In an unexpected reversal, an FDA advisory committee voted 7-2 on Wednesday to support approval of AMX0035, an investigational drug being evaluated for amyotrophic lateral sclerosis (ALS).
In late March, the same panel voted 6-4 that data from a single trial -- the phase II CENTAUR study -- did not support a conclusion that AMX0035 was effective.
CENTAUR showed AMX0035 slowed functional decline in ALS patients, most of whom were already taking two FDA-approved ALS medications, riluzole (Rilutek) and edaravone (Radicava).
Wednesday's vote was based on prior and new evidence, the seriousness of ALS and the unmet needs of ALS patients, and the status of an ongoing phase III trial of the novel sodium phenylbutyrate-taurursodiol drug.
The new information boosted support for the drug, some advisory committee members said.
"I voted yes," said Robert Alexander, MD, of the University of Arizona and Banner Alzheimer's Institute in Phoenix. "I felt that there was now additional evidence to believe that there is a survival benefit associated with the drug and that, in my mind, was sufficient to change my vote."
At the advisory committee meeting, drugmaker Amylyx presented new CENTAUR survival benefit analyses, additional analyses comparing CENTAUR outcomes with natural history data and with treatment-naive participants from historical ALS clinical trials, and biomarker evidence from CENTAUR and from the study of AMX0035 in Alzheimer's disease.
These new analyses did not provide independent confirmatory evidence of the clinical effect of AMX0035 in ALS, FDA staff reviewers argued -- and some advisory committee members agreed.
"I voted no," said Caleb Alexander, MD, MS, of Johns Hopkins Bloomberg School of Public Health in Baltimore. "I voted no last time and, unfortunately, I don't believe the evidence that we've reviewed, while promising, constitutes substantial evidence of effectiveness."
In both PEGASUS and CENTAUR, the one biomarker studied most in neurodegenerative diseases -- neurofilament light, a marker of axonal damage -- showed no change in people treated with AMX0035, which was "concerning," said advisor Avindra Nath, MD, of the NIH's National Institute of Neurological Disorders and Stroke in Bethesda, Maryland, who nonetheless voted yes.
In his opening remarks, FDA Office of Neuroscience Director Billy Dunn, MD, emphasized that ALS drugs may require more flexibility than usual from regulators.
Regulatory flexibility means increased tolerance for concluding a drug is effective when there is residual uncertainty it may not be, and decreased tolerance for concluding a drug is ineffective when there is residual uncertainty it may actually work, Dunn noted.
"Have we done this in ALS? We most certainly have," he said. "Both of our novel approvals were based on the application of substantial regulatory flexibility."
Being flexible could pose a problem if AMX0035 is approved soon and its ongoing phase III trial, which is scheduled to have topline results in 2024, reads out negative, Dunn indicated.
But Amylyx co-CEO Justin Klee said if that happens, his company will "do what is right for patients," which includes voluntarily removing the drug from the market.
Dunn's call for flexibility and Klee's statement, coupled with testimonies from patients and advocates, swayed several advisory committee members.
"I was persuaded by the seriousness of the disease and the unmet need, but I was also struck by the public statement of the CEO committing them to voluntarily withdraw the drug if the phase III study is negative," said Bryan Traynor, MD, PhD, of the NIH's National Institute on Aging in Bethesda.
"I voted yes. I voted no last time," said Thomas Montine, MD, PhD, of Stanford University in California. "The seriousness of the disease, the unmet medical need, the moving testimonies of patients and families, the consistent testimony of experts in treating patients with ALS ... although there are still limitations, in aggregate, my judgement was for yes, to support."
Wednesday's advisory committee vote is nonbinding and serves as a recommendation to the FDA, which is scheduled to decide whether to approve AMX0035 by September 29.
In June, to approve the drug (marketed as Albrioza) for ALS, contingent on the provision of data from the PHOENIX study.