2).

Gene therapy approaches to enhance follistatin expression have also been tested in small, open-label clinical trials for rare muscle diseases. Both trials reported improvements in 6-minute walk test (6MWT) scores and localized muscle hypertrophy at the injection site (1, 2). However, these results should be taken with caution due to the small sample sizes, lack of blinding, and the inherent variability of open-label study designs, which can overestimate efficacy.

Debunking Minicircle

Minicircle is a biotech company that advertises the ability to genetically induce overexpression of follistatin in humans via plasmid mediated transfection - a lofty claim. They’ve alleged that this therapy can lower epigenetic age, increase follistatin serum level twofold, and increase fat free mass by 1 - 2 kg, all for the cheery price of $25,000.

Putting digressions about the lack of randomized controls & high likelihood of placebo effect aside, Minicircle is still acting in bad faith by claiming that their delivery platform even works. Max Berry has a solid writeup poking holes in Minicircle's claims of efficacy in detail, but in short its main fatal flaw in claiming to be legitimate is failing a therapeutic dosage sniff test:

→ Plasmid therapy is inherently difficult, because plasmids are not meant to be shoved into cells; both plasmids and cellular membranes have negative electric charges, and repel one another. 

-> To get around this, Minicircle uses a polymer called polyethylenimine to bunch up and “hide” the plasmid, so it can be sneaked into cells. Specifically, they used 50 micrograms of polymer, with a ratio of polymer:plasmid of 4:1 (i.e. delivery of around ~12.5 micrograms plasmid).

-> In similar dosage amounts of polymer & DNA, that would lead to a ~500 to 1000-fold change in protein levels (1, 2), done in vivo. 

-> Despite this, Minicircle claims that serum FST levels increased only ~twofold. What gives?

APJ receptor agonists

The newest contender on this list! Apelin receptor agonists (often abbreviated as APJ receptor agonists) are ligand agonists of the apelin receptor, a GPCR expressed ubiquitously throughout the human body. They mimic apelin, a peptide implicated in metabolism & nutrient sensing.

APJ has gained excitement as a target for treating sarcopenia because 1) it observationally appears to increase post exercise in humans, a known method of treating sarcopenia; and 2) apelin supplementation reverses sarcopenia in mouse models.

Delightfully, we’ve started seeing APJ receptor agonists move towards clinical use. Not long ago, BioAge’s APJ receptor agonist, azelaprag, demonstrated efficacy in alleviating muscle atrophy in healthy volunteers aged 65 and older during a Phase Ib bed rest study; and until recently, were running a Phase II study using it in combination with tirzepatide to treat obesity (unfortunately this study didn’t have the happiest of endings, due to an unfavorable safety signal showing elevated liver enzymes in participants on tirzepatide and azelaprag together).

The leading thought to why APJ receptor agonism potentially has protective effects on metabolism & sarcopenia is that APJ induces mitochondrial biogenesis in skeletal muscle (1, 2, 3). While some studies have implicated that APJr induced mitochondrial biogenesis is mediated via AMPK (the latter of which will be discussed at length in a later section!), this association is mixed (1, 2, 3).

Surprisingly, epidemiological evidence suggests that unlike mice, apelin levels don’t associate as strongly with age, especially in the context of age related sarcopenia (1, 2). On the other hand - it has demonstrated epidemiological association with cardiovascular risk (1, 2, 3), often comorbid with sarcopenia/obesity. Therefore, apelin’s relationship is complex and not necessarily straightforward - and we will have to wait and see if APJ receptor agonists are the real deal.

The future of sarcopenia drug targets

Drugs to improve muscle metabolism & energetics

Despite muscle size and strength being the most common vectors to target with drugs, sarcopenia is not driven by these and these alone; age-related loss of muscle endurance is a quiet but significant driver of sarcopenia and frailty.

Take an oft used fitness metric like Vo2 Max for instance. While not commonly mentioned in the same breath as muscle loss (no pun intended), it still has a very strong relationship  with likelihood of all-cause death; declines precipitously with age; and is in part driven due to age-induced declining of muscle quality (1, 2, 3, 4).

