I heard about the FOP programme at Regeneron the way you hear about most things in a big company, occasionally and in passing. Aris Economides gave a talk on it a couple of times. I missed both, then heard from my colleagues that it was inspiring, and that FOMO drove a curiosity in me about what the story actually was. Then I procrastinated.
When the trial results were press released there was excitement in the building. A rare disease programme hitting a milestone like that is not an ordinary day. My curiosity grew, and I decided I should write about it. Because, you know, writing is how I discipline myself into learning something properly. Then I procrastinated again. I told myself I would wait for the trial to be published so I could time the post to it, and then I forgot about it entirely.
I left the company. I moved to India. And a few weeks ago I learnt that the FDA approval came through, before the trial results were ever published.
That was the trigger.
So I have spent the past weeks reading, and I should clear something first. I was at Regeneron while this programme was taking final shape, but I was nowhere close to it, and I have no insider information whatsoever. Nothing here comes from a corridor conversation, and my sources are Aris's own review article and a long list of papers from the literature. The story naturally turned out to bear an outsider's perspective.
I wish I had done this homework while I was still there, so I could have stopped Aris at any of the times I crossed paths with him and asked him about it directly. But I think it works better this way. What follows is what the published record alone will give you.
And the reason I could not let it go is that this story is not really about human genetics, which is my narrow field of vision, even though that is of course at the core of it. It is about what it takes to develop a drug for a puzzling, debilitating illness. That is a perspective I think anyone who imagines themselves doing that one day ought to have.
The news
On 19 August 2026 the FDA approved garetosmab, developed by Regeneron for a rare disease called fibrodysplasia ossificans progressiva (FOP). Garetosmab, a monoclonal antibody against a protein called activin A, is the second drug ever approved1 for this disease, but it is the next best thing to a cure these patients can have, shown by the outcome of the phase 3 trial.
The disease
FOP is an extremely rare disease with estimates of around 900 diagnosed across the world. It's a bone-forming disease. The telltale sign appears at birth: malformed great toes, characteristic of the condition. That remains the only sign for years.
The bone comes later, usually in childhood, preceded by an injury, a fall, an injection, sometimes nothing one can identify. A lump appears and it hardens. Don't mistake it for scar tissue with calcium in it. It is real bone, laid down through a cartilage stage, the same route by which a growing child builds a femur. It happens in muscle or tendon or ligament, in a place where a skeleton is not supposed to be.
It happens in episodes. A flare, then months or years of nothing, then another bone somewhere else. Between them the disease is silent.
The formed bone never goes away, and every episode adds to what is already there. Joints fuse. The spine locks. Most are in a wheelchair by thirty, and half do not live past their mid fifties. Death is often painful. It comes from an immobilised chest wall, neck and jaw that slowly halt swallowing and finally breathing.
The obvious thing to do with a lump of bone in the wrong place is to cut it out. In FOP you must not. Resection puts back more bone than it removed. Surgery is contraindicated. So is a biopsy or even an intramuscular injection. Every ordinary instrument medicine has for looking at a lesion or for getting a drug into a muscle is a way of making the disease worse.
That shuts down most of the options for intervening. Nothing helps once the bone is formed. Anything that works (including garetosmab) has to work before the bone starts.
The company
First things first. A hearty congratulations to team Regeneron, especially Aris Economides, vice president who runs its skeletal diseases group. Aris joined the company straight out of his PhD, and has been there ever since. He championed this programme, and Regeneron moved the molecule through phase 3 to approval for a disease with a mere 900 diagnosed patients in the world.
On first impression this could look easy. An antibody against a protein, made by a company that is a pioneer at making antibodies. A rare disease, a protein you can block, and a manufacturer already equipped to block it. A company without deep pockets has to bet everything on it, and the market is too small to build a business around. A large one can absorb it, and there is often a priority review voucher at the end of it, which can be worth more than the drug will ever earn.
That is a reasonable thing to assume, and it is not what happened here.
You see, the antibody was never the hard part. It's the target. Uncovering the right target is the story. And the reason a company with no particular reason to be in this disease went deep into it is serendipity and curiosity more than a strategic move. Regeneron happened to be holding an antibody against activin A, or was planning to make one, for something entirely unrelated to bone. It then appeared that there might be another use for it. That use was not straightforward, and somebody decided it was a challenge worth undertaking.
The timeline
One of the things that I pay attention to when reading about a new medicine is the timeline. The commonly quoted ones measure the time from when a gene was mapped to a disease to the date of FDA approval. That measurement is what answers the most asked question, how long does it take to develop a drug. By that standard it is 20 years for garetosmab. The gene was mapped in 2006 and the drug was approved in 2026.
But that shortsighted timeline misses some important history, and it understates how long it really took for a cure to arrive for the patients. As you unroll the timeline, you'll see that it keeps going back. 48 years, if you start from the assembly of the protein family that activin A belongs to, built out of nothing but sequence homology, by people in four unrelated fields. 61 years, if you start the clock from the experiment that showed bone can be induced in places where no bone belongs, done in a rabbit in 1965 by someone who had never heard of this disease. 286 years, if you start from the first clear description of the disease itself, in a letter to the Royal Society published in 1740, describing a boy whose ribs had joined across his back.
That is what solving a disease actually costs. And almost none of that was spent by people working on the disease.
What follows below is a glimpse of that longer timeline, not a full history of it. That's too big to fit in here.
It is worth knowing how the story is structured. The story stem winds around the disease, from the first description to the drug. But then there are branches that join at points where the disease goes quiet and something in the background takes over. That is not a digression. That is what FOP was waiting for. And none of it looked like a line at the time. It only becomes one backwards.
Before travelling back, let me give you a snapshot of where we are heading. It's not a spoiler. It's not what the answer turned out to be. It's rather how anyone came to know it.
FOP is caused by a single nucleotide change in the gene ACVR1. It encodes a receptor protein, named activin A receptor type I, which is part of a superfamily called TGF-beta. There are 12 receptors and about 33 ligands in this family, which branches into two pathways, each orchestrating different biology. ACVR1 sits in the branch that builds bone and it binds to a bone morphogenetic protein (BMP). Activin A is not a BMP.
The first record
On 14 April 1736 a 14 year old boy walked into St Bartholomew's Hospital in London and asked what could be done for him. John Freke, a surgeon there, wrote down what he saw.
