A panel of the Food and Drug Administration’s expert advisers on Wednesday voted 6 to 4 against approving Amylyx Pharmaceuticals’ treatment for ALS. The FDA now has until June 29 to decide whether to follow the panel’s advice or let the closely watched drug on to the market.
Amylyx’s drug made headlines in 2020 after data from a small phase 2 study suggested it extended the lives of ALS patients a few months and slowed the disease’s progression by about 25%. The FDA asked for a larger phase 3 trial to confirm those results but reversed course last year and said it would consider approval based on that smaller study. Its advisers were not convinced the existing data are strong enough.
People with ALS are in desperate need of new and better treatments for the fatal neurodegenerative disease. But it doesn’t help if they don’t work. The agency should follow the panel’s advice and wait for more data from that larger trial.
ALS is unforgiving in the speed and certainty with which it kills. People live on average two to five years after their initial diagnosis and in that time lose their ability to walk, eat and eventually breathe. Amylyx’s drug combines two ingredients, sodium phenylbutyrate and taurursodiol, that the company contends act in concert to protect against neuron death.
During the open public hearing section of the FDA meeting, people with ALS and their caregivers gave emotional testimonies that made clear the community is willing to tolerate significant risk for even small advances in treatment. Having more time to live independently, or even just a few extra months with family, are truly meaningful outcomes.
The problem is the drug might not actually buy any extra time.
In its presentation, the FDA’s experts narrowed in on a range of issues with Amylyx’s study, including the small size of the trial, the possibility that patients could tell whether they were receiving the drug or placebo, the high percentage of participants in the drug portion who dropped out and the company’s definition of “death,” which included hospitalizations and tracheotomies in addition to actual deaths.
When the benefit is murky and the need is as great as it is with ALS, clinicians and statisticians wade deep into the data weeds for something real to pull out. Finding a signal of efficacy in neurodegenerative diseases can be particularly tricky because the disease progresses differently in different people, and doctors often can’t predict which group a newly diagnosed patient will fall into. That heterogeneity makes it difficult to assess a drug’s value unless, of course, it is extremely effective.
Sadly, few neuroscience drugs turn out to be unambiguously successful. And the ALS community has seen time and again treatments that look promising in phase 2 but go on to fail in larger studies.
In the case of Amylyx’s drug, the trial was designed well, but its small size and the variability in the disease’s progression had the potential to create the illusion of a benefit. “If you happen to have a couple of people that are more rapidly progressing in the placebo group, then it’s going to look like the drug is having a good effect,” said Catherine Lomen-Hoerth, director of the University of California, San Francisco ALS Center.
Everyone wants expanded treatment options, and everyone wants patients and their families to have hope. But approving drugs without solid evidence of their benefit can harm patient communities in the long run.
There’s the obvious risk of people taking expensive treatments with little or no effect — and the potential for those costs to be borne by patients because insurers balk at the questionable data. And the approval can create blowback that pushes the FDA in one of two directions, neither of them good: It can lower the regulatory bar, potentially allowing treatments with even shakier data onto the market; or it can raise the bar, potentially slowing the development of better drugs.
Amylyx, whose share price has been cut nearly in half over the last week after indications that the panel’s vote would not go its way, has already begun a larger Phase 3 study of its drug. Amylyx executives said on Wednesday that some 150 people have signed up for the study, which will eventually include 600 patients and should be completed late next year.
Meanwhile, a group of European researchers is running a phase 3 study of taurursodiol on its own, which could help determine how much of the potential benefit of Amylyx’s drug comes from that ingredient or whether the sodium phenylbutyrate enhances the purported neuron-protecting effect.
Until Amylyx has results from the larger trial, people with ALS have options. Sodium phenylbutyrate is approved to treat urea cycle disorders, so doctors can prescribe it off label, though it is costly and insurance companies might not cover it. Taurursodiol, meanwhile, can be ordered from Amazon or Walmart — in fact, this is what many patients are already doing. ALS advocates rightly note that the quality and dosage of supplements purchased online is always suspect.
And in late 2021, a bill was enacted allowing the Department of Health and Human Services to provide grants so that patients not eligible for ALS studies can gain access to experimental drugs. Amylyx has also launched an expanded access program for that group that doesn’t qualify for clinical trials.
These options are imperfect. But they provide a reasonable stopgap while more data is collected — data that can both assure patients they are getting a worthwhile drug and preserve the FDA’s integrity.