Kaplan-Meier curve comparing risk of all-cause death between subjects of different Vo2 Max quartiles. Source

Interestingly––despite being overlooked as a therapeutic option for sarcopenia, there are some clinical hints that suggest how metabolism/endurance boosting drug targets can help protect against sarcopenia. One interesting target of this variety that comes to mind is PPARδ.

PPARδ 

Peroxisome proliferator-activated receptor (PPAR) drugs have historically been associated with their role in metabolism and diabetes. Several of the former are already approved (rosiglitazone, pioglitazone, fenofibrate, etc.

PPARδ is an isoform of PPAR, a nuclear receptor implicated in cell survival, differentiation, and metabolism. It is expressed in a wide variety of tissues – from spleen to lung to skeletal muscle. 

PPARδ: a member of a fascinating family of nuclear receptors. Source

In the early 2000s, a researcher at the Salk Institute named Ronald Evans discovered that by engineering overexpression of PPARδ in mice, they were able to run for remarkably longer and farther than wild type mice could run; on top of that, they were resistant to high fat diet induced weight gain, too.

PPARδ overexpressing mice have vastly enhanced endurance over WT mice. Source

Excitingly, this finding about PPARδ has held water since Evan’s first paper in mice; the observation of increased running endurance in mice with elevated PPARδ has been independently replicated multiple times, though studies are of varying quality (1, 2, 3, 4, 5). 

While still not fully understood in its mechanism of action, the current leading theory is that overexpression of PPARδ shifts energy usage in cells from glycolysis to fatty acid oxidation, dramatically changing how fatigable muscle is. This energy usage “switch” is in turn implicated with a higher concentration of type I muscle fibers – i.e. slow twitch, fatigue resistant skeletal muscle fibers. Similar to apelin, PPARδ has been considered an exercise mimetic; observational studies suggest that exercise upregulates PPARδ (1, 2, 3, 4). 

Transgenic mice overexpressing PPARδ have redder muscles, indicating a higher presence of type I, oxygen rich muscle fibers. Source

Smelling an opportunity to develop a first-in-class drug with incredible promise for metabolic disease, GlaxoSmithKline got to work on pushing forward GW50516, a small molecule PPARδ agonist, for metabolic disorders. GW50516 made it as far as Phase II clinical trials, when sadly its path to approval was cut short – a worrisome toxicity signal suggesting the drug had high carcinogenicity in rats stopped development of GW50516 and other PPARδ agonists cold.

Despite concerns over its potential cancer risks, GW50516 has gained a foothold in the performance enhancement community under its new name, “cardarine.” Illicit users praise cardarine for its ability to boost endurance and resilience in sports like cycling and running. Its performance-enhancing effects have even led to controversy, with elite Olympic runners facing penalties for using it to gain a competitive edge. 

But is PPARδ activation inherently unsafe? Perhaps not. This year, the FDA approved two PPARδ agonist drugs: Merck’s seladelpar and Ipsen’s elafibranor, both for the treatment of biliary cholangitis. Another called mavodelpar made it as far as Phase 2b without any cancer related safety signals. 

Interestingly, the company that sponsored development of mavodelpar also did a leg immobilization study in healthy volunteers, which appears to suggest that PPARδ has a protective effect against muscle wasting.

PPARδ agonist mavodelpar protects against loss of muscle strength in a leg immobility study. Source

These approvals and small suggest that, under controlled and clinical contexts, PPARδ agonists (and other similar targets in this space) may have a place as a pillar of future sarcopenia therapy.

Drugs to promote neuromuscular function

One therapeutic angle for sarcopenia receiving more limelight in recent years is by improving function of the neuromuscular junction.

The neuromuscular junction (NMJ) is the critical interface where motor neurons communicate with skeletal muscle fibers to enable muscle contraction. It acts as a specialized synapse, transmitting signals from the nervous system to muscles through the release of acetylcholine, a neurotransmitter.