There came a boy of healthy look and 14 years of age, to ask of us at The Hospital, what should be done to cure him of many large swellings on his back which began about three years since, and have continued to grow as large on many parts as a penny-loaf, particularly on the left side. They arise from all the vertebrae of the neck, and reach down to the os sacrum. They likewise arise from every rib of his body, and joining together in all parts of his back, as the ramifications of coral do, they make, as it were, a fixed bony pair of bodice.
Two things to pay attention to in Freke's vivid description. The timing: a healthy looking boy who noticed swellings growing on his back for three years. He was an ordinary child until he was eleven. The disease waited, and then it started. The coral: the swellings are not separate lumps on the boy's back. They arose from every rib and joined across all parts of it, becoming one continuous piece, closing around him like bodice. There was never a discrete thing to cut away. Nothing clinical has been added to that record in 286 years.
For most of those years the disease had the wrong name, myositis ossificans progressiva. The problematic part is 'myositis', which means inflammation of muscle. The disease was believed to be a disease of the muscle for nearly two and a half centuries.
If you think about it, it was a reasonable guess. The lumps come up in muscle, often after an injury, and they are hot and swollen while they appear, and there was no way to examine the swelling beyond what you could see at the patient's bedside.
In 1972 Victor McKusick struck out 'myositis'. He said the bone does not come from muscle. It comes from the connective tissue running through and around it, and the muscle is an innocent bystander. He replaced myositis with fibrodysplasia, and it has been fibrodysplasia ossificans progressiva ever since.
McKusick had the tissue right in 1972, and then nothing happened for thirty four years.
It was not that no one wanted to try anything. Asking which gene causes a disease was not a question that anyone could ask by then. Finding a human disease gene from its position on a chromosome, with no idea in advance what that gene might be, did not exist as a technique until the mid-1980s.
When the gene mapping technique did arrive, there was a second problem waiting already. Linkage needs families, ideally several generations, affected and unaffected in each, so you can watch a stretch of chromosome travel down the family alongside the disease. FOP immobilises people in childhood and adolescence, and people with FOP rarely have children. So there were no multigenerational families to map the genetics.
So the disease waited. But the vocabulary it was waiting for was already being built, in laboratories that had never heard of FOP. In 1965, seven years before McKusick fixed the disease name, a surgeon working on why bone grafts heal had already reproduced the core of FOP's disease process in a rabbit and published it.
The family
In 1965, Marshall Urist, an orthopaedic surgeon at UCLA, was trying to answer an ordinary question that had puzzled bone surgeons for eighty years. Bone grafts work. Why? The assumption since 1881 was that the graft's own living cells make the new bone, so a graft is a delivery vehicle for bone forming cells.
Urist took bone, killed anything living in it by dissolving out its mineral with acid, and implanted the residue2 into a rabbit's muscle. Bone formed. In the muscle, where no bone belongs, through a cartilage stage, the same route by which a growing child builds a femur. No donor cells could make it as there weren't any. So the new bone had to be coming from host cells, converted into bone-makers by something in the debris. He called it autoinduction, and six years later he named that something bone morphogenetic protein.
Note, the new idea there is induction, not ossification, which is already a recognised concept. What was new is a signal that bestows a new power, bone-making capability, on cells that could never do it before.
Now reread Urist's experiment as a clinical description. Cell-free material placed in skeletal muscle, and endochondral bone comes out of it. That is FOP. In 1965, forty one years before anyone knew which gene was involved, the core disease process was remarkably mimicked in a rabbit by a man who had never heard of FOP. The disease was demonstrated long before it could be studied.
And that is the pathway the FOP field would be fixated on eventually. Which is what made the next forty years of wrong answers possible.
While the bone people were doing that, three strangers were building something none of them meant to build.
It starts in 1978 with two cancer virologists. De Larco and Todaro were working on cells transformed by a mouse sarcoma virus, and they found those cells were secreting something that made ordinary fibroblasts behave like cancer cells, growing in soft agar where normal cells will not. They called it sarcoma growth factor. It was later split into two, and one half of it became transforming growth factor beta. The naming is after an artefact in a dish.
Its gene sequence was published in August 1985. Four months later, in December, a reproductive endocrinologist named Mason published the sequence of inhibin, the fertility hormone, and noticed it looked like the cancer factor. He reported these are members of one gene family. That sentence is where the superfamily begins. In 1987, a fly geneticist working out how a fly embryo decides which side is its back found that his gene was another relative. And in December 1988 the bone morphogenetic proteins were cloned and filed in as members of the same family, twenty three years after Urist's rabbit experiment.
Look at what those four people had in common. Nothing. Not a tissue, not an organ, not a function, not a disease, not even an assay. A cancer experiment, a fertility hormone, a fly's embryo, and a protein from digested bone. The only thing that connected them was that their protein sequences resembled each other. The entire family was assembled out of sequence and nothing else.
Which is also why the family is named after the wrong thing. Whichever member gets sequenced first becomes the one everything else is compared to, and, in this particular case, it was a matter of four months. Transforming growth factor beta was published on 22 August 1985, and inhibin on 19 December 1985. Reverse that, and the family would be called the inhibin family. Urist's bone protein was filed in 1988 under a name that came from cells growing in soft agar.
And in 1988 that is all there is. A family, and no map of it. Nobody knew which member spoke to which, or that the family divides into two halves that do totally different things. The receptors were yet to arrive. When they did, each one would be named after whichever ligand it seemed to bind, and nobody had any way of telling a right name from a wrong one.
Activin arrives in this story the way most things in it arrive, sideways.
In 1932 an American physician called McCullagh injected a water extract of testis into castrated rats and observed what happened to the pituitary. Castration normally releases the brake that restrains the gonad-stimulating hormones secreted in the pituitary, causing the pituitary cells to swell and go vacuolated. Pathologists of that era called them castration cells. McCullagh noticed that the injection prevented the castration response in the rat's pituitary. And it did nothing for the prostate. He inferred that whatever that extract contained was not a male hormone but something else that inhibited the pituitary response. He called it inhibin.
Then fifty years of nothing. Inhibin was found to be a real substance in bioassays but nobody knew what it was exactly. The protein was purified finally in 1985, out of pig follicular fluid. It turned out that ovaries, more than testes, are the more abundant source and you get litres of it from a slaughterhouse. And in June 1986 two laboratories purifying the protein encountered a fraction of the extract doing the exact opposite of what they expected: stimulating the pituitary rather than suppressing it. It turned out it was the same protein but different subunit configuration. Inhibin is an alpha bound to beta subunit. When beta binds to beta, you get the inverse action. And that's how activin was born, out of an accident.
