My husband and I took our kids to see Coyote vs. Acme this weekend. I went in expecting a new storyline from a cartoon I loved as a kid. I came out thinking about drug development, which I realize is not the normal reaction to ninety minutes of Looney Tunes.
We went to one of those theaters with reclining seats and allegedly fresh popcorn delivered to your chair. Our boys loved the movie. So did I. But somewhere along the way, my mind wandered.
The story behind the film is fairly well known at this point. Warner Bros. finished it in 2023 and then decided not to release it—not because it tested badly, but because the studio concluded that taking a tax write-off made more financial sense than putting a movie it had already spent tens of millions making into theaters. So the film went on a shelf. Three years later, another company bought it and released it.
The movie wasn’t the problem. The math was.
And that’s when I started thinking about healthcare.
We hear versions of this all the time: somewhere there are shelves full of treatments and cures being hidden from us. There aren’t. Drug companies are not warehouses stacked with cures they refuse to sell. Most experimental drugs that disappear from development disappear for the most mundane and important reason imaginable: they don’t work.
Biology is hard. Clinical trials fail. A molecule that looks brilliant in a lab can turn out to be useless in a human being. Anyone who tells you the cure for your disease is sitting in a freezer because a company doesn’t want you to have it is leaving a lot of the story on the board.
But healthcare does have shelves.
And some things land there even when the science hasn’t failed.
A therapy that was donated rather than discarded
Methylmalonic acidemia is a rare inherited metabolic disease. Children with it can’t properly break down certain proteins and fats, so toxic byproducts accumulate in the body. It brings metabolic crises, kidney disease, neurological damage, and for some children, eventually a liver or kidney transplant. There is no approved treatment that addresses the underlying cause.
For years, a company had been developing a gene therapy for it, designed to deliver a working copy of the defective gene. The program got orphan drug and rare pediatric disease designations. It cleared regulatory review. It reached the point of screening patients for a first-in-human trial.
Then, in 2023, the company stopped.
The therapy hadn’t failed. There were no disappointing results, because no patient had ever received it. The company discontinued the program for commercial reasons and withdrew its application to test the therapy in people.
That could easily have been the end of it. Instead, the company donated what it had — the manufactured therapy, the reagents, the regulatory materials — to the National Institutes of Health, where researchers had been partners on the work from the beginning. Investigators at the National Human Genome Research Institute and the National Center for Advancing Translational Sciences picked the program up, did the additional development work, redesigned the clinical plan, and went back to the FDA.
On May 8 of this year, the FDA cleared the therapy to begin a Phase I/II trial at the NIH Clinical Center.
It is not a cure that somebody buried. It is not even a proven treatment. It is an experimental therapy about to be tested in a small number of children for the first time, and it may well fail, as experimental therapies routinely do.
That’s the part I can’t get past. The scientific question almost never got asked because the commercial question had already been answered.
For one owner, continuing no longer made economic sense. For another, the unanswered question itself was reason enough to keep going.
The biology hadn’t changed. The math had.
Everybody can sell it. Nobody owns the evidence.
That story is one version of the problem. There’s a larger and less dramatic one.
Medicines that are already approved, already manufactured, already prescribed to thousands of people are sometimes found to have promise in diseases entirely unrelated to the ones they were developed for. This is called drug repurposing, and on paper it sounds almost absurdly sensible. If we already understand a drug’s chemistry, its manufacturing, its behavior in the human body, and a great deal about its safety, why wouldn’t we investigate every condition where credible evidence suggests it might help?
Sometimes we do. Often we don’t, and the reason is usually economic rather than scientific.
Once a medicine loses patent protection and inexpensive generics arrive, the question of who will spend millions of dollars proving it treats another disease becomes genuinely hard to answer. The original manufacturer may no longer have enough upside to justify the expense. Generic manufacturers compete on price and are not in the business of financing clinical development. Everybody can sell the medicine, which can mean nobody owns the evidence.
Nineteen years
Alkaptonuria is an extraordinarily rare inherited disorder — something on the order of one in a hundred thousand to one in a quarter million people. Patients accumulate a substance called homogentisic acid over the course of their lives, and it slowly damages connective tissue, producing severe arthritis, joint replacements, and complications in the heart and kidneys. For most of medical history there was nothing to offer beyond managing the damage.
But there was an existing medicine, already in use for a different rare metabolic disorder, that researchers found could dramatically reduce the substance that accumulates in alkaptonuria. The molecule wasn’t new. The mechanism wasn’t new. The hard part was proving what a known drug could do for a different group of patients.
The pivotal study was run inside the NIH’s intramural program. Forty patients. Three years of treatment against no treatment. It enrolled between April 2005 and March 2006, and it found improvements in pain, energy, and physical functioning alongside a greater than ninety-five percent reduction in the acid driving the disease.
It worked. And eventually a company willing to carry the application across the finish line took it up.
But look at the timeline.
Nineteen years.
Academic researchers, patient advocates, publicly funded investigators and eventually a commercial sponsor handed the work from one to another because no single party had both the capability and the incentive to carry it alone.
And even the win came narrow. The approved indication covers the reduction of urinary homogentisic acid in adults. Children with the same disease, whose joints have not yet been destroyed and who arguably have the most to gain from starting early, remain outside the label.
We built a remarkable system for rewarding the person who invents a medicine. We never really built one for the person who figures out what else that medicine can do.
The space between what medicine knows and what the system recognizes
There’s a third shelf, and patients live on it in much larger numbers.
