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In March and September 2022, I served on an FDA Advisory Committee reviewing the application of Amylyx Pharmaceuticals for the novel drug AMX0035 for patients with amyotrophic lateral sclerosis (ALS).

I voted against approval of this drug at both meetings, first as part of a 6-4 majority and then with the minority in a 7-2 vote.

On September 29, the FDA announced approval of the drug, which now has the brand name Relyvrio. I still believe that approval should have been deferred, pending the results of a large phase III study currently underway in Europe.

Past Experience With ALS and Other Diseases

I am a neurologist and clinician-investigator who has worked on ALS and other neuromuscular diseases for many years, first at the University of Pennsylvania and now in the National Institute of Neurological Disorders and Stroke at NIH. We have long sought to reduce the burden of this horrible disease.

One experience from early in my career has affected my approach to novel treatments. In the early 1980s I saw an ALS patient and his family who sold their home in Philadelphia to pay $45,000 (over $130,000 in today's dollars) for a snake venom extract from Florida. The person selling this extract had been featured in a positive story on "60 Minutes." I cannot think of anything worse than taking advantage of patients and families suffering from ALS. Unfortunately, ALS patients are often drawn into trying treatments that have little-to-no proof of efficacy.

Unsubstantiated claims of efficacy have impeded therapeutics development for other diseases too. Over 30 years ago, the parents of a child with adrenoleukodystrophy, a severe hereditary neurological disease, sought to develop a treatment. The story was featured in the 1992 film "Lorenzo's Oil," which portrayed the treatment as effective. However, randomized, placebo-controlled trials were never done, and all these years later we still don't know whether it is effective.

In another case, Sarepta Therapeutics received FDA approval in 2016 for eteplirsen (Exondys 51), an exon-skipping drug for Duchenne muscular dystrophy, despite a lack of convincing evidence that it had clinical benefit or even a clinically meaningful biological effect. The approval was granted with the understanding that a follow-up study would be conducted to confirm clinical efficacy, but this has not yet happened. Meanwhile, Sarepta has continued to market the drug for and has now received FDA approval for two other drugs for Duchenne muscular dystrophy with a similar mechanism of action (and similar lack of evidence for clinical efficacy).

FDA's Role

The FDA is charged with assuring drug safety and confirming that new drugs have the benefit they are claimed to have. Recently, it seems , particularly for diseases with a heavy burden of unmet need like ALS.

Traditionally, proof of efficacy has required two phase III studies (i.e., two randomized, placebo-controlled trials adherent to prospective statistical analysis plans and with sufficient power to show clinically meaningful benefit). However, the FDA grants approval where the need is great and a single well-designed and implemented phase II trial and additional data give "substantial evidence" of efficacy.

The Amylyx Story

The Amylyx drug AMX0035 is a combination of two generally available compounds, sodium phenylbutyrate and taurursodiol, which are thought to affect the ALS disease mechanism. The biological rationale for these compounds is relatively weak, in contrast to other drugs currently under development (like tofersen) that specifically target the genetic cause of the disease in patients with familial ALS.

The on which the application for FDA approval of AMX0035 was based had a number of shortcomings, including:

1. An error that led to the first 27 participants not being randomized (the first 18 received the active agent, and the next 9 were given placebo to compensate)
2. Gastrointestinal side effects with the active agent that may have led to unblinding (although a survey at the end of the study did not show this)
3. Thirteen participants started treatment with edaravone (Radicava), a recently approved ALS drug, during the course of the trial
4. Historical controls (some dating from the 1990s when standard care for ALS was considerably different) were included in the statistical analysis
5. The primary endpoint, the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R), does not have a well-established minimal clinically important difference based on patient experience
6. The statistical analysis assumed linearity of ALSFRS-R change, which does not fit the data
7. Post-hoc statistical re-analysis was included in the application for approval

For all these reasons, I feel the AMX0035 phase II trial did not show substantial evidence of efficacy.

A confirmatory is currently underway in Europe (where it is required for approval), but the trial was discontinued in the U.S. pending the FDA review.

One factor that may have led members of the FDA Advisory Committee to change their votes at the September meeting was a comment by an Amylyx co-CEO that the company would consider withdrawing the drug if the phase III result is negative. However, it may be difficult to hold the company to this, and to agree on what a negative result would be.

The ALS Patient Perspective

Another factor that may well have led to FDA approval of AMX0035 is the strong support from ALS patients and family members.

I met recently with representatives of , an ALS advocacy group. I was impressed by their plans for reducing the ALS burden and by how passionate and well-informed they are. When I suggested that Amylyx make the drug more readily available for free by extending its expanded access program and restarting the phase III trial in the U.S., they argued that it is difficult for a small company to do this on a larger scale.

Furthermore, people now living with ALS have a limited life span and little time to spare. We agreed about the heavy disease burden and the exorbitance of the price ($158,000 per year) that Amylyx has recently chosen to charge, and we share the hope that the phase III trial will result in a drug we can all agree is safe, effective, and affordable.

is an NIH Distinguished Investigator at the National Institute of Neurological Disorders and Stroke (NINDS). The opinions expressed are the author's own and do not necessarily reflect the views of the NIH or FDA.

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