By 1990 activin had left reproductive biology altogether. The factor that tells a frog embryo which of its cells become muscle and bone turned out to be activin, and graded doses of it gave graded changes in the cells' fate, which is how a morphogen behaves. So the people who went looking for activin's receptor were developmental biologists. Nobody in that hunt was thinking about bone, and nobody had ever seen a receptor for any member of this family.
They found one in 1991, by the oldest method that existed. Mathews and Vale, from the same laboratory that discovered activin, labelled activin A with radioactive iodine and used it as bait to fish out whatever it gripped on the cell surface. What was caught was ACVR2A, the very first receptor of the entire superfamily, and it came with a surprise. It was a serine threonine kinase, when every growth factor receptor the field knew before was a tyrosine kinase. A new class of receptor was thus born, pulled out using a hormone from an ovary.
And that is the last time anyone found a receptor in this family by its ligand. A second one came a year later by looking for sequences that resembled the first. Then in 1993 the same trick at scale: take the conserved stretch of that kinase, go fishing with the sequence bait instead of the hormone. Four receptors caught in the net at once, and the series ran to seven within three years. They were caught blind. Nobody knew what a single one of them bound. They were named for the thing they resembled, and the naming is honest if you read it literally, activin receptor-like kinases, ALK1 through ALK7. The resemblance that had assembled the ligands was now assembling the receptors, and it was doing it much faster than anyone could figure out what they were for. To highlight one of them, ALK5 is the TGF-beta receptor.
Then the orphan receptors were tested against ligands, and two of them held on to activin. One was ALK4. The other was ALK2, which is ACVR1, the FOP gene. Both took activin into their names on that evidence, and the evidence was real. ALK4 was later found to pass the signal on into the cell. But ALK2 did nothing. It just bound activin. But these were realised only later and not known in 1993, because binding was the only thing anyone could measure then. The machinery inside the cell that carries the signal onward was not found until 1995 and 1996. Until then you could only tell if a receptor binds to something. You could not tell if that binding did anything to the cell.
So ACVR1 was discovered by sequence resemblance and named by binding, and at that moment there was nothing in existence that could have shown the naming to be wrong. The signalling map came afterwards. When it did, the family split into two halves that answer to different sets of ligands and handle different machinery inside the cell. ACVR1 sat on the bone half while activin sat on the other. A name given in 1993 (ACVR1) was checked against the signalling map drawn in 1996, and it has been treated as a misnomer ever since.
The goose chase
While all of that was happening in other people's laboratories, the FOP field had not gone quiet. Through the 1980s and the 1990s, Fred Kaplan and Michael Zasloff at the University of Pennsylvania were doing work that looks like administration rather than science. They were finding FOP patients. A disease this rare drops one at a time, scattered across countries. Usually they get misdiagnosed at first, so they took referrals from anywhere, wrote to families and slowly assembled an international register of people with FOP.
The first real finding came in 1996, appearing in the New England Journal of Medicine. Shafritz, Shore and Kaplan took cells from FOP patients and measured the bone morphogenetic proteins, BMP-1 through BMP-7 one after the other, looking for a protein that the patients' cells made too much of. One of them turned up. BMP-4 was found to be expressed more in patients' cells than controls'. The suspicion was older than the paper, and it says so in the introduction, that too much BMP had already been proposed as the cause of the disease. What was new after the NEJM paper is that there was now a number under it, BMP-4.
Note which half of the system they searched, the ligands. That was the only half you could search. By the mid 1990s the BMPs were a numbered list, and they were cloned and catalogued, so you could take them one at a time and measure. The receptors though were not a list yet. They had been fished out blind just three years back, half of them still had no confirmed ligand, and there was nothing to read them out with, since the machinery inside the cell they signalled was found only in 1995 and 1996. You could ask what the patients' cells were making too much of. But you could not yet ask what the receptors on their surface were talking to inside the cell.
What followed was ten years of a wild goose chase. Every research effort built on the finding from the NEJM paper. If the patients' cells make too much BMP-4, the fault should be in the gene for BMP-4. They sequenced it. Nothing. If the protein is not built wrong, then perhaps it is switched on wrong, so in 1998 they worked out the structure and the transcriptional control of the human BMP4 gene. Nothing there either. If the ligand is not made wrong and not controlled wrong, perhaps its brake is broken, so they went to a protein called noggin that holds BMPs down, BMP-4 among them, and that is a story of its own and comes next. And if not the ligand, its gene, its control or its brake, then the receptor that binds it, BMPR1A, BMP-4's own receptor, which in 2005 turned out to be trafficked abnormally in FOP cells and that carried no mutation either. Ten years of search, and the true FOP gene was nowhere in the vicinity of that search space.
To be fair, none of that is foolish. Each research effort was a rung laid above the one below it in the BMP-4 ladder that was brought to the scene by the NEJM paper. The issue was the BMP-4 finding at the bottom of the ladder was not a false one. By 2003 they did find that BMP-4 was transcribed five to seven times faster in patient cells than in control cells, though they couldn't say why. As far as anyone could tell, it was a real finding. A wrong measurement gets dropped in a year or two, and it will not come back. A right measurement pointing at the wrong part of the pathway can run futile for a decade. And that's what happened.
Now look at what was on the list they measured: all BMPs one to seven and nothing else. The protein that actually drives this disease was outside the search before the search began. It doesn't matter anyway, as a broader list wouldn't have helped either. Activin A is not raised in FOP patients either, not during a flare and not between flares. Nothing in these patients is being made in excess. The assumption underneath the entire ladder was that a disease of too much bone has to come from too much signal, and that logically sound assumption turned out to be wrong in the FOP puzzle.
The BMP4 ladder had ended on a receptor, BMPR1A, which led to nothing. BMPR1A belongs to the BMP type I receptors, a group with only three members. The FOP gene is one of them. The goose chase after all took the field to the right shelf, but just made them pick the wrong neighbour. The right one had been there since 1994. ACVR1 had been fished out blind with the other orphans, had bound activin, had been named for it, and then it entered the BMP family in 1994, when the BMPs were tested against the same seven receptors, and ACVR1 was found to bind BMP-7. The same sentence that assigns ACVR1 to BMP-7 says explicitly that it doesn't bind BMP-4. So the gene that causes FOP was already in its home, the BMP receptor family, when the field was hunting for the gene in the BMP space.
