On March 30, an FDA advisory panel voted 6 to 4 against recommending approval of what might be the most effective treatment to date for amyotrophic lateral sclerosis. The panel’s decision is not binding, and the FDA could disregard its recommendation when it issues its final decision on the treatment, called AMX0035, in June.
For people like me who have been diagnosed with ALS, the rejection landed like a sucker punch. This devastating disease progressively robs people of their ability to move, speak, and eventually breathe. While the disease course varies, most with it die within five years. There are no effective treatments or cures.
Eighteen months ago, the ALS community was given cause for hope. In September 2020, Amylyx, a biotech company focused on neurodegenerative diseases, announced that in a Phase 2/3 randomized controlled trial with 137 ALS patients, its drug, AMX0035, slowed the rate of functional decline by 34%. The results were published in The New England Journal of Medicine. A follow-on study showed that patients on AMX0035 were 44% less likely to die during the study period, with a maximum of 35 months of follow-up.
What’s more, AMX0035 isn’t a novel therapy. It is a combination of Buphenyl (sodium phenylbutyrate), an FDA-approved drug for treating urea cycle disorders, and taurursodiol (also known as tauroursodeoxycholic acid), an over-the-counter supplement. Both are considered safe.
Given the quality of the studies, the promising results, and the desperate need for new ALS drugs, the FDA suggested to Amylyx in the summer of 2021 that it apply for approval. The company submitted its new drug application (NDA) on November 2, 2021. By then, though, the political winds had changed. While Amylyx was working on its application, the FDA found itself in the midst of a political firestorm. On June 7, 2021, the FDA had approved Aduhelm (aducanumab) for treating Alzheimer’s disease, despite near-unanimous opposition from its advisory board. The FDA did this even though, in a major Phase 3 study, Aduhelm did not appear to work any better than placebo.
Criticism was swift and came from many quarters. Three scientists resigned in protest from the FDA advisory panel. Meanwhile, doctors complained that, given the unclear efficacy data, approving the drug opened patients up to inappropriate risk. Aduhelm can cause brain bleeds and swelling in some who take it. Congress is now investigating.
Although Aduhelm was barely mentioned during the hearing on AMX0035 — which was convened by the FDA’s Division of Neurology, which also reviewed Aduhelm — its shadow was apparent as reviewers emphasized shortcomings in the Amylyx study instead of its strengths. They raised concerns that the randomization was not done properly in earlier stages of the trial, or that unblinding could have resulted because of the drug’s bitter taste. They also noted that, while the study met its primary endpoint, the results of secondary endpoints such as respiratory function were mixed. Reviewers argued that the sample size was small, even though 137 participants is large by ALS study standards.
For these reasons, when it came time to vote, six of the nine scientists on the panel voted against approval. Three voted in favor, as did the sole patient representative.
The final decision is now up to the FDA and, after the Aduhelm debacle, few expect it to overrule one of its advisory panels again.
But it should. That’s because the question the review panel answered — Is there enough scientific evidence to “establish a conclusion” that this drug combination works? — is different than the one the FDA now needs to address: Given the potential benefits and minimal risk, should this drug combination be marketed for ALS? While the answer to the first question might be “probably, though but we can’t be 100% sure,” the answer to the second is definitely “yes, and let’s do more research to confirm.”
Aduhelm is a new drug, a monoclonal antibody that targets amyloid, a protein found in clumps in the brains of people with Alzheimer’s disease, as well as those without the disease. In contrast, the two components of AMX0035 — Buphenyl and taurursodiol — are already on the market. Taurursodiol is available from Amazon and other marketplaces, and most ALS clinics are now prescribing generic Buphenyl off-label.
Without FDA approval, however, insurance companies are routinely denying coverage for generic Buphenyl, which has a retail price of more than $100,000 per year. This is forcing those who can afford it to pay thousands of dollars a month to compounding pharmacies. Those who can’t are left out in the cold.
Approving AMX0035 while requiring a validation study is not only the right decision on the scientific merits, it is also a matter of health equity. The FDA and Amylyx could address concerns about study enrollment by capitalizing on advances in big data and real-world evidence to design a Phase 4 validation study to ascertain efficacy while still ensuring access to AMX0035. These kinds of studies are already contributing to oncology drug approvals.
While the FDA may have made missteps with Aduhelm, denying approval for AMX0035 won’t fix them. What it will do is keep people with ALS from accessing a promising treatment because of cost, ensuring that when the Phase 3 results are finally revealed, many won’t be alive to see them.
The shadow of Aduhelm should not cloud the FDA’s decision on AMX0035 and other therapies that can change the course of ALS.
Bernard Zipprich is a health care investor and entrepreneur. He was diagnosed with ALS in 2020. He lives in New York with his wife and one-year-old son.