The agency pushed the PDUFA date back citing new data analyses that constitute a significant amendment to the NDA.
In the wake of a disappointing FDA AdComm review, Amylyx has announced that the FDA has pushed its pending PDUFA date for AMX0035— originally set for June 29, 2022—out 3 months to September 29, 2022.1
The decision to extend the review of Amylyx's investigational treatment for amyotrophic lateral sclerosis (ALS) stems from additional data analyses that were submitted for review. According to the FDA, the additions were significant enough to warrant a major amendment to the application, resulting in the extension.
"We are confident in the potential of AMX0035 to help people living with ALS and other neurodegenerative diseases, and we continue to work closely with the FDA as they complete their review," said Justin Klee and Joshua Cohen, co-CEOs and cofounders of Amylyx, in a statement.
The news follows a less than stellar review by the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee back in March,2 who voted 6–4 (6 no; 4 yes; 0 abstain) that the data from the phase 2/3 CENTAUR trial (NCT03127514) and open-label extension study did not adequately establish AMX0035 as an effective treatment for ALS.
Citing weak data and concerns over the trial's conduct, committee members grappled with the trial's shortcomings amid emotional and passionate pleas from members of the ALS community who delivered hours-long remarks during the meeting.
"It’s clear that there’s a very compelling degree of unmet need and it’s also clear that many with ALS are willing to accept the product as is and are willing to assume the risks associated with it," G. Caleb Alexander, MD, MS, member of the committee, said in his reasoning for voting no. "Despite this, law and statute and regulatory guidance are clear. There are many features of CENTAUR that limit its persuasiveness as a standalone trial in a regulatory sense."
Participants in the CENTAUR clinical trial were randomly assigned 2:1 to AMX0035 or matching placebo, administered twice daily by mouth or feeding tube for a planned duration of 24 weeks. Patients eligible for the open-label extension were given the option to enroll and receive the active drug for up to 132 weeks.
In November, Amylyx submitted its new drug application to the FDA for AMX0035, with data from CENTAUR showing that the trial met its primary end point.2 The company reported an average ALSFRS-R score of 2.32 points higher among AMX0035-treated patients (n = 87) than placebo (n = 48) after 24 weeks of treatment. 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 to –1.66 points per month with placebo (difference, 0.42 points per month; 95% CI, 0.03-0.81; P = .03).3
A survival analysis from CENTAUR published in 2020 showed that the therapy was associated with a 6.5-month longer median survival compared with placebo. In total, those treated with AMX0035 has a median overall survival of 25 months (95% CI, 19.0-33.6) compared with survival of 18.5 months in the placebo group (95% CI, 13.5-23.2) for a hazard ratio of 0.56 (95% CI, 0.34-0.92; P = .023), equating to a 44% lower risk of death.4
The estimated probability of survival at 1 year for those in the treatment group was 80.9% (95% CI, 71.1–87.7) and for placebo was 72.9% (95% CI, 58.0–83.3%). For 2 years, the estimates were 51.6% (95% CI, 38.9–62.9) and 33.9% (95% CI, 19.4–49.1), respectively. The median time to censoring was 21.3 months.
A phase 3 study, PHEONIX, is an ongoing 48-week, randomized, placebo-controlled trial whose efficacy outcomes are ALSFRS-R over 48 weeks and survival. It will also assess secondary efficacy outcomes such as change in slow vital capacity measured both at home with a self-administered spirometer to support virtual data collection and at clinic sites, serial assessments of patient-reported outcomes, ventilation-free survival rates, and others.