Noggin is not a member of the BMP family. It is a secreted protein that shuts down BMPs from outside the cell. Knowing how it does that is important as the idea comes back at the end. A BMP works by clutching two receptors at once, a type I and a type II. Noggin hugs BMP around covering exactly the two spots that connect the BMP to the receptors. Purely mechanical. Nothing is destroyed or switched off. The BMP is still there in the tissue but incapacitated, unable to talk to the receptors.
So, noggin earned its entry into the FOP story through logic. If a disease of too much bone doesn't come from making too much BMP, the same excess could come from losing the thing that restrains it. That idea needs no fault in any BMP gene at all, which was convenient, because the FOP field had sequenced BMP-4 and found nothing. Noggin was the brake, and a broken brake would look exactly like a stuck accelerator.
The claim arrived in 1999. A French group reported that an FOP patient carried a 42 base pair deletion in the noggin gene, and the year after, the same group published a linkage map to the chromosome where the noggin gene sits. Two results, arriving separately, agreeing with each other and with the hypothesis everyone already held. On paper that is what a solved disease looks like.
Penn tested the noggin claim across thirty one families, starting with a linkage analysis, and found no evidence. They even sequenced the gene itself, in four families and eighteen patients, and found no mutations. They published the null result in 2000, one year after the claim. The question of noggin as the FOP gene should have closed, except it didn't.
In 2001 three further noggin mutations were reported, in three more families. In 2002, Penn published a paper whose title says the reported noggin mutations are PCR errors. Yet new noggin claims were continuing to appear in 2005. In 2008, two years after the real FOP gene had already been found and published, a paper appeared claiming mutations in noggin and in ACVR1 together, and drew two separate rebuttals in the same issue of the journal. One of those rebuttals carries about twenty names, and one of them is Aris Economides. That is how he enters this story, and it is not because he worked on FOP. His first paper, in 1993 in Science, was on noggin, and he had spent the fifteen years since on the proteins that hold BMPs down, and nothing but BMPs. He was there as an expert on the protein under trial, the protein that was never the answer to the FOP puzzle.
The final nail in the noggin coffin was none of the rebuttals but the very first patient in whom the noggin mutation was found, the case that ignited a second goose chase alongside the BMP-4 one. When the FOP gene and the causative mutation were eventually found (which is the next part of the story), the noggin patient zero turned out after all to be a case of ordinary FOP carrying the ACVR1 mutation. The noggin mutation was an innocent bystander. Nobody had to argue it down.
By 2000 the first FOP genetic maps were starting to come in. In January 2000, a Penn group took the four FOP families and drew a linkage map, which pointed to a locus on chromosome 4 with the LOD score that just surpassed the significance threshold. But more than that what increased the confidence on that locus was the authors' own closing line, that the interval contains at least one gene involved in the BMP signalling pathway. The map had landed where the hypothesis wanted it to land.
The material behind that score was four families. With that sample size, the strongest result the study could produce sits barely above what a false peak can reach. It also ran several hundred markers, so the odds of some random locus clearing the threshold were not small. The same year supplied the demonstration. The other genome scan of 2000, the linkage scan that produced the noggin locus, ran on seven families and produced a statistically significant LOD score. Two maps, in the same year, both above threshold and both wrong.
After the map came the gene hunt. Candidate genes inside the chromosome 4 interval were sequenced, and no mutations were found. Which genes those were was never recorded. Nor is it known whether the BMP pathway gene that made the interval attractive in the first place was among them.
Reading one gene across a handful of patients was ordinary work, and labs were doing exactly that outside the interval too, one BMP gene at a time on intuition, which is what the previous ten years of this section have been. One thing is certain though: ACVR1 was not among the genes anyone read. Had it been, the mutation was sitting there to be found, the same single base in every patient, and the search would have ended in an afternoon. What the era could not do was read the entire list. Twenty odd BMPs and growth factors, seven type I receptors, five type II, the antagonists, several hundred exons across dozens of patients, and one gene at a time was the unit of work. Sequencing everything was not a decision anyone refused to take. It was simply not possible. So the discovery had to wait for something to point the scientists at a locus on the long arm of chromosome 2, where ACVR1 was waiting to be sequenced.
The gene
The next linkage scan came from the same Penn group, and there was nothing remarkable about it. Five families, against four last time. No new method, no new markers. What was different is that every family in it had been handpicked to ensure a strict phenotype: malformed great toes at birth and bone forming in the characteristic pattern, in every affected family member. No ambiguous case was allowed into the study. They could afford to be that strict only because they had far more patients to start with, having assembled them one at a time over a period of twenty years.
What they found was another locus, this time on chromosome 2. It was no better than what they had seen before. In fact, it scored lower than either of the two wrong signals of 2000, and it did not reach the threshold for statistical significance. And like before, there was a BMP gene sitting inside the region, which is what made them consider this locus despite its weak statistical significance, with an intuition that perhaps they were close to the answer this time. They were.
The moment of truth arrived when they sequenced the candidate gene. Case after case carried the same mutation, same single base, in every patient they looked at. That one finding validated the locus, leaving no place for any doubts. Ten years of gene hunt finally ended. The gene behind FOP was finally found. It was ACVR1.
The mutation
The same base. Not just the same gene, the exact same base. Seven families carried it, and so did thirty two out of thirty two patients who had no family history at all. There are only two ways to interpret that. Either all of those people are distant relatives who inherited one ancient mistake, or that particular letter breaks on its own, over and over, in people who are not related.
They checked, and the answer couldn't be any clearer. The five families came from different ancestries, and the stretch of DNA carrying the mutation was different in every one of them. There is no common ancestor behind it. The nucleotide change was absent from 159 unaffected people and from the variant databases of the time. In six of the sporadic cases they sequenced both parents and found the mutation in none. So the mutation had appeared new in the child. The authors described it in the paper as one of the most specific codons in the human genome to be tied to a disease.
The reason is chemistry, and it arrived only three years later. The letter sits in a CpG, a C followed by a G, which is the most fragile pair in the genome. The C in that pair carries a methyl group, and a methylated C decays into a T3 faster than any other letter turns into anything else. So the mutation is not descent. It is a chemical accident happening again and again in people who have never met4.
The same chemistry also allows us to estimate the number of individuals carrying the mutation around the world. The mutation happens about once in every 10 million times a gamete is made, and the child can inherit it from either parent, so roughly one birth in five million. FOP shortens life, so at any moment fewer carriers are alive than were born. The calculation gives the prevalence as on the order of a thousand people alive on earth with FOP, close to the 900 diagnosed around the world.
