By a slim margin, advisers to the Food and Drug Administration have concluded that the agency should hold off approving a closely watched, experimental medicine for ALS until researchers generate more evidence that it works.
Composed of neuroscience and drug development experts, the 10-person advisory committee on Wednesday voted 6 to 4 against the medicine, named AMX0035 and developed by the Cambridge, Massachusetts-based biotechnology company Amylyx Pharmaceuticals. In a study of about 140 volunteers, AMX0035 appeared to show modest benefits on survival and day-to-day function for patients with rapidly progressing ALS, better known to some as amyotrophic lateral sclerosis or Lou Gehrig's disease.
"It's clear that there's a very compelling degree of unmet need, and it's also clear that many with ALS would accept the product as is and are willing to assume the risks associated with it, including the risk that it may not work," said Caleb Alexander, a professor of epidemiology and medicine at the Johns Hopkins Bloomberg School of Public Health.
"Unfortunately, there are many features of [Amylyx's study] that limit its persuasiveness as a standalone trial in a regulatory sense," he added. Alexander was one of the committee members who voted against the company's drug.
For patients and advocacy groups, many of which have campaigned for the drug, Wednesday's vote is a major disappointment. To date, the FDA has approved just two medicines specifically for ALS, with one, riluzole, offering a small survival benefit and the other, Radicava, showing a modest effect on day-to-day functions. Most patients live about three to five years after symptoms arise.
The FDA isn't required to follow its advisers' recommendations. But it usually does, making approval of AMX0035 now more of a long shot. A final decision is expected by late June.
Still, the agency has, in the not-too-distant past, issued surprising verdicts for experimental medicines targeting the brain and nervous system. In 2016, it controversially approved a treatment for a rare neuromuscular disease that had strong backing from patient advocates but limited supporting data.
And last year, for the first time, the FDA cleared a drug meant to slow the progression of Alzheimer's disease. That decision proved contentious, too, due to the mixed results that were generated in clinical testing, as well as the unusual relationship forged between regulatory officials and the drug's developer, Biogen.
Several speakers who testified during a public portion of Wednesday's meeting raised the precedent set by that decision and pushed the FDA to act similarly with Amylyx's drug.
"Why do we not have urgency and humanity here?" asked Sandra Abrevaya, who spoke on behalf of her husband Brian Wallach, who has ALS.
Abrevaya and Wallach were among about two dozen ALS patients, family members and caregivers who spoke Wednesday and urged the FDA to approve AMX0035, emphasizing the importance of even small benefits.
"Incremental change is meaningful to us," John Russo, who has ALS, told the committee Wednesday. "More time is precious for both those living with ALS and their families."
FDA representatives made note at the top of Wednesday's meeting how they've benefitted from hearing the perspectives of ALS patients and groups. Initially, the agency had signaled that Amylyx would need to run an additional, larger clinical trial before submitting an approval application, but changed its position shortly after a meeting with ALS advocates last spring.
"We continue to keep in mind the context that ALS is a rare, devastating disease with enormous unmet medical needs," said Teresa Buracchio, director of the division in the FDA's neuroscience office that evaluates drugs for neurodegenerative disorders.
Even so, FDA scientists and statisticians had a lengthy list of issues with the key study meant to show Amylyx's drug is effective, particularly with regard to its design and the methods Amylyx used to analyze results. Though the findings look promising, "we have considerable concerns that the data may not be sufficiently robust to meet the approval standard," Buracchio said.
Among those concerns were errors in how patients were randomized to either the drug arm or the placebo arm. Agency staff also worried about patients figuring out which group they were in, and thereby inadvertently skewing the results, because Amylyx's drug can have a bitter taste and gastrointestinal side effects.
More crucially, FDA scientists also questioned whether the slowing in functional decline observed among patients taking Amylyx's drug was influenced by how the company treated patient deaths during the study, and by missing data for other participants.
The FDA also found the roughly 5-month survival benefit reported by Amylyx for its drug to be "not persuasive," noting the effect observed might be due to chance or differences in disease course.
"This was a difficult vote and decision," said Bryan Traynor, a senior investigator at the National Institute of Aging. "I thought that there were considerable concerns voiced by the FDA about the trial conduct and the interpretation of the results."
In making a case for Amylyx, co-CEO Justin Klee defended the company's choices in study design and data analysis. He noted, for example, that Amylyx on two occasions did not hear back from the FDA after detailing the planned methodology for the trial.
Amylyx was supported by ALS researchers who spoke on the company's behalf.
"I know that different statisticians have different opinions. But at the end of the day, we are talking about the lives of people who have a rapidly progressing and fatal disease," said Sabrina Paganoni, an assistant professor at Harvard Medical School and a principal investigator for the AMX0035 study.
"This drug does not stop or reverse the disease. Nothing does," Paganoni added. "But we see a positive impact on both function and survival. And these results are valid."
Amylyx is currently sponsoring a much larger trial aimed at confirming its drug's functional and survival benefits. The trial plans to enroll around 600 ALS patients and produce full results in 2024. Those results will be highly anticipated, particularly if the FDA chooses to reject AMX0035.
Josh Cohen, Amylyx's other co-CEO, said the company would complete the study regardless of the regulator's decision, which is due by June 29. However, enrollment is currently stopped in the U.S. as the FDA weighs its choice.