Panel Votes 6 to 4 to Reject Amylyx ALS Drug
FDA’s Peripheral and Central Nervous System Drugs Advisory Committee delivered a near mixed vote 3/30 on whether Amylyx Pharmaceuticals’ experimental amyotrophic lateral sclerosis (ALS) therapy AMX0035 should be approved. Panel members voted 6 to 4 that data from the single randomized, controlled trial and the open-label extension study did not establish a conclusion that sodium phenylbutyrate/taurursodiol is effective in treating ALS patients.
Panel members mostly agreed with FDA skepticism (see earlier story) about the NDA’s data. An FDA briefing document had agency reviewers finding that the study “demonstrated only a modest p-value using non-preferred analysis methods that ignore the loss of data due to patient deaths during the study and relied on a questionable linearity assumption of the ALSFRS-R [ALS Functional Rating Scale-Revised] over time. There was also a moderate proportion of missing data and a randomization implementation problem such that the first 18 patients in a row received the drug, which reduce the persuasiveness of the study.”
The NDA submission is based on results from a Phase 2 trial that met its main endpoint of slowing disease progression, according to the company. While FDA initially said Amylyx needed to conduct a Phase 3 trial before seeking regulatory approval, company discussions with the agency led to filing the NDA based on the Phase 2 study results. A Phase 3 trial is now underway and expects to enroll 600 patients.
Most panel members acknowledged the persuasiveness of patients who testified and urged the panel members to support the therapy’s approval. Banner Alzheimer’s Institute chief scientific officer Robert C. Alexander noted the moving testimonies, but he said “in the end, I had to agree with FDA that this study on its own doesn't establish that this drug is effective in the treatment of ALS for the reasons they enumerated, including the relatively small initial sample size, in particular the size of the placebo group, the amount of missing data, potential imbalances between the treatment groups, probably more importantly the modest effect in the primary endpoint and the weaker absent support from the secondary endpoints. It was difficult to know how much weight to assign the survival analysis given the exploratory nature. So I think we need to wait for the results of the confirmatory trial to determine whether or not the therapy is effective.”