The important thing to know is the mutation keeps coming. It is barely ever passed on to the next generation, so selection has no job here. It's purely the chemistry that replenishes the pool of patients continuously.
The hypothesis
To understand the mutation site and how the field thought through its mechanism, you need to know first how the receptor signalling works. The signalling starts from the ligand outside the cell, and it is a pair of halves, usually identical. It gathers four receptors around itself, two type II and two type I, and the assembly as a whole is what does the job. All four are transmembrane proteins of the same build: a small ligand-binding piece hanging outside the cell, one stretch crossing the membrane, and a kinase hanging inside. The type II kinase is on all the time, and its only job inside the cell is to switch on the type I receptor beside it. The type I receptor then switches on the downstream proteins, propagating the signal into the nucleus and turning on target genes. Which type I receptors assemble into the complex determines which of the two signalling pathways that define the two branches of the family switches on.
The switch that the type II kinase throws is a short stretch called the GS domain, on the type I receptor, just inside the cell, between the membrane and the kinase. It is the type I receptor's identity and is absent on type II. The switch shifts between two positions. Unphosphorylated, it folds back against the kinase and holds it shut. Phosphorylated, it becomes the dock where the signal lands. There is even a guard on the off position, a small protein that sits on the unphosphorylated box and keeps the type II kinase from firing it by accident. That is where the FOP mutation landed.
Nobody needed an experiment after that. The location alone gave the answer. The mutation is in the brake, and a mutation in a brake releases the brake. It was not even a guess. Eleven years earlier, point mutations in this same box in a different type I receptor had been shown to make it fire with no ligand present. By 1999 a permanently switched-on version of this very receptor, built the same way, was a standard reagent in labs. Nobody had to invent anything to believe the FOP mutation switched the receptor on.
The mutation landed in the one part of the receptor the field knew best, and that is what made everyone so confident about what it was doing. What the field knew was the job of the domain the mutation was sitting on. Not the mutation itself. Knowing what a brake does lets you form a hypothesis about the mutation in it. That is not a finding about the mutation. So the gap is not ignorance. They knew a great deal, and it was exactly enough to stop asking questions. There was a second blind spot underneath it. That part sits inside the cell, so all the attention went to what happens after a ligand has already docked on the outside. Nobody had a reason to ask what the receptor was answering to in the first place. So the answer was near unanimous, and it was the only one this stretch of the protein could ever have produced: the mutation made the receptor fire on its own.
The GS domain mutation that the field had been using as a reagent in labs is Q207D, and that is how it is referred to. The mutation swaps glutamine, an uncharged amino acid, for an aspartate, a negatively charged one, at position 207, right next to the FOP mutation. The mutation was not built with FOP in mind, and it could not have been. It was built years before anyone knew the disease had anything to do with this gene, for an ordinary reason. If you want to know what a cell does when this pathway is running, the simplest way is to hand the cell a version of the receptor that is running all the time, and watch. Q207D was that version, made by copying onto this receptor the trick that had already worked on its relative.
The FOP mutation, R206H, sits one residue away from the reagent Q207D, side by side in the same short box. So when the FOP mutation was published in 2006, it arrived one letter away from a spot that the field had been deliberately mutating for years to force the receptor constitutively on. So, the disease mutation looked like the lab's own switch, made by nature.
The amino acid swaps in the two adjacent mutations though are not the same. The amino acid swap in Q207D adds negative charge, mimicking the effect of phosphorylation. That is why Q207D makes the receptor behave as though the type II kinase has already fired at it. R206H is different: it puts no negative charge, and it imitates no phosphate. The 2006 paper's own modelling claimed only that the amino acid change makes a short helix less stable, and this might loosen the guard protein's grip. Same neighbourhood, different logic.
Any residual doubt the field had about reading the FOP mutation's mechanism from Q207D was cleared when a real FOP patient5 with a mutation on exactly the same residue as Q207D arrived in 2009. The patient carried the Q207E mutation, which swapped the same glutamine but this time for a glutamate (instead of aspartate in Q207D). Glutamate is also acidic, like aspartate. A natural version of the Q207D mutation, in a FOP patient, solidified the hypothesis that the classic FOP mutation made a constitutively active receptor.
A standard way to understand what a mutation does to a protein is to go to the protein's three dimensional structure, and you look at where the changed amino acid sits and what it is touching. The field had such a picture, but it was not of ACVR1. No structure of ACVR1 existed then, and none would for years. What they had was the crystal structure of a relative protein from the other branch of the family, solved in 1999, and it covered only the half of the protein that hangs inside the cell. The half that binds the ligand was not in it.
Everything the field knew about the brake came from that one picture: the box folded back against the kinase and holding it shut, the small guard protein sitting on top of it, the phosphates that the folded shape cannot accommodate so that it has to let go, activating the kinase. Infusing this structural insight into ACVR1 was reasonable as inside the cell these receptors are built alike and share the mechanics.
Everything looks good until you go back to the original structure reference paper and see what it says about the Q207D reagent mutation. It says explicitly that the residue the Q207D reagent copies sits well away from the folded loop and working centre of the kinase, and that its role in switching the receptor on is not apparent from the structure. So, the structure didn't explain even the reagent mutation, let alone the FOP one. Yet, the field anchored its hypothesis on this reference.
In 2008, the constitutive activation hypothesis got another layer of support from experimental data. The FOP mutation was for the first time observed in the living cells, connective tissue cells from FOP patients cultured in a dish. The cells signalled with no ligand added to them. Emphasis on the term 'added', as we will come back to this experiment soon. So the hypothesis was no longer a guess but a real one with empirical support.
Then six years later somebody put the receptors carrying the three mutations, the reagent Q207D and the two FOP mutations R206H and Q207E, side by side and tested them. The reagent mutation turned out to be far more active than the other two. The Q207E that shared the same residue as the reagent behaved more like the classic FOP mutation than the reagent one. And of the three, only the engineered one signalled with nothing supplied to it. The authors wrote that the reagent has severe limitations as a model for FOP. That was the first hit to the sand castle that the field was building on the foundation of a reagent mutation for the past eight years. But the real blow that would shatter the castle came a year later from a company that was not working on anything related to this question at all.
The hypothesis turned out not only to have cracks all over it, but also holes. The field either turned a blind eye to them, or acknowledged them and went on holding the hypothesis anyway. A receptor that fires on its own fires wherever it sits. Every cell in the body carries the gene for this one, from conception. So the model would predict bone forming in many places at once and never stopping. However, in the real world, the disease is quiet for years, then one flare, in one place, usually after an injury, then quiet again. It is there in the earliest record of the disease, written down by Freke in 1740: a boy of healthy look, whose swellings had begun three years before he was seen at fourteen.
