FDA Extends Review of ALS Therapy

The FDA has extended the review timeline of the new drug application for Amylyx Pharmaceuticals’ AMX0035 (sodium phenylbutyrate/taurursodiol) for the treatment of patients with amyotrophic lateral sclerosis (ALS). The updated Prescription Drug User Fee Act (PDUFA) goal date is Sept. 29, 2022 (formerly June 29, 2022).

ALS is a progressive neurodegenerative disease that affects nerve cells in the brain and spinal cord.

The FDA has extended review time to allow for review of additional analyses of data from the company’s clinical studies. This move follows an 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.

The regulatory agency has accepted the NDA in December 2021 based data from the CENTAUR trial, which evaluated the therapy in 137 people with ALS. Patients who started on AMX0035 during the placebo-controlled phase of the trial demonstrated a 44% lower risk of death compared with those who started on placebo during the placebo-controlled phase. Median survival duration through the open-label long-term follow-up phase was 25.0 months in the group that started on AMX0035 and 18.5 months in the group that started on placebo.

But in materials released by the FDA ahead of the meeting, the agency indicated that the results of the primary endpoint is “not highly persuasive, without the significant support from secondary endpoints.” In fact, regulators indicated there was no survival benefit at 24 weeks. Regulators also had concerns about the fact that it was a small trial, there were issues drug study conduct, and about the appropriateness of statistical methods for efficacy analyses.

The company is 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 (RPSFTM), 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.

Post hoc analyses performed included a RPSFTM and subgroup analysis. As of the July 2020 cutoff date, results of the final overall survival in the intent-to-treat group showed a significantly longer median survival duration of 6.9 months in those originally randomized to AMX0035 compared with those originally randomized to placebo. At the March 2021 cutoff date, results showed a significantly lower hazard of death and longer median survival duration of 4.8 months in those originally randomized to AMX0035 compared with those originally randomized to placebo.

Sabrina Paganoni, M.D., Ph.D.

“The results of these long-term analyses of the CENTAUR trial provide further evidence that AMX0035 may offer a survival benefit in people with ALS and provide insights into potential new approaches to analyze survival data in ALS trials,” Sabrina Paganoni, M.D., Ph.D., principal investigator of the CENTAUR trial, said in a press release. She is also investigator at the Sean M. Healey & AMG Center for ALS at Mass General and associate professor of PM&R at Harvard Medical School and Spaulding Rehabilitation Hospital.

Amylyx is now recruiting for a phase 3 trial, called PHOENIX, which will enroll 600 patients comparing AMX0035 with placebo.

AMX0035 is an oral combination of two small molecules: sodium phenylbutyrate (PB), which is a small molecular chaperone designed to reduce the unfolded protein response (UPR), preventing cell death resulting from the UPR, and taurursodiol, which is a Bax inhibitor designed to reduce cell death through apoptosis. AMX0035 is designed to target the endoplasmic reticulum and mitochondrial-dependent neuronal degeneration pathways in ALS and other neurodegenerative diseases.

Applications for AMX0035 for the treatment of ALS are under review by Health Canada and the European Medicines Agency.