Failure of ALS drug puts a spotlight on controversial FDA approvals

Daniel Gilbert, Washington Post, March 16, 2024

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.


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.”


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.


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


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.


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.”

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