Then there is a second hole, and it is nowhere near bone. ACVR1 has another job, in the liver, where it drives the production of hepcidin, the hormone that sets how much iron the body takes in. Push that pathway up and iron absorption falls, which is why people born without working copies of TMPRSS6, a brake on that same pathway, are anaemic for life. A receptor that is on all the time would have made FOP a disease of chronic anaemia as well as a disease of bone. Chronic anaemia is not a clinical feature of FOP.
The mechanism
Aris Economides from Regeneron had been standing near this disease for years when the hypothesis took its final shape. He entered the room in 2008 as part of the jury when noggin was under trial. Noggin had been his subject since he arrived at Regeneron in 1993, and noggin works by taking a signal out of circulation from outside the cell, never by touching a receptor. That was the kind of thing he knew how to do.
After ACVR1 was discovered to be the FOP-causing gene, Regeneron decided to go after it with an antibody. The gene appeared as a target of the right shape: a receptor sitting in the membrane with a piece of itself hanging outside the cell, washed by the fluid outside, and that is something antibodies travelling in the blood can grip. But the hypothesis the field was holding on to said the receptor fires by itself, with nothing bound to it. If that was the case, there is nothing a Regeneron antibody from outside the cell can do, and the programme is dead before it started.
So Regeneron was left with no choice but to test the hypothesis that had stood since the gene was found, and that nobody had needed to check, because until then nothing depended on the answer. And they would not do it in a dish, because nobody knew which cell in the body makes the heterotopic bone, and an assay has to be run in some cell. Pick the wrong cell, and a clean answer would mean nothing. So, it was clear. The experiment had to run in a living animal.
A living animal with FOP in every cell could not exist. Put the mutation into a mouse and the mouse dies at birth. The same single letter that people live with for decades is lethal to a mouse. So the experiment needed a different animal: one in which the mutation appears only after the mouse is grown.
Regeneron built it. The mutated stretch of the gene was installed backwards on the opposite strand, where it cannot be read at all. And a normal copy of the gene was put in its place so that the animal develops as an ordinary mouse. Alongside it is placed a Cre-lox system, a standard piece of mouse engineering that cuts and flips marked pieces of DNA on command. Give a grown mouse a dose of tamoxifen and the switch is thrown: the normal copy comes out, the mutated stretch turns around in the right direction, and from that moment the animal is reading the mutated version of the gene.
That solved two problems at once. First, the breeding animals never have the switch thrown, so they remain healthy and propagate the colony. Second, the animals that are switched on are adults, and they behave like patients. Injure a muscle, bone forms in it.
Now that the FOP animal model existed, Regeneron asked the question the field had gone nine years without settling: does the FOP receptor need a ligand to fire? One way to test it is to take away the ligand and see whether the disease still happens. Rather than guessing which ligand to take away, Regeneron just mopped every ligand this receptor could be answering to out of the tissue using a decoy, which was the ligand-binding part of a type II receptor fused to an antibody tail. It floats in the space between cells and catches ligands before they reach a real receptor, and never the receptor itself, which is left whole, kinase and mutation included. To cover all the ligands, they used the broadest decoys they had, ACVR2A and ACVR2B, broad enough that the answer could not escape them, without yet suspecting what the answer was.
Given to the mice before the injury, it blocked heterotopic bone completely. Not less bone. Just none. A receptor that fires on its own fires whether or not anything is there to bind it, so emptying the space around it should have changed nothing at all.
The animal experiment proved that the FOP receptor does not fire on its own, and that it needs a ligand to switch it on. Regeneron then settled the evidence from the past, the patient cells in a dish that had signalled when no ligand was added. No ligand added is not the same as no ligand present. It turns out cells secrete ligands of their own into the medium, and the serum they are fed brings more. The hypothesis that had survived nine years despite the cracks and the holes was finally shattered, by a company that had entered the FOP field through a side door.
The catch-all trap had answered one question and produced another. Having proved that the receptor needs a ligand after all to fire, the next question was which ligand. Two things pointed at activin A. The first is that unlike BMPs6, activin A is not a resident protein sitting quietly in tissue. It is released at damage, by inflammation and repair, which is exactly when and where FOP makes bone. The second was it is right there in the receptor's name: activin A receptor, type I (ACVR1), treated as a misnomer for the two decades since 1993. The answer to the question had been hiding in plain sight.
Two experiments in the FOP mouse settled the answer. Activin A soaked on to a scaffold and implanted into muscle turned to bone. In their normal littermates, the implant did nothing at all. Then the reverse: an antibody that mops activin A out of the tissue, given before the injury, fully prevented the bone formation7. Activin A was enough to cause the disease, and blocking it was enough to stop the disease8.
The antibody used in that mouse experiment was REGN2477, also called garetosmab, the very molecule the FDA approved eleven years later. The antibody was never made for this purpose. It came from a muscle programme at Regeneron that had nothing to do with bone, and it was brought in as a reagent for the experiment, which then turned into a drug.
So, a single letter change in the ACVR1 sequence made the receptor answer a ligand it normally does not. The mutation did not take away anything from the receptor. It still answers BMP exactly as it always did. But it also answers a member of the other branch, a stranger to bone signalling. Note, activin always binds the normal receptor, and that is how ACVR1 got its name in the first place. It just does not fire the signal inside the cell, and that is the new power the receptor received from the mutation.
Why should a ligand from one branch of the family fit a receptor from the other in the first place? Because of the homology the whole family was built on. The parts are variations of a single blueprint, so they still dock across the branch line. What was missing was permission to pass the signal on, and that permission is held in the very stretch where the FOP mutation sits. Tweaking it miswires the two branches of the family.
The drug
When the right target landed, things picked up speed. What normally follows a successful identification of a target is the lead discovery programme. Screen candidates, pick a lead, optimise it, and then some years later something is ready to go into humans. None of that happened here. The antibody already existed, from a muscle programme that had nothing to do with bone, and the experiment that identified activin A had used that same molecule.
So there was nothing left to design. The molecule that discovered the target is the one that went forward against that same target, on the same logic, read out on the same thing. Phase 1 opened in healthy volunteers in July 2016, the first FOP patient was dosed in February 2018. Under three years from a mouse to a human.
