Amylyx's ALS drug faces tough FDA scrutiny ahead of 2nd advisory panel meeting

An FDA independent advisory panel will convene again to discuss Amylyx Pharmaceuticals' contested amyotrophic lateral sclerosis (ALS) drug, after a meeting in March left the drug with little hope for FDA approval. And for this second try, the odds still don’t look in Amylyx’s favor.

Amylyx’s new analyses were still not “sufficiently independent or persuasive” to serve as confirmatory evidence of AMX0035's effectiveness, the FDA said in its briefing document about the application.

This time, Amylyx submitted new analyses of survival data from its main study, along with biomarker results from a phase 2 of the drug in Alzheimer’s disease, prompting the reconvening of the advisory committee tomorrow. 

One of the new analyses used participants' response rates to assess the treatment's effects. The agency said that it does “not appear that this data can be considered independent confirmatory evidence” as it uses the same data as the primary analysis.

The company also presented a survival prediction algorithm for the drug, created from natural history data from more than 10,000 ALS patients from 12 specialized centers across Europe. The FDA shot down these data as patients in the database were not in a clinical trial and found “a variety of concerns” about the reliability of the analysis, such as external controls and a lack of pre-specified protocol.


Finally, Amylyx tried utilizing a placebo crossover design to provide an estimate of the treatment’s survival benefit. The agency flagged it as not new data but simply a new method for analyzing the same survival data presented in the original submission, finding concerns on a “heavy reliance on strong unverifiable assumptions.” Plus, best practices for the analysis were not implemented, including the consideration of sensitivity analysis using other methods.

As for the biomarker results from the Alzheimer’s study, the agency noted that the relevance to ALS is unknown.

“It is unclear if these findings, even if they were demonstrated to be indicative of benefit in [Alzheimer's disease], would be generalizable to ALS,” FDA staffers said in the briefing.

The agency found it challenging to make a regulatory decision as a phase 3 trial is ongoing and may report different results. The data presented again by Amylyx were not persuasive enough, the FDA said.  

Last time the panel met on the topic, the agency expressed concerns that the statistical result in the phase 2 study was “not exceptionally persuasive” and found analytical and interpretive issues associated with the consideration, noting that the data “may not be adequate” to serve as a single study capable of proving effectiveness. It also flagged concerns that the statistical analysis methodology did not “appropriately account” for deaths that occurred during the study.

The result from the March meeting was four member votes for “yes” on the AMX0035 application and six for “no.”

The committee was asked to reconsider the available effectiveness data in the context of the unmet need in ALS, the ongoing phase 3 trial for the drug and the seriousness of the disease in question.

Despite the delay in the U.S., the drug was granted conditional approval this June in Canada based on the phase 2 data. Amylyx will have to turn over its phase 3 trial to the regulatory agencies in the country.