FDA advisers back Amylyx ALS drug, reversing earlier position

A group of Food and Drug Administration advisers now supports a closely watched medicine for ALS, a stance likely to increase its odds of being approved by the agency in the coming weeks.

In a meeting Wednesday, members of the expert committee voted 7-2 in favor of the drug, called AMX0035, concluding the evidence generated to date is substantial enough to clear it for the U.S. market. The vote was a reversal, as the same group of experts narrowly sided against the drug during a similar meeting at the end of March.

Though the FDA isn’t required to follow the recommendations of its advisers, it typically does. The agency expects to issue a verdict on AMX0035 by Sept. 29. If approved, it would join a short list of available therapies for ALS, or amyotrophic lateral sclerosis, a rare, often rapidly progressing disease that destroys nerve cells and is usually fatal within two to five years once diagnosed.

“Last time I was on the fence and wasn’t really sure which way to go,” said Avindra Nath, a clinical director at the National Institute of Neurological Disorders and Stroke and a committee member. “This time, [the discussion] helped me move a little bit more towards yes.”

The case for AMX0035 was supported by testimony from two well-known ALS researchers who spoke on behalf of Amylyx Pharmaceuticals, the drug’s Massachusetts-based developer, as well as nearly two dozen other doctors, advocates and patients who testified at the meeting’s open public hearing.

“AMX0035 needs to be something we can offer our patients now,” Merit Cudkowicz, director of the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital, said Wednesday. 

Cudkowicz served as one of the principal researchers in the primary clinical trial that Amylyx is using to support an approval. Results from that study, some of which were published in The New England Journal of Medicine, show patients who received Amylyx’s drug lived somewhat longer and declined more slowly than those given a placebo.

Two committee members, G. Caleb Alexander of Johns Hopkins Bloomberg School of Public Health and Kenneth Fischbeck of the National Institutes of Health, voted against AMX0035.

“Unfortunately, I don’t believe the new evidence that we’ve reviewed — while promising, [and] combined with that prior evidence — [constitutes] substantial evidence of effectiveness,” said Alexander. “We essentially have a single study with many non-trivial scientific concerns.”

With few other treatment options, ALS patients and advocacy groups have repeatedly urged the FDA to approve AMX0035. However, FDA staff were critical about the data Amylyx has collected and the ways in which the company analyzed them. They previously called the data “not exceptionally persuasive,” even though Amylyx’s trial met its main goal — a rarity in ALS drug development. They’ve acknowledged the devastating nature of ALS and the demand for more treatment options, however.

“We are highly sensitive to the urgent need for the development of new treatments for ALS,” said Billy Dunn, director of the Office of Neuroscience in the FDA arm that evaluates new drugs.

Dunn spoke at length during the early part of Wednesday’s meeting, and at one point pressed Amylyx’s co-founders to say they would voluntarily withdraw AMX0035 from market — provided it secures approval — if a larger, ongoing trial meant to confirm its value ends up failing. Justin Klee, one of the co-founders, agreed the company would.

The positive vote Wednesday means an approval is likelier than it was earlier this year, though still not certain.

In March, the FDA’s advisory committee was almost evenly split on AMX0035. That main clinical trial showed patients treated with the drug were able to better retain essential functions related to eating, breathing and moving. They also lived a median 4.8 months longer than those in the placebo arm. Even so, the then group of 10 advisers voted 6 to 4 against approval.

Since then, Amylyx has gathered more data and run after-the-fact analyses that, according to the company, provide further evidence its drug helps patients. The company claims, for instance, that the survival benefit rises to roughly 10 months when accounting for patients who started on a placebo but then switched to AMX0035 in a subsequent “open-label extension study.” It was these new data that motivated the FDA to take the highly unusual step of reconvening its advisers to further discuss AMX0035.

Ahead of Wednesday’s meeting, though, FDA staff appeared to remain skeptical of how Amylyx interpreted data, noting the new survival analyses cannot be considered independent confirmatory evidence. Yet, they also instructed advisers to consider the nature of ALS and the scarcity of effective treatments.

“In the neurological space, we will unfailingly consider the evidence, whatever its quantity, in that context,” the FDA wrote in briefing documents released earlier this week.

Agency staff noted, too, how the FDA has been flexible in the past with potential therapies for brain and nervous system disorders. In 2017, a drug called Radicava was cleared for use as an ALS treatment, based on results from a single study that some doctors say aren’t as strong as what’s been seen with AMX0035. And then last year, the FDA issued a first-of-its-kind approval for Aduhelm, a controversial Alzheimer’s disease medicine with a mixed track record in testing.

To Mark Weston, the designated patient representative, the FDA’s position during the Wednesday meeting was a source of frustration. “Why did the FDA [ask Amylyx] to go through this again?” he asked. “I know you guys haven’t made a decision. I know that’s not done yet. But there’s not a lot of positive discussion about the results of this new analysis.”

“It almost feels like this is a setup to say … ‘We know we’re going to approve the drug, but we have to go through these motions,’” he added.

“I can assure you that this isn’t just something to go through the motions,” Teresa Burrachio, director of the FDA division that specifically reviews drugs like AMX0035, said in response. “We note the limitations of the analyses, but we still haven’t taken it off the table that they could be considered as confirmatory evidence, and that’s why we’re here today.”

Weston was one of the seven votes in favor of AMX0035, as was Bryan Traynor, a senior investigator at the Senior National Institute for Aging. Traynor said his vote was “first and foremost” reflective of the serious need for new ALS treatments. But it was also influenced by Amylyx’s commitment to pull its drug if confirmatory testing doesn’t pan out, as well as commentary from the FDA, which said it has methods to remove AMX0035 from the market.

Alexander, meanwhile, wasn’t as convinced about the backstop of a market withdrawal.

“The FDA, with all due respect, significantly understates the complexity and likelihood of their pulling a product from the market,” he said. “Frankly, I’m not sure it’s ever taken place.”

Amylyx’s confirmatory trial, dubbed PHOENIX, has enrolled more than half of the targeted 600 participants. Results are expected in 2024.

Editor’s note: This story has been updated with additional detail from the meeting.

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