The only thing that changed after that was the name: REGN2477 to garetosmab (brand name: Pasatru).
Note, Regeneron's original plan was different. It came into FOP with the intention to develop an antibody against ACVR1 itself, and the whole ligand question had been forced by that intention. Now that the receptor was known to need a ligand to fire, there was every reason to go back to the original plan. In fact, several groups built antibodies against ACVR1, including Regeneron. But then came a surprise.
In cells the ACVR1 antibodies did what they were designed to do. They sat on the receptor and shut the signal down, on the normal receptor and FOP receptor alike.
In the mice they did the opposite. The treated animals made more heterotopic bone than the untreated ones. And they went on making it even when activin A was blocked, which should have left nothing to drive the receptor at all. It turned out the antibody had not just failed to block the receptor. It had taken over the ligand's role.
The fault turned out to be the shape of the molecule, not the part of the receptor it latches on to. A bivalent antibody has two arms, which grip two receptors at once, bringing them together. And for the FOP receptor being held together is itself the activating event. No ligand required. Make the antibody with a single arm and it blocks the receptor exactly as intended. That is a harder molecule to turn into a medicine, and there was no reason to take it on, because the antibody against the ligand was already working.
The surprise also settled something about how these receptors sit on a cell. If a ligand had to gather four receptors into a complex, then an antibody clamping two type I receptors together would achieve nothing, because the type II receptors that trigger the firing would still be away. It appeared that they were not away. The type I and II receptors are already together before any ligand arrives. The ligand does not build the complex. It simply rearranges the complex that is already assembled.
This new insight makes the field's old answer look better now than it has appeared before. So, the receptor was never idle. It was always assembled, always poised, but held shut. R206H did not switch it on by itself. But it lowered the bar for what counts as a legitimate nudge. Activin A clears that bar. So does a Y-shaped protein that happens to grab two receptors at once.
A receptor is a family property. Seven type I receptors are built on one plan, the same resemblance that assembled this family in the first place, with the same switch region inside the cell and the same partners reading them. So anything aimed at ACVR1 is aimed at a shape its relatives carry too. That is the standing problem with the small molecules: the kinase you want to shut down looks similar to the kinase on the other receptors that you don't want to disturb.
A receptor is also a machine, and the ACVR1 antibody experiment had just shown what could go wrong when you target a machine. Taking hold of a machine, you can accidentally start it instead of shutting it down. That is a risk you take on the moment you aim at the receptor.
A ligand is neither. It is cargo. Clamp cargo and nothing fires, because there is nothing in it to fire. A cargo is the part of the system that is not shared. The mutation of course sits in the receptor that's everywhere, but what makes the disease appear in a specific place after an injury is a single molecule that turns up at damage. That is the part a drug can aim at without hitting anything else.
None of this is a new idea. Noggin does exactly this. It never touches a receptor. It wraps the BMP itself and hides the two surfaces the receptors would have to reach, so nothing ever fires. Sequestration is the whole of it.
And there is a last turn in that. Noggin holds down BMPs, and only BMPs. It does not touch activin A. So the protein the field chased for seven years as the cause of FOP could never have treated it. What carried across was the principle: take the ligand out of circulation and leave the machinery alone.
Looking back it is hard to miss. The man who had spent fifteen years taking BMP ligands out of circulation walked into a receptor disease and solved it by taking a ligand out of circulation.
The first real test in patients was LUMINA-1. A phase 2 trial in 44 adults with FOP, garetosmab against placebo for twenty eight weeks. The first patient was dosed in February 2018.
It missed. The primary endpoint was the change in total lesion activity on a PET scan, meaning every active site in the body added together, the heterotopic bone a patient already had when they enrolled in the trial plus anything new they developed after the enrolment. Garetosmab came out 24.6% below placebo, and the p value was 0.07.
The endpoint was counting bone the drug was never going to remove. Garetosmab stops new bone from forming, it does not dissolve bone that is already there. It was something the mice experiments had shown before. Dose the animals three weeks after the injury, formed lesions stopped growing and new ones stopped appearing, but only a few of the smallest ones shrank.
Separate the two kinds of bone and the drug effect appears. Counting only lesions that were not there at the start, the PET scans found 29 in the placebo group and 3 in the treated group. The crossover made the same point: the placebo patients who carried on into the second period had produced 23 new lesions between them, and just one after they moved to garetosmab.
It was a post-hoc analysis, after the primary endpoint failure. It cannot rescue the completed trial, but it presented the clearest evidence to support a fresh trial.
The phase 3 trial, OPTIMA, was launched with the revised primary endpoint. The PET activity measure was dropped altogether and instead a simpler method was chosen: a whole-body CT scan, one at the start and one at the end, and count the lesions that were not there at the start.
63 patients, 56 weeks, placebo against two doses. The placebo group developed 19 new lesions, the high dose group (the dose that was eventually approved) produced two. That's a 90% reduction9, strikingly similar to the post-hoc result from the LUMINA-1 trial. The drug had produced the same result twice. Regeneron also reported a post-hoc analysis counting lesion volume rather than lesion count, which showed a 99% reduction, the number quoted in the press-release.
OPTIMA has still not been published, so every number above comes from the company's release and the FDA's approval announcement.
The treatment comes with a trade-off, which is the consequence of cutting activin A's ordinary functions. Patients lose their eyebrows and eyelashes. They get acne, boils, infected nail folds, extra hair growth in other places, mouth ulcers and nosebleeds. The infections in that list are not a cosmetic matter. There were more of them at the higher dose, and they are printed on the label as a warning, because an abscess or a cellulitis can need treating in hospital. And the drug comes with a second warning, which is the oldest fact about activin A in this story arriving last. Nobody should be on this drug while pregnant, because activin A is a reproductive hormone, and that is why the first trial of the molecule in humans enrolled only women who could not become pregnant.
The approval is only for adults for now, because the trials enrolled only adults. However, the disease does not wait for adulthood. Whatever has formed before a patient turns eighteen and becomes eligible for the drug is permanent. So the version that would come closest to a real cure is the one yet to be demonstrated in a trial: give it in childhood, before the first flare, while the child still has everything to keep.
Some thoughts
Everyone says drug development is hard. It is one of those sentences repeated so often that it has stopped carrying any meaning. What is rarer is to hear someone say which part is hard. There are many hard parts, the money, the manufacturing, the trials, the regulators. But you know what, the hardest of them, in my personal opinion, is the biology.
