FDA Advisory Committee Supports Approval of AMX0035 for ALS

Despite additional data that some members said only added modestly to the evidence, an FDA advisory committee voted to support approval of AMX0035 (sodium phenylbutyrate and taurursodiol). In a 7 to 2 vote, the Peripheral and Central Nervous System Drugs Advisory Committee late on Wed. Sept. 7, 2022, supported approval of Amylyx Pharmaceuticals’ therapy to treat patients with amyotrophic lateral sclerosis (ALS).

While not binding, the committee’s recommendation will be considered by the FDA in its review of the pending new drug application (NDA) for AMX0035.The Prescription Drug User Fee Act (PDUFA) target action date is Sept. 29, 2022.

This was the second time the advisory committee considered the question of whether the data support the effectiveness of AMX0035. At the first advisory committee meeting in March 2022 in which six of the 10 members voted no on the question of whether the open-label extension of the phase 2 CENTAUR trial established a conclusion that AMX0035 is effective in the treatment of patients with ALS.

After Wednesday’s vote, several committee members mentioned they were swayed in part by the additional analysis presented by Amylyx. Some indicated the unmet and the seriousness of ALS, as well as encouraging signals from the ongoing phase 3 PHOENIX trial, encouraged them to switch their no votes to yes.

One of the committee members who initially voted no was Liana G. Apostolova, M.D., a professor in neurology Indiana University School of Medicine, Indiana Alzheimer’s Disease Center, in Indianapolis, She said after vote the slope of the confirmatory evidence, while not unequivocally persuasive, is reassuring.

Robert C. Alexander, M.D.

Another no to yes vote was from Robert C. Alexander, M.D., chief scientific officer at Banner Alzheimer’s Institute Research and professor, department of Psychiatry at the University of Arizona College of Medicine – Phoenix

“I appreciated the testimony of the ALS patients and their families,” he said. “Just like last time it really underlines the seriousness of ALS and the profound medical need. It was a close call.”

Related: FDA Advisory Committee Votes Down ALS Drug

At the March 2022 meeting, agency officials indicated that the results of the primary endpoint data from the CENTAUR trial was not highly persuasive, without the significant support from secondary endpoints and regulators indicated there was no survival benefit at 24 weeks.

Following the March meeting, Amylyx submitted additional analysis of survival data from the CENTAUR study and its open-label extension, along with biomarker results from a recently completed phase 2 study of AMX0035 in Alzheimer’s disease. Additionally, the company in May 2022 announced publication of long-term survival analysis of the CENTAUR trial. This analysis used a different model, the rank-preserving structural failure time model, a method frequently used in oncology to account for placebo crossover. Using this model, AMX0035 is estimated to provide a 10.6-month longer median survival duration for participants.

Of the two committee members who voted no on Wednesday, G. Caleb Alexander, M.D., professor of Epidemiology and Medicine at Johns Hopkins Bloomberg School of Public Health, Center for Drug Safety and Effectiveness in Baltimore, said the new evidence, while promising, doesn’t constitute substantial evidence of effectiveness.

“We essentially have a single study with many nontrivial scientific concerns, including confirmatory evidence that's not prespecified, derived from the same study and post hoc natural history analyses,” he said after the vote. “The FDA, with all due respect, significantly understates the complexity and likelihood of pulling a product from the market … it’s no substitute for the evidentiary thresholds that are required for market access.”

Earlier in the meeting, company officials agreed that if AMX0035 were approved but the phase 3 trial confirmatory PHOENIX didn't support earlier findings, they would remove the drug from the market.

PHOENIX is enrolling a larger and broader group of people living with ALS than were enrolled in the phase 2. The primary efficacy outcome is the composite measure of survival and Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) total score progression over 48 weeks and survival and tolerability over 48 weeks.

Agency officials did note in materials ahead of this second advisory committee that no new data from the CENTAUR study or its open-label extension were submitted; the submission consisted of new analyses of previously submitted survival data. FDA officials indicated that this second analysis is highly correlated with the primary analysis. The agency’s concern was that this does not appear to be independent confirmatory evidence because it uses the same data as the primary analysis.

Kenneth Fischbeck, M.D.

Kenneth Fischbeck, M.D., NIH distinguished investigator at the National Institute of Neurological Disorders and Stroke, National Institutes of Health, the second committee member to vote no, said after the vote some problems with the study include the randomization and an analysis that was not pre-specified. “I don't think that it quite met the standards that we should have here to move forward with giving approval to the company before we have results of phase 3. I hope that we get the results expeditiously and we can move on with a safe and effective treatment.”

AMX0035 is approved in Canada with the brand name Albrioza, and a marketing application is also pending in Europe.