In brief, here’s how it works:

1. An electrical impulse (action potential) travels down a motor neuron to the nerve terminal.

2. This triggers the release of acetylcholine into the synaptic cleft.

3. Acetylcholine binds to nicotinic acetylcholine receptors on the muscle fiber membrane (sarcolemma), causing an influx of ions.

4. The ion flow generates a new action potential in the muscle fiber, leading to muscle contraction.

In sarcopenia, the NMJ’s structure and function can deteriorate, contributing to weakened muscle contraction and atrophy. This loss of function also affects motor coordination - as the precise activation of muscles needed for smooth and efficient movement becomes impaired. Reflexes slow down as signal transmission is delayed, making it harder to react quickly to changes in the environment. These issues contribute to difficulties with balance and postural stability, significantly increasing the risk of trips, stumbles, and falls, which are a leading cause of injury and reduced independence in older adults. Everyday activities like walking, climbing stairs, or carrying objects become increasingly challenging, further diminishing quality of life.

Therapeutic strategies aimed at improving NMJ function focus on:

• Enhancing acetylcholine signaling

• Preventing synaptic degradation

• Promoting the repair or regeneration of the NMJ structure

In fact, some drugs targeting the NMJ are already approved for NMJ dysfunction, though not specifically for sarcopenia. Myasthenia gravis, an autoimmune disorder of the NMJ, has several approved treatments that enhance or stabilize NMJ function, such as acetylcholinesterase inhibitors (ACHEIs) - which boost electrical signaling to skeletal muscle via preventing the breakdown of acetylcholine.

Current therapies targeting neuromuscular junction (NMJ) disorders are limited in their ability to address the root cause: denervation, or the progressive loss of nerve connections to muscle fibers. This process involves the degeneration of motor neurons in the spinal cord and peripheral nerves, leading to the disruption of their connections at the NMJ.

Similar to how mature skeletal muscle growth occurs exclusively via hypertrophy of existing muscle, the loss of motor neurons can only be offset by the reinnervation of denervated muscle fibers by neighboring motor neurons. However, this compensatory reinnervation is often incomplete and less efficient, resulting in the formation of larger, less precise motor units (1, 2, 3, 4); consequently, structural change following denervation in net diminishes fine motor control and muscle quality - even with compensatory mechanisms. 

Further reading

• https://sarahconstantin.substack.com/p/sarcopenia-experimental-treatments

• https://sens.org/legs-of-iron-feet-of-clay/

• https://trevorklee.com/why-cant-we-just-give-steroids-to-people-with-muscular-dystrophy/

• https://link.springer.com/article/10.1007/s40266-018-0566-y

Companies to watch in this space

• AAS: Lipocine

• SARMs: Veru, Viking Therapeutics

• APJ: BioAge

• Myostatin / Activin A: SixPeaks, Regeneron, Versanis (acquired by Eli Lilly), Roche, Keros Therapeutics, Merck (acquired Acceleron), Scholar Rock Therapeutics

• Muscle Metabolism / Exerkines: Mitobridge, Pelagos Pharmaceuticals, Amplifier Therapeutics, Poxel SA

• Miscellaneous: Epirium Bio, Biophytis, Rejuvenate Biomed

2) The Bacillus Calmette–Guérin (BCG) vaccine is indicated first and foremost for preventing tuberculosis, but has found new life as an immunotherapy against bladder cancer

3) Watch: Pharmaceutical patents, explained

4)

I wonder how legitimate these other inhibitors of glucagon are...? In any case, in this new post Ozempic world I suspect we'll start to see moonshot drug repurposing efforts for obesity – due to some weird preclinical finding in relation to glucagon / GLP-1.

5) At long last, scientists have invented Modafinil 2

6) Adorable biology lore: the first genetically cloned cat was named CC, for "Carbon Copy". That has to be the most tongue-in-cheek naming in biology since the discovery of SHH.