The single clinical trial Amylyx Pharmaceuticals presented to support approval of its ALS drug is “not exceptionally persuasive,” according to the briefing document the FDA released ahead of this week’s planned advisory panel, which will review the treatment.
Even though Amylyx was able to show positive results in a single, small study, the briefing document raises multiple concerns about the trial’s goals and whether the data is enough to support a regulatory nod. While the FDA can approve new medicines based on a single “adequate and well-controlled” study—and the agency has noted ALS is indeed an indication where this is a likely scenario—Amylyx’s data package from the Centaur trial had several deficiencies, according to meeting documents posted Monday morning.
Shares of the Cambridge, Massachusetts biotech more than halved after the documents were posted, falling 54% to $11.34 compared to a prior close of $25 apiece.
Centaur, a phase 2/3 137-patient trial, did turn up a positive result “on a prespecified but non-preferred” endpoint in ALS. But the FDA said the analysis should’ve properly accounted for deaths that occurred due to the nature of the disease even though those deaths were not a result of the treatment. AMX0035 is a combination of sodium phenylbutyrate and taurursodiol.
“The prespecified statistical result was not exceptionally persuasive, and there were analytical and interpretative issues associated with its consideration,” the briefing documents note.
The major question was whether the data showing a slowing in disease progression was adequate to anchor a drug approval. Amylyx was encouraged to “urgently” begin work on a late-stage trial to confirm the Centaur data. Nevertheless, the FDA allowed Amylyx to submit a new drug approval request before finishing the second phase 3
Amylyx did previously embark on that phase 3 trial, and the company also continued to evaluate data from the Centaur’s open-label extension, which showed a survival benefit. The FDA division, however, also expressed concerns about the survival advantage given the extension saw a number of patients drop out.
The FDA has wide leeway to consider the level of risk that patients with devastating diseases like ALS may be willing to tolerate. But the agency “had lengthy and thoroughly discussed presubmission reservations about the strength of the data” that Amylyx presented.
Now, the Peripheral and Central Nervous System Drugs Advisory Committee will meet Wednesday, beginning at 10 a.m. ET., to consider whether the evidence is enough to support the AMX0035’s regulatory approval in ALS.
The ongoing phase 3 aims to recruit 600 patients around the world and is expected to wrap up in 2024.
For its part, Amylyx argues that there is a significant unmet need in ALS and the Centaur study was relatively large compared to the usual standard in the field of ALS. The study was developed in accordance with FDA guidance for ALS trials with an endpoint geared towards assessing functional decline in daily activities plus a widely used scale for ALS treatment and care.
Amylyx did assess death as a critical endpoint, but the agency argues that deaths should have been accounted for on the primary endpoint. In March 2016 and again in March 2019, the FDA recommended that deaths be included in the primary endpoint analysis. Amylyx responded by expressing concern about the limitations of the analysis the FDA was suggesting. Secondary endpoints included muscle strength and respiratory function.
The endpoint Amylyx employed was also used to support the 2017 approval of Radicava, an ALS drug marketed by Mitsubishi Tanabe Pharma America. Deaths were again not assessed as the main outcome during the open-label portion of the trial, which focused on safety, according to the documents.