For Rick Bedlack, director of the ALS clinic at Duke University, tough times come with the job. He and his team treat about 500 people with the rare, fatal disorder that rapidly erodes nerve cells. Friday, though, was particularly difficult.
“It’s no doubt one of the saddest days I’ve experienced in a long time,” Bedlack said.
Late last week, one of the few approved drugs for amyotrophic lateral sclerosis suffered a major defeat. A large clinical trial meant to confirm it works instead found it no better than placebo at slowing the disease. Now, Amylyx Pharmaceuticals, the biotechnology company behind the drug, may pull it from the market.
Doctors are already bracing for such an outcome, while still holding out hope Amylyx will find a silver lining as it digs through the results. In the meantime, the company will stop promoting the drug, which is sold as Relyvrio in the U.S., and prescribers say they’ll no longer recommend it to patients.
“This past year and a half, we’ve had more choices than ever,” said Michael Weiss, director of the neuromuscular diseases division at the University of Washington Medical Center. “Now, we’re actually going in the wrong direction again, and that’s got to be very sad and frustrating for patients.”
Currently, there are four medicines in the U.S. approved specifically for ALS.
The oldest, riluzole, received Food and Drug Administration approval in the 1990s for its ability to keep patients alive a couple months longer. Another, Radicava, came to market in 2017 after showing a slight benefit on patient function in a small trial. The FDA then greenlit Relyvrio in the fall of 2022 and, most recently, Biogen’s Qalsody for a sliver of the ALS population with certain genetic mutations.
One of the two active ingredients in Relyvrio can also be bought online as a supplement for about $30. A closely watched study in Europe is evaluating this chemical, known in short as TUDCA, by itself as a treatment for ALS. Until that study produces results, Cathy Lomen-Hoerth, director of the ALS Center at the University of California, San Francisco, said she plans to switch her Relyvrio-treated patients over to TUDCA.
Altogether, the options are far from curative. ALS patients continue to live an average of two to five years following a diagnosis, during which time they progressively lose essential functions like walking, talking and breathing. Doctors have said that, with Radicava and Relyvrio, the benefits are so modest that patients often don’t notice them.
According to Amylyx, Relyvrio didn’t hit the main goal of the confirmatory trial — a 664-person study codenamed “PHOENIX” — nor did it succeed on “secondary outcomes” that measured aspects of health like respiratory function, quality of life and long-term survival.
Justin Klee and Joshua Cohen, Amylyx’s co-CEOs, don’t yet know why the trial failed so unequivocally, though they’ve noted how ALS is a complex disease that both manifests and presents in different ways. The company intends to analyze the results, confer with experts, and sometime in the next eight weeks decide Relyvrio’s fate.
“It’s disappointing, because I think everyone was very excited about the [earlier] data around Relyvrio,” said Lomen-Hoerth.
Those data were from a smaller, 137-person study published in 2020 in The New England Journal of Medicine. Titled CENTAUR, the study indicated Relyvrio had kept patients alive several months longer and provided a small but significant effect preserving essential functions.
These results were what Amylyx used to secure FDA approval.
Leading up to its decision, the FDA had been skeptical of Relyvrio. The agency initially wanted Amylyx to run an additional, larger study to confirm the drug’s benefits before filing for approval, but relented after receiving intense pushback from ALS patients and advocates.
Then, once Amylyx submitted its marketing application, the FDA took the highly unusual step of twice convening a team of outside experts to weigh the pros and cons of Relyvrio. Many drugs up for approval don’t undergo even one of these advisory committee meetings.
In those meetings, FDA staff were critical of the ways Amylyx designed its trial and analyzed data. They also had concerns the results related to function and survival weren’t robust or persuasive enough to warrant approval.
At the same time, Billy Dunn — then the director of the neuroscience office in the FDA division that evaluates new drugs — acknowledged the dire need for more ALS treatments. At Dunn’s request, Amylyx pledged during the second meeting to pull Relyvrio from the market if it failed in confirmatory testing.
That promise helped tip the scales for the committee, which had previously sided against the drug. Members voted 7-2 in support the second time around, thereby setting Relyvrio up for approval since the FDA usually follows the recommendations of its advisers.
Bedlack now expects the failed Relyvrio trial to embolden those who have condemned the FDA’s recent flexibility toward therapies for ALS and other serious nervous system disorders.
“Critics will definitely seize upon this,” he said. “But … before we scrap the whole idea of regulatory flexibility, we need to remember there are examples where it was validated.”
Qalsody is one such example, according to Bedlack, who pointed to research presented at a recent scientific meeting showing the drug offers “extraordinary” benefits. Notably, in the trial that led to its approval, Qalsody didn’t significantly slow the progression of ALS. Rather, it appeared to substantially reduce levels of a protein tied to neurological damage.
For others, Relyvrio itself demonstrates that the FDA’s approach is working.
“To me, it seems like the perfect model,” Lomen-Hoerth said. “You approve a drug for a year based on potentially exciting information from a smaller trial, yet you continue to fund the larger trial. And then when those results come out you make decisions about pulling the drug.”
Merit Cudkowicz, director of the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital, echoes that sentiment. She still believes an early approval based on a single positive study that’s then followed up by another trial within 18 months is the “way forward for a serious illness like ALS.”
“This time the repeat study wasn’t positive — next time, or most times, I think it will be,” Cudkowicz, who also served as a principal investigator in the CENTAUR trial, wrote in an email.
If the FDA does become less flexible, Bedlack fears drug developers may turn away from ALS. “Over 100 companies have ALS drugs in some stage of preclinical or clinical development. When I started, it was like one a year. And I hope this doesn’t destroy all that interest.”
“I think that will depend on that question of: Are we going back to the dark ages of two large, long, randomized, double-blind, placebo-controlled trials before we approve drugs? I hope we don’t,” Bedlack added.
Weiss, meanwhile, isn’t very worried.
“I don’t think this is going to change things dramatically,” he said, referring to the PHOENIX results. “Maybe there’ll be a little bit of a pause or lull, but there’s still a huge patient need. So I think drug companies will continue to be interested in the ALS market for the foreseeable future.”