Some therapies are used routinely, off-label, for conditions their labels don’t mention — supported by published evidence, endorsed by specialists, reflected in professional guidelines. Off-label doesn’t mean experimental or unsupported. But an FDA-approved label, an insurer’s coverage policy, and a physician’s medical judgment are three different things, and they don’t always point the same direction. A patient whose doctor believes a treatment is appropriate, and for whom evidence exists, and whose diagnosis simply doesn’t satisfy a payer’s criteria, ends up in the gap between them.
Which is the same question again, wearing different clothes. If a therapy is already on the market from multiple manufacturers, who has the incentive to fund the studies that would formalize every use for which it might be appropriate? Sometimes someone does. Often nobody does. And the patient waits in the space between what clinical medicine has learned and what our regulatory and payment systems formally acknowledge.
We talk about medical innovation as though it follows a sequence: discover something, test it, get it approved, get it covered, give it to patients. Anyone who has spent time around sick people knows it rarely works that neatly.
Sometimes a program loses its sponsor before anyone even gets the chance to find out whether it works. Sometimes doctors learn that an old generic may do something useful and nobody can figure out who should pay to prove it. Sometimes the drug works, but the approved dose is miserable to live with. And sometimes physicians are already using a therapy because the evidence is good enough for them, while the insurer is still staring at the label.
These aren’t really the same problem. But they keep leaving patients in the same place: waiting for somebody to own the next step.
Somebody at the FDA is asking too
In May, the FDA opened a formal request for public input on exactly this. The agency asked patients, clinicians, and researchers to identify approved drugs where scientific evidence could support new uses but, in its own phrasing, there appear to be limited commercial incentives to pursue them. Rare diseases were named among the priorities, alongside metabolic and neurodegenerative conditions.
The comment period closed in June, and whether the effort survives the agency’s current turbulence is an open question. But the framing was notable coming from a regulator, because it amounts to asking: what do we already have that could be doing more for patients, if only somebody had a reason to finish the work?
That’s the shelf I mean. It isn’t stocked with secret cures. It’s stocked with unanswered questions.
Could this generic medicine treat a rare disease? Could an effective treatment work at a dose people could actually tolerate for years? Maybe something approved for adults could help children. Maybe two existing drugs work better together. Maybe a different formulation solves the side effect that causes patients to quit treatment.
We can come up with the questions.
The harder one is: whose job is it to find out?
Back to the coyote
Since 1949 we have treated Wile E. Coyote as the joke. He orders another product from Acme, it malfunctions spectacularly, a rocket sends him into a canyon or an anvil finds his head, and he gets up and orders again. Watch it long enough and you start to wonder whether the fool in the arrangement is really the customer.
The film gives him something he never had in the cartoons, which is recourse. But I don’t want to dress that up into more than it is, because the movie itself refuses to. Wile E. doesn’t sue Acme out of some civic awakening about product liability. He sues because he is still, after all this time, trying to catch the bird, and a courtroom is the one place he can be certain the Road Runner will turn up. He builds a trap in the hearing room. That is the actual plan.
Then he doesn’t spring it. The Road Runner testifies that he saw what Wile E. endured, calls him a friend, and asks whether he’s coming back to the desert — and Coyote lets it go. The case is dismissed anyway, for insufficient evidence. What ends up mattering isn’t the verdict at all. It’s the crowd of other characters waiting outside afterward, having realized for the first time that filing was something they could do.
I’ve been turning that over all afternoon, because it describes the patients I work with better than any tidier version would. Patients who fight are not, as a rule, policy people who happened to get sick. They are people who want a specific thing for themselves or for their kid, and who learn the architecture of the system only because they crashed into it. Their motives are personal. Sometimes they are narrow. Occasionally they are not especially noble. That should not disqualify anyone.
A system that works only when the people it has already harmed arrive with pure intentions and unlimited stamina is not a working system.
The part I’m fixated on is the case that fails for lack of evidence — in an essay about who owns the work of producing evidence.
Patients ask versions of the coyote’s questions constantly. Why can’t I take this differently if the approved schedule is impossible to live with? Why isn’t this approved for my disease when doctors already use it for people like me? Why hasn’t anyone studied the combination? Why does my child have to wait years after adults get access? Why do we already know what to test next, and still have no one whose job it is to test it?
Those aren’t abstract questions. Each one requires somebody to do something: run a study, test a different schedule, develop a formulation, seek a label change, generate the evidence an insurer will accept.
And somebody has to pay for it.
That’s where the math comes back.
A company with a large approved use may have little reason to spend millions proving a much smaller one. If the next study involves two companies’ products, one may essentially be paying to increase the value of the other’s drug. If the medicine is already generic, there may be nobody left with enough financial incentive to sponsor the work at all.
None of that requires a villain.
The gap is ownership.
There’s an irony in the film nearly meeting the fate its own plot was built around. Someone made something. Someone else decided the economics didn’t justify letting people have it. It sat until a different owner ran a different calculation.
Medicine isn’t a movie. The science is infinitely harder and the stakes aren’t remotely comparable.
But I keep thinking about everything sitting one step short of an answer.
The drug we already know something about. The pediatric use nobody has studied. The better dose nobody owns. The combination involving two companies’ products. The rare disease too small to make the trial math work.
I don’t want less drug development. I want more of it. I want companies willing to bet billions on medicines that have never existed before, because patients need those bets to keep being made.
But maybe the next great problem in medicine isn’t only figuring out what we can invent.
Maybe it’s figuring out who is responsible for finishing what we’ve already started.
