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.
The phase II trial on which the application for FDA approval of AMX0035 was based had a number of shortcomings, including:
Related on the SLP
- 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)
- 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)
- Thirteen participants started treatment with edaravone (Radicava), a recently approved ALS drug, during the course of the trial
- Historical controls (some dating from the 1990s when standard care for ALS was considerably different) were included in the statistical analysis
- 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
- The statistical analysis assumed linearity of ALSFRS-R change, which does not fit the data
- 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.
