FDA Questions ‘Modest’ Benefit in ALS Drug
An FDA advisory committee briefing document on Amylyx Pharmaceuticals’ experimental amyotrophic lateral sclerosis (ALS) therapy AMX0035 provides no ringing endorsement from agency reviewers. Although the therapy is not under consideration for accelerated approval, many FDA watchers are painting another Biogen Aduhelm-type scenario due to patient advocacy group pressure urging additional therapy options due to ALS’ unmet need. FDA’s Peripheral and Central Nervous System Drugs Advisory Committee (PCNS) will take up the matter on 3/30.
The NDA submission is based on results from a Phase 2 trial that met its main endpoint of slowing disease progression, according to the company. While FDA initially said Amylyx needed to conduct a Phase 3 trial before seeking regulatory approval, company discussions with the agency led to filing the NDA based on the Phase 2 study results. A Phase 3 trial is now underway and expects to enroll 600 patients.
According to the briefing document, FDA reviewers found that the study “demonstrated only a modest p-value using non-preferred analysis methods that ignore the loss of data due to patient deaths during the study and relied on a questionable linearity assumption of the ALSFRS-R [ALS Functional Rating Scale-Revised] over time. There was also a moderate proportion of missing data and a randomization implementation problem such that the first 18 patients in a row received the drug, which reduce the persuasiveness of the study.”
FDA also found it necessary in the Conclusion Section of the document to recite its draft guidance on substantial evidence, which states: “Reliance on a single, large, multicenter trial to establish effectiveness should generally be limited to situations in which the trial has demonstrated a clinically meaningful and statistically very persuasive effect on mortality.” The agency further said that in Amylyx’s single trial, “there are questions about the statistical persuasiveness of the results for the variety of reasons…”
Notwithstanding FDA’s concerns about Amylyx’s submission, the agency appears to offer a glimmer of hope for the company and ALS patients. In the briefing document, FDA said: "The statutory standards for effectiveness apply to drugs developed for ALS, just as the standards apply for all other drug development. However, FDA has also long stressed the appropriateness of exercising regulatory flexibility in applying the statutory standards to drugs for serious disease with unmet medical needs, while preserving appropriate assurance of safety and effectiveness.”