In a close call, an FDA advisory committee said data from a single trial for AMX0035, an investigational agent being studied to treat amyotrophic lateral sclerosis (ALS), did not support a conclusion that the drug was effective.
The 6-4 vote of the Peripheral and Central Nervous System Drugs Advisory Committee was based on findings from the phase II study and supported the FDA's position that the study results may not be "sufficiently persuasive."
AMX0035 is a proprietary combination of sodium phenylbutyrate and taurursodiol from Amylyx Pharmaceuticals. In CENTAUR, AMX0035 appeared to slow functional decline in people with rapidly advancing ALS compared with placebo over 24 weeks, showing an improvement of 2.32 points (P=0.034) on the 48-point ALS Functional Rating Scale-Revised. Secondary outcomes were not significantly different between the two groups and adverse events mostly were gastrointestinal.
Data from an of CENTAUR suggested that AMX0035 reduced the risk of death by 44% compared with placebo over a maximum follow-up of about 3 years. "This is the first time that we have seen a benefit in both function and survival in an ALS clinical trial," said principal investigator Sabrina Paganoni, MD, PhD, of Massachusetts General Hospital in Boston, who spoke at Wednesday's .
"I found this a very difficult decision," said advisory committee member Dean Follmann, PhD, an NIH statistician who voted yes, in support of the drug. "I went back and forth during the day, but ultimately I agreed with the sponsor's primary analysis."
"It's clear that there's a very compelling degree of unmet need," added committee member Caleb Alexander, MD, MS, of Johns Hopkins Bloomberg School of Public Health in Baltimore, who voted no. "It's also clear that many with ALS would accept the product as is and are willing to assume the risks associated with it, including the risk that it may not work."
"Despite this, law and statute and regulatory guidance are clear," Alexander pointed out. "And unfortunately, there are many features of CENTAUR that limit its persuasiveness as a standalone trial in a regulatory sense."
"The good silver lining is you have a trial ongoing that could potentially resolve the uncertainties that this trial presents," observed committee member Liana Apostolova, MD, MS, of Indiana University School of Medicine in Indianapolis, who also voted no.
There's no cure for ALS and in recent years, the FDA has faced increasing pressure to approve new drugs for the disease. "I want to assure both the ALS community and the committee that we at the FDA have heard the concerns of the ALS community," said Teresa Buracchio, MD, Director of the FDA's Division of Neurology, in the meeting's opening remarks.
"I want to stress that we have not made any final decisions on the approvability of this application," Buracchio added. "Our concerns should not be viewed as necessarily indicative of our final decision."
The advisory committee vote is nonbinding and serves as a recommendation to the FDA, which is scheduled to approve or reject AMX0035 on or by June 29. Amylyx already has started its phase III PHOENIX trial of approximately 600 people with ALS in Europe and the U.S. and said it's committed to that study no matter what the agency decides.
The FDA asked the wrong question, noted ALS Association CEO and president Calaneet Balas, MSc, MBA, who spoke at the advisory committee meeting.
"A better question would be, do we know enough about the safety and effectiveness of AMX0035 to make it a treatment option for people living with ALS today? The answer would be a definitive yes," Balas said."We all want certainty, but the only certainty today is that ALS is cruel and it is fatal."