Data Not Conclusive on Amylyx ALS Drug: FDA
FDA reviewers appear pessimistic that new analyses and data from Amylyx can push its amyotrophic lateral sclerosis (ALS) drug AMX0035 (sodium phenylbutyrate and taurursodiol) across the approval finish line as the submission heads to a 9/7 Peripheral and Central Nervous System Drugs Advisory Committee meeting. Earlier this year, the ALS drug was rejected by the same committee, voting 6-4 that the company did not offer conclusive proof that its drug works. Shortly after the meeting, Amylyx submitted the new analyses and data, which constitutied a “major amendment” to its application.
In a just-posted briefing document, FDA seems to still be leaning on its recommendation for a confirmatory trial made before Amylyx originally submitted the NDA. The agency notes that the company has an ongoing Phase 3 study in 600 patients with ALS worldwide. It has currently