Evolution has had hundreds of thousands and sometimes millions of years to get a job done, often perfectly. Then something goes wrong inside one of those processes, and a person falls ill, and we arrive with a mere couple of decades of studies and a great deal of confidence about what the fault is and how to fix it. It is almost never that simple.
Understanding a piece of biology takes more than one person, more than one field, and more than one period of time. Parts have to come together before the biology decides to reveal itself. The story I have just told is an unusually clean example of that, and let's retrace its shape one last time.
Start with the receptor, because the biology in this story turns out to be a decent picture of the story itself.
The complex was never taken apart and put back together. It sat on the surface of the cell already assembled, all components in place, poised but held shut. Nothing was missing except the permission for the signal to pass, and the mutation supplied that by lowering the bar for what counted as a legitimate nudge.
The history has the same shape. By the time anyone could explain FOP, every part of the explanation had been lying in the literature for years. Activin A was isolated in 1986. ACVR1 was cloned in 1993 and named, correctly as it turned out, after activin. The BMP pathway was worked out through the 1990s. The families had been assembled and their DNA banked. Not one piece was missing.
So what was the ligand here? I think it was a person.
Aris did not start with a missing fact. He brought a position. He had been standing near the disease since 2008, and he arrived there through the wrong gene, as the noggin expert on a jury. He was inside a company that could make an antibody and build an engineered mouse. He happened to be at the right place at the right time in the right position. The assembled puzzle pieces were waiting for someone standing where he stood to see the shape.
So what to take from all of this?
Much of the work that took decades to solve could be solved in an evening today. For example sequencing of a handful of patients would have solved the variant discovery or some of the receptor or ligand biology would have fallen out of a high-throughput screen. That is all true, but it is not the take-home.
The take-home is the shape of the puzzle and what it took to solve it. I don't think that will change in time. Today's hard problem is some other thing that today's technology cannot touch, and in ten years it will look silly that people fiddled so long with what by then looks like trivial biology. How hard a problem is depends entirely on from where you look at it. What remains the same is the concept of the problem and what solving it demands.
And what it demands is never one thing. It is not a single bottleneck. It is not about just missing data or a missing understanding. Many things have to arrive together, and sometimes the problem itself remains invisible until it becomes obvious for someone to acknowledge it.
There is a saying that fits this. When it is time, it will happen. Until then it will not, however hard anyone goes at it. I half believe that. This story gives the counterexample. The field had the right pathway for ten years and spent them searching the wrong genes. Everything needed was already there and nothing happened. Readiness on its own is not enough. Someone has to be standing there when the time comes.
Which is why I think serendipity and coincidence are in the blood of biological problem solving, and I do not think they can be taken out of it.
The question in the air is whether AI will solve biology and hand us the cures. I think biology is humbling, and that statement is about the subject rather than the tools. Plenty of bottlenecks will be solved by brute-force compute, including the ones this story ran into. Structure prediction, screening, even reading a literature that no one person can hold all in their head, all of that is real and it will help.
But go back in this story to those ten years. There was no shortage of effort or hands. If you had given the field a thousand times the person-hours, you would have got a thousand times as many searches of the wrong genes, finished sooner. The measurement they were building on was correct. The pathway was correct. The node was wrong, and nothing inside the work they were doing was going to tell them so.
That is the part I am not sure if one can automate. Intelligent machines multiply whatever you are already doing. They do not tell you that what you are doing is aimed at the wrong place. And the step that actually solved the FOP puzzle was not a search at all. Nobody solved FOP by looking harder. What it needed was somebody able to take a step back and notice that the frame through which the problem was being looked at was wrong. That comes out of plain curiosity and from coincidence putting a curious person in front of something that needs solving. Ambition, money, a prize, a wish to do good, all of those can be drivers. I do not think any of them is the engine.
One last thing, about me.
I have no stake in this disease. No one I know personally has it, and none of my research work has been on this topic. I worked at a company where this was happening and I knew the person who drove this programme as a colleague with whom I interacted only occasionally. And that coincidence pulled me into this topic.
I have spent more time on this piece than on anything that I have written. And it was out of nothing but curiosity. I am glad I did. I am leaving it with something that I did not have before: a view of a drug programme from end to end, and a feel for how a biological problem actually gets taken apart. You get that not from reading a paper, but following a question until you find all the answers.
I intend to do more of these on GWAS stories. Long form writing teaches me far more than short form does. It also forces me out of the small pond I have been swimming in, and makes me look at the world beyond it, so I can put what I know and what I do not know in a better context.
I wrote at the start that I wish I had done this homework while I was still there at Regeneron, so I could have got a first-hand account of the story from the people who drove the programme. But come to think of it, all those years the whole story was sitting right beside me, and I never took notice. It took a nudge, a press release on the FDA approval, to finally make me look.
The first was Sohonos (palovarotene), an oral drug approved in August 2023. It is less effective, and it carries a boxed warning that it closes the growth plates in growing children.
Urist was not the first to put demineralised bone into an animal. Nicolas Senn had done it in 1889, believing the acid sterilised the graft for infected patients. What Urist added was a bioassay: the same preparation, across several species, with a dose and a time course, giving the same answer every time.
Here it is the G that changes, not the C, because the C doing the decaying is the one on the opposite strand.
Not quite every patient carries this one change. A small number, whose disease takes an unusual form, carry other mutations in the same gene. None of those recurs the way this one does.
He is one of the small number of patients mentioned earlier who carry a different mutation in the same gene. His disease has the classic features and some atypical ones besides.
If you wonder why a BMP was not the obvious suspect for the ligand that drives the disease, it is because BMPs are present everywhere, all the time. So a BMP explanation would need a separate reason why bone appears only after an injury and only in specific places.
The earlier footnote said a BMP explanation would need a separate reason why bone appears only after an injury. That reason does exist. Bone needs more than a signal, it needs cells at the site ready to answer one, and something about an injury prepares them. The requirement holds however the receptor is driven, so on that ground alone a BMP could still be proposed as the driver. This experiment is what rejects it. Every BMP was left where it was, only activin A was taken away, and no bone formed.
The same answer arrived twice that year. At Kyoto, Toguchida's group took cells from FOP patients, turned them back into stem cells and then into connective tissue cells, and asked the same question in a dish, with no mouse anywhere. They got what Regeneron got. Their word for it is still the best one anybody has offered: neofunction.
The result cleared statistical significance, but only with a p value of 0.03. It is not a sign of a weak drug, it is just the size of the trial. With 63 patients counting events this rare, even a large effect has little margin to spare against the threshold.