The wild success of the Ice Bucket Challenge, one of the past decade’s feel-good social-media sensations, obscured its origins as a form of extortion. Its source, though murky, might be traced to Norway, where early nominees were pressured to choose between jumping into a frigid body of water and taking care of the weekend’s bar tab. By early 2014, the moral ante had been upped: the penalty for noncompliance became, rather more nobly, a contribution to medical research. This structure—which incentivized bravado at the expense of charity—persisted until the spring, when American firefighters helped repackage the experience. Now a high-pressure hosing was the reward for a donation to a colleague’s cause of choice. That July, a golfer decanted water on his own head in an effort to cheer up his cousin’s husband, who had amyotrophic lateral sclerosis, or A.L.S., and invited others to donate to the “A.L.S. Foundation.” By the end of the month, the idea, now connected to one disease, had taken on a life of its own. Bill Gates engineered an elaborate self-soaking contraption, posted high-definition footage, and challenged Elon Musk. The taunt was at once socially contagious, righteous, and fun. But there were still some disposed to see it as a threat. President Barack Obama, when drafted by Ethel Kennedy, Justin Bieber, and Donald Trump, declined in favor of a hundred-dollar contribution to A.L.S. research.
Organizations dedicated to A.L.S., unaccustomed to such largesse, were dumbfounded. At any given time, some thirty thousand Americans have the disease, which is characterized by a continuous loss of motor neurons until muscle function stills. Sustained patient-advocacy campaigns are limited by the fact that no one survives. As Gwen Petersen, a thirty-seven-year-old patient, told me, “There were the usual fund-raising walks, but asking an A.L.S. patient to walk is kind of tone-deaf.” Merit Cudkowicz, the chair of neurology at Massachusetts General Hospital, said, “Patients are generally so overwhelmed with the day-to-day of their lives that the patient voice and advocacy were missing. And then it happened, and it’s been very powerful, in mostly a really good way.” In the pre-Challenge era, research was largely fruitless; the only drug on the market had been approved in 1995. But the viral campaign generated two hundred million dollars in aggregate donations, and one clinician hailed a “new era” in which she could “talk to patients with more hope.” There was, in fact, no such thing as the “A.L.S. Foundation,” but the assets of the A.L.S. Association, the top search result, grew fivefold, to a hundred and thirty million dollars. The group tripled its allocation to research.
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One company working on the problem was a Cambridge-based startup called Amylyx, which traced its origins to a frat house at Brown University. In early 2013, Josh Cohen, an appealingly dishevelled junior, had an idea for a mechanism to slow the progression of degenerative diseases such as Alzheimer’s and Parkinson’s. Reading around in the literature, he struck upon studies of two known compounds that seemed to suit his notion. One was a generic drug for urea-cycle disorders. The other was an acid found in bear bile, which is a mainstay of Chinese medicine; it can be bought on Amazon for thirty-seven cents a pill. Late one evening, Cohen ran into a fraternity brother named Justin Klee, who asked him why he looked so unwell. Cohen told Klee that he’d been spending his nights researching whether these two molecules might, in combination, prevent neuron death. Within a day or two, they’d decided to start a company.
The pair had almost no idea what they were doing, but a prominent Alzheimer’s researcher agreed to collaborate—if only to show two endearing college kids how difficult research really was. To his surprise, initial experiments returned positive results. Potential investors, however, were skittish. As Cohen told me, “There had recently been a long spate of failures in Alzheimer’s, and we were just these two young guys.” As the Ice Bucket Challenge became ubiquitous, they chanced to get a meeting with Cudkowicz. She had recently run her own trial with one of the compounds, but there is little commercial incentive to study generics, and she couldn’t secure the funding to continue. Cohen and Klee, however, had already obtained a patent for their two-drug combination, which they called AMX0035. Cudkowicz persuaded them to pivot to A.L.S.
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Their decision was in part emotional. Klee told me that they were struck by the selflessness of A.L.S. patients in trials: “You hear so often, ‘I know this may not help me, but I’m doing this for the people who get the diagnosis after me.’ ” But the new focus also made practical sense. Alzheimer’s trials each involve thousands of patients, but those for A.L.S., which is rarer, might enroll only a few hundred. Cudkowicz co-chaired a research organization that offered Amylyx a ready-made trial infrastructure. Advocacy groups were looking to distribute their Ice Bucket money, and Amylyx collected a grant from the A.L.S. Association and A.L.S. Finding a Cure. Substantial investor capital followed. One of the company’s largest funders was a Dutch biotech entrepreneur named Henri Termeer, who demonstrated that rare diseases could be rendered profitable—as long as payers would tolerate high prices. Amylyx began a Phase II study that followed a hundred and thirty-seven patients for six months, with a subsequent “open-label extension,” during which all trial participants could receive the drug for free. When the results came back, Cohen and Klee called the Alzheimer’s researcher, after midnight, and told him to pour himself a drink. “They didn’t say anything about money,” he has said. “They told me, ‘Guess what: Amylyx is going to help A.L.S. patients.’ ”
According to a study published in 2020, AMX0035 seemed to slow patients’ decline by about twenty-five per cent during the trial period. A later finding gave even greater reason for optimism: in the trial’s extension, those who never got the placebo in the first place survived an average of five months longer. The drug had few side effects, apart from some gastrointestinal distress. Cudkowicz told me, “You get so used to things not working out that you try to shield yourself from disappointment, and it was just amazing that their idea worked.” Still, the results were not unambiguous. In an editorial, two outside researchers advised that the “tantalizing preliminary data” be interpreted with restraint: the effect was “modest,” and a larger trial would be needed as confirmation. Cudkowicz concurred. “We did not design this study to be the single study for F.D.A. approval,” she said.
Historically, the F.D.A. has required two “adequate” trials before it approves a drug. In Amylyx’s case, a subsequent trial was likely to take three more years. The A.L.S. community, however, felt that there was no time to waste. The majority of current patients would be incapacitated or dead if they had to wait that long. Dr. Neil Thakur, the A.L.S. Association’s chief mission officer, observed on the organization’s podcast that the study’s results were “not a slam dunk.” “The findings aren’t as strong as what the F.D.A. typically does to skip a Phase III trial,” he said. “So I think they’re going to need some help to make that decision.” Advocacy groups began to mobilize. Brian Wallach, a forty-two-year-old who had co-founded a young organization called I AM A.L.S., believed that his life and those of thousands of fellow-sufferers hung in the balance. “Please do not let another generation of A.L.S. patients die in pursuit of the perfect,” he later told regulators. “We want to live. You have the power to make that possible.”
Drug regulation in America has been driven by public calamity. In 1937, a company in Tennessee sold Elixir Sulfanilamide as a remedy for streptococcal infections. The active ingredient had been dissolved in a chemical used in antifreeze, and a hundred people died, many of them children. The Food and Drug Administration, which had been feeble since its founding decades earlier, was empowered to insure that drugs weren’t needlessly harmful before they could be sold. Nevertheless, useless potions proliferated. In 1961, at the National Congress on Medical Quackery, the U.S. Secretary of Health, Education, and Welfare pointed out that, along with actual snake oils and other nostrums, bottled seawater was being sold for up to twenty dollars a gallon as a “panacea for virtually all human ailments.” Soon after, the antiemetic thalidomide was determined to cause severe birth defects overseas. One F.D.A. official had steadfastly resisted corporate pressure to approve it, and public confidence in the institution swelled. Congress radically expanded the agency’s mandate, granting it authority over not only safety but also efficacy.
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In the next decade, though, free-market pundits and economists increasingly saw the F.D.A. as an example of excessive regulation. The average development times for drugs had grown considerably, and fewer were coming on the market. Some critics attributed this decline in pharmaceutical dynamism to the perverse incentives of the career bureaucrat. There were, they pointed out, two primary kinds of errors that regulators might make. They might approve a product that turned out to be unsafe—as they did in 1976, when they signed off on a swine-flu vaccine that, in some cases, led to paralysis—and face the public’s wrath. Or they might fail to act quickly on a drug that later proved effective—as in the case of beta-blockers, which were available in Europe years before they were deemed fit for consumption in the U.S. The first kind of error, a so-called Type I error, was conspicuous, and thus likely to be corrected. But the second kind, a Type II error, had no natural constituency to demand redress. The libertarian economist Alex Tabarrok came to describe these victims as interred in the “invisible graveyard.”
On October 11, 1988, members of ACT UP, a newly formed coalition of AIDS activists, stormed the F.D.A.’s headquarters, then in Rockville, Maryland. In the midst of the H.I.V. epidemic, a lengthy drug-approval process seemed unconscionable. Gregg Gonsalves, a former member of ACT UP, told me, “People came up to me in ACT UP meetings and asked if there was a drug that could help with one opportunistic infection or another. There was nothing for them. And to say that out loud is hard.” The group’s members didn’t want to be told what risks they could take. Richard Klein, a retired F.D.A. official, told me, “A guy called me up, and he was really angry that he couldn’t use whatever H.I.V. therapy from Mexico he wanted to get. He said, ‘I can go to Vegas and gamble away my last nickel and nobody would say anything about that, but this is my life—why can’t I gamble with it?’ ”
As the historian Lewis A. Grossman notes in his excellent book “Choose Your Medicine,” previous generations of activists had focussed on a patient’s right to have a say in her care. In one study in the nineteen-sixties, about half of doctors surveyed thought that it was medically acceptable to perform a mastectomy on an unconscious woman without her explicit consent. In a 1970 Senate hearing on the safety of oral contraceptives, every member of the proceedings was a man. The women’s-health movement changed all of this.
For some activists, the emphasis on autonomy included promoting unorthodox treatments—rejecting chemotherapy in favor of, say, apricot kernels. What distinguished ACT UP was its longing for access to the products of the “government-industrial-academic biomedical complex.” Protesters outside the F.D.A. building wore white lab coats stained with fake blood; others held a die-in, with cardboard gravestones bearing epitaphs like “I Died for the Sins of FDA.” This sentiment brought AIDS activists into uneasy alignment with the right. Grossman describes a surreal episode of “Crossfire” that aired just hours after the protest. The guests were the AIDS activist Peter Staley, who had worn a “Karate Kid” bandanna and scaled the F.D.A. building’s façade to hang a “Silence = Death” banner, and Pat Buchanan, whose recent memoir had described Gay Pride Week as a “celebration of sodomy.” Buchanan said, “Mr. Staley, this is going to astonish you, but I agree with you a hundred per cent. I think if someone’s got AIDS and someone wants to take a drug, it’s their life, and if it gives him hope he ought to be able to take it.”
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