Justin Klee and Josh Cohen had pulled off an improbable success, turning an idea they hashed out as undergraduates into a drug that aimed to slow one of the world’s most implacable and deadly neurological diseases.

On the strength of a single clinical trial, they’d won U.S. regulatory approval for their drug to treat amyotrophic lateral sclerosis, or ALS. They expected that a larger trial would cement the effectiveness of their treatment. Instead, the trial showed that their drug, Relyvrio, doesn’t work.

The co-CEOs of Cambridge, Mass.-based Amylyx Pharmaceuticals said last week they would voluntarily stop promoting Relyvrio — which brought in more than $380 million last year — and consider pulling it from the market. Amylyx instantly lost 80 percent of its $1 billion stock market value. The failure dealt a blow to the community of those suffering from ALS, a disease with no cure that kills by progressively shutting down the body’s ability to move, speak and ultimately breathe.

The episode highlights the agonizing choices facing the U.S. Food and Drug Administration on drugs that could give desperate patients a shot at living longer but lack the convincing evidence from two rigorous trials that it typically requires. The agency has used a flexible approach in recent years to approve drugs for particularly devastating conditions such as ALS, Alzheimer’s and Duchenne muscular dystrophy, a fatal disease that causes the muscles of young boys to waste away.

Critics say the FDA has swung the pendulum too far, approving drugs despite concerns about their effectiveness by its own staff and outside experts.

“When they lower the standards for one product, however urgently needed it might be, it has a tendency to serve as a model,” said Diana Zuckerman, president of nonprofit National Center for Health Research.

“The FDA recognizes there is a substantial unmet medical need for safe and effective treatments for ALS, as there is for so many of the devastating neurological diseases,” the agency said in a statement. “All our decisions are guided by science and exhaustive review of the data in any application,” including Relyvrio, it said.

Each time the FDA deviates from its typical requirements to approve a drug gives companies and advocates leverage to seek similar consideration, critics of the practice say, though it isn’t clear how much weight such appeals carry with agency officials.

At an FDA meeting this past May, a patient representative advocated for the agency to approve a gene therapy to treat Duchenne, saying officials had shown flexibility in approving an ALS drug the previous month. That ALS drug, made by Biogen, had failed to meet its targets in a clinical trial but showed promise for reducing nerve damage. An independent panel of experts voted 8-6 in favor of approving the Duchenne therapy, though some who voted yes still harbored doubts.

“We still are in an area where there is a lot of uncertainty,” Peter Marks, FDA’s director of the Center for Biologics Evaluation and Research, said after the vote last year. “We will now take this back and do something that we have to do every day at FDA,” he added, “manage through the uncertainty.”

The FDA approved the Duchenne therapy, made by Sarepta Therapeutics, despite agency staff’s concerns over its safety and effectiveness.

Tracy Sorrentino, a spokesperson for Sarepta, said, “We believe the totality of the evidence supports the conclusion that Elevidys” — its gene therapy — “modifies the trajectory of Duchenne.”

Allison Murphy, a spokeswoman for Biogen, said its research found evidence its drug slowed the progression of ALS and cited a positive opinion last month from a committee of the European Union’s drug regulator.

Caleb Alexander, a Johns Hopkins internist who served on the FDA’s advisory panel for Relyvrio in 2022, recalled advocates bringing up the agency’s approval of an Alzheimer’s drug, Aduhelm, the year before despite a panel of experts rejecting it. “People were saying explicitly, ‘You showed enormous regulatory flexibility with [Aduhelm], as you should have. Do the right thing here,’” said Alexander, who voted against approving Relyvrio.

“The FDA gets an enormous amount right,” Alexander added. Still, he said, “I think that’s a real risk that the leniency shown to one product reinforces that shown to another product, and over time one has a gradual weakening of the evidence standards.”

Klee and Cohen, for their part, said they’ve met many people diagnosed with ALS in their 30s with young children, contending that withholding a treatment that could buy them more time would be wrong.

“Ten times out of 10, this was the right path,” Cohen said in an interview Monday. “Sometimes science doesn’t work out quite the way you hope.”

Ice Bucket Challenge to FDA approval

Cohen, 32, and Klee, 33, were undergrads at Brown University when they came up with an idea to combat the death of brain cells. They eventually took aim at ALS, a terminal diagnosis given to about 6,000 patients per year in the United States.

