In the original panel discussion, held in March 2022, the majority of members of the committee voted that AMX0035 did not fully demonstrate sufficient efficacy as a treatment for ALS.
According to a new announcement, the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee is planning to reconvene on September 7, 2022, to discuss the new drug application (NDA) for AMX0035 (Amylyx Pharmaceuticals), an investigational agent in review for amyotrophic lateral sclerosis (ALS), weeks before the scheduled PDUFA date.1
The news comes less than a month after the agent received approval in Canada, making it the first new therapy for the disease since 2018.2 It also comes a few months after the original discussion by the committee.
This second time meeting of the panel will also feature conversation assessing whether AMX0035 demonstrated a significant enough efficacy in the phase 2/3 CENTAUR study (NCT03127514) and open-label extension, the basis of the NDA. AMX0035, an orally administered fixed-dose coformulation of sodium phenylbutyrate-taurursodiol, originally had a PDUFA target action date of June 29, 2022, which was then pushed back early that month to September 29, 2022, to allow more time for the FDA to review data.3
"We remain engaged with the FDA to advance AMX0035 through the review process as efficiently as possible,” Tammy Sarnelli, Global Head of Regulatory Affairs, Amylyx, said in a statement.1 "We are pleased that the members of the advisory panel will review additional analyses from our clinical studies, including recently published analyses, supporting the previously reported functional and overall survival benefit for AMX0035. As we have heard from the ALS community, there is a crucial need for new and effective treatments in ALS, and our team will continue to work around the clock to advance treatments for ALS in the US."
In March, the AdComm panel voted 6–4 (6 no; 4 yes; 0 abstain) that the data included in the NDA did not adequately establish AMX0035 as an effective treatment for ALS, with several members citing concerns over the trial’s conduct and robustness of the data. Additionally, some felt as though the ALS Functional Rating Scale-Revised (ALSFRS-R) scores for patients in the placebo arm were high, which may have altered the perception of the data. Other members who voted no claimed the ongoing phase 3 PHOENIX study (NCT05021536) might help answer lingering questions regarding the medication’s efficacy.4
At the 2022 American Academy of Neurology Annual Meeting, April 2-7, in Seattle, Washington, NeurologyLive® caught up with Justin Klee and Josh Cohen, cofounders and cochief operating officers of Amylyx, who provided their thoughts on the AdComm meeting. Klee said, "In terms of the panel, I think it’s important that we have open discussions on critical therapies like AMX0035. We were encouraged at first, similar to the presentation here at AAN. The FDA agreed that the safety profile appears quite good. Secondly, we were encouraged that in a very heavily biostatical discussion, Dean Follman, PhD, the biostatistician on the panel, thought that the way we handled things was done in an appropriate manner, and that it would support the efficacy of the treatment. Overall, there’s more to come. Of course, the ultimate decision is up to the FDA, but we’re proud of our team and the data."
"To add to what Justin said, there was some important scientific discussion on the statistical handling, questions about blinding and things like that," Cohen said. "It’s important to say, firstly, the statistical model that we designed was pre-specified, and was designed prior to seeing any of the data. It was designed with David Schoenfeld, who’s one of the top statisticians. I think he’s the most cited statistician in the ALS field. We stand by all the modeling choices and assumptions."
Patients with ALS in CENTAUR were randomly assigned 2:1 to either AMX0035 or matching placebo, administered twice daily by mouth or feeding tube, for a planned duration of 24 weeks. The investigational agent met its primary end point, with a reported averages ALSFRS-R score of 2.32 points higher than placebo (P = .03) at the end of the analysis. Additional data showed that from baseline, there was a 2.92-point higher mean ALSFRS-R score for the AMX0035 group (P = .01) and a –1.24 points per month change in total ALSFRS-R score compared with –1.66 points per month with placebo (difference, 0.42 points per month; 95% CI, 0.03-0.81; P = .03).5
In October 2020, survival data showed a median survival of 25 months (95% CI, 19.0-33.6) for those on the study drug vs 18.5 months in the placebo group (95% CI, 13.5-23.2) for an HR of 0.56 (95% CI, 0.34-0.92; P = .023), equating to a 44% lower risk of death. Furthermore, at 1 year, the estimated probability of survival was 80.9% (95% CI, 71.1-87.7) for the AMX0035 group compared to 72.9% for those on placebo (95% CI, 58.0-83.3). For 2 years, the estimates were 51.6% (95% CI, 38.9-62.9) and 33.9% (19.4-49.1), respectively.6
PHOENIX, the ongoing 48-week, placebo-controlled trial assessing AMX0035, is expected to have data read out in 2024. With an estimated enrollment of 600 participants with definite or clinically probably ALS within 24 months of symptom onset, the study will also use ALSFRS-R as the primary outcome, along with survival. "We made the point at the advisory committee hearing that regardless of what happens in our process, we intend to complete the study. We think it’s critical data,” Klee added in the April conversation with NeurologyLive®. "Everybody wants more data. More data is always good. Everybody wants more data, but we have to balance that with the needs of patients today. None of these decisions are easy."