FDA Reverses Course on NDA Submission for Amylyx ALS Drug

From Left: Amylyx Co-founders Justin Klee and Joshua Cohen/Courtesy Amylyx Pharmaceuticals. 

Five months after telling Amylyx Pharmaceuticals that it would require a Phase III trial to confirm the positive results from its Phase II CENTAUR trial of experimental amyotrophic lateral sclerosis (ALS drug) AMX0035, the U.S. Food and Drug Administration (FDA) has given Amylyx the go-ahead to submit a New Drug Application (NDA). 

Could this be the first indication – following approval of Biogen’s Alzheimer’s drug Aduhelm – that the regulator is beginning to change its evidence threshold on experimental drugs for neurological diseases with high unmet need?

Amylyx’s decision to submit the NDA, announced Wednesday morning, came on the heels of recent discussions with the FDA, including a pre-NDA meeting held on July 15. It is a reversal of course for the regulator, who in April told Amylyx that it would require an additional placebo-controlled study before it could submit for approval.

“I think it's been a progression of continued analysis, continued conversations that has ultimately led to this point,” Amylyx co-founder and co-CEO Joshua Cohen told BioSpace. “We've continued conversations, including the pre-NDA meeting, where we ultimately saw that the best course forward was indeed to submit the NDA and that the data from CENTAUR would be the basis of that NDA.”

In a 2:1 placebo trial comprised of 137 participants, half of whom were treated with AMX0035 for 24 weeks, the drug showed a 6 ½ month survival benefit for the treatment group. Patients on placebo were moved onto AMX0035 immediately following the 24 weeks. The median survival duration through the open-label long-term follow-up phase was 25.0 months in the group that started on AMX0035 compared to 18.5 months in the group that began on the placebo.

“I think the take-home is that this is the first time a treatment in ALS has shown a benefit in both function and survival, which, of course, being a progressive fatal illness is what one would want to see,” said Amylyx Co-founder and Co-CEO Justin Klee.

He noted that the company will continue to follow up with survival analysis over time as these numbers are only based on a six-month differential between the cohorts.

“While the survival benefit is very exciting, it's also probably an underestimate of the survival benefit, because after six months, everyone went on active treatment,” Klee said.

He added that analysis of secondary endpoints such as vital capacity and muscle strength “all moved in the right direction.”   

The decision, which came on the heels of the FDA’s refusal of Brainstorm Cell Therapeutics Inc.’s NurOwn – another drug with arguably more going for it than Aduhelm – sparked anger in the ALS community. This was particularly true because the drug demonstrated evidence of a clinically significant response in a pre-specified subgroup of patients with early-stage disease based on the ALS Functional Rating Scale.

“The ALS community has been demanding the same regulatory flexibility for AMX0035 and NurOwn. The FDA needs to do the same thing for ALS as they did for Alzheimer’s,” Nicole Cimbura, whose husband lost his battle to ALS in 2019, told BioSpace in a previous interview.  

Direction in hand, the co-execs told BioSpace that they are now working around the clock on the NDA submission and anticipate that a decision could come prior to the end of 2021. 

Amylyx previously filed a New Drug Submission (NDS) with Health Canada in June and is anticipating a decision somewhere around the 10-month timeframe (which is the norm for the regulator). The company also intends to submit a Marketing Authorization Application (MAA) for AMX0035 to the European Medicines Agency (EMA) by the end of 2021.

“We know people with ALS have no time to wait regardless of where you live, so we're going to keep pushing,” Cohen said.