The duo hustled to find mentors, enlisting connections like Klee’s mother’s college boyfriend to make an introduction to a prominent professor, they recalled in a January interview. They had humbling moments, like when one potential backer realized that their Cambridge office was in a residential zone, and asked, “Are you in an apartment?” They were.

Klee and Cohen got a boost from a viral social media phenomenon in 2014 that involved people dousing themselves or others with ice water and filming it to raise money for ALS. The ALS Association gave them a grant from the proceeds of that campaign.

“The Ice Bucket Challenge is a big part of the reason we’re here,” Klee said in January.

Their dorm room research developed into a dissolvable powder that aimed to protect neurons in people with ALS by reducing cellular stress and dysfunction. A clinical trial with 137 participants found those who received the drug had a 25 percent slower rate of decline in activities like walking and talking compared with a placebo group over 24 weeks, according to a paper in the New England Journal of Medicine. A subsequent data analysis calculated that participants who took the drug lived on average about 10 months longer than a control group.

In most cases, Amylyx’s trial wouldn’t satisfy the FDA. The agency usually requires compelling evidence from two clinical trials with hundreds of participants to consider a drug for approval. But its guidelines also allow that in certain cases, a single trial can be enough to prove a drug’s effectiveness.

To make such a call, the agency weighs the “persuasiveness” of the trial and the “seriousness of the disease” — particularly when there is a lack of good treatments. The FDA had approved just two other drugs for ALS at the time and exercised a measure of flexibility in both cases.

In March 2022, a committee of outside experts who advise the FDA voted 6-4 that Amylyx lacked evidence that its drug worked. The agency’s staff also found that the study’s positive result “was not exceptionally persuasive,” and expressed other concerns with the company’s analysis.

But outside the regulatory review, ALS patients and advocates were putting pressure on the FDA to move faster and use their discretion to approve more therapies — even if it meant accepting a safety risk for a potentially modest benefit. The FDA took the unusual step of holding a second advisory committee meeting in September 2022 to consider additional data from Amylyx, which brought out emotionally raw testimony.

Brian Wallach, a staffer in the Obama White House, was diagnosed with ALS on the same day that he and his wife brought home their second daughter from the hospital. He addressed the committee with his own, barely intelligible voice before a friend took over reading his statement.

“I am a 41-year-old father of 5- and 7-year-old girls,” the friend read. “Instead of thinking you are protecting me, I want you to recommend approval so that I have the chance to live.”

The FDA staff’s review had called the drug’s effectiveness into question. But this time, the advisory committee voted in favor, 7-2.

Amylyx had launched a larger, longer-term trial. But the FDA didn’t wait for the results to come in, approving Relyvrio in fall 2022.

‘They still need a solution’

There was no requirement for Amylyx to continue its larger trial, but it did.

“If you believe in a drug, you shouldn’t be nervous to study it,” Cohen said in the January interview.

When the results came in less than two months later, they showed the benefit was not even as reliable as a coin toss. The news stunned Amylyx’s founders, some Wall Street analysts and ALS advocates.

“It cannot be overstated how painful these findings are for people with ALS who are looking for hope and options,” said Andrea Goodman, CEO of I AM ALS, the advocacy group founded by Wallach and his wife. Wallach added in a statement, “we are grateful to Amylyx for their transparency.”

Sheri Strahl, president of the ALS Network, called Relyvrio’s failure “a major setback” but said that “every failure helps us better focus on what might actually work.” She added, “Even in moments like this, there is reason for hope.”

Umer Raffat, an analyst at Evercore ISI, pressed Cohen and Klee on a call after Amylyx disclosed the Relyvrio results. “Are you 1,000 percent sure,” he asked, that no group of participants in the trial showed a result that deserved following up?

“The top line results are clear,” Klee responded, according to a transcript compiled by S&P Global Market Intelligence.

The value of Klee’s and Cohen’s stock in the company each plunged to about $10 million from more than $50 million, but they said they remained focused on the ALS community.

“As hard as it may be for us, I can’t even imagine what it’s like for someone with ALS and their family reading the news,” Klee said.

Amylyx is developing other ALS drugs. “Possibly Relyvrio will not ultimately be the solution for people living with ALS,” Cohen said. “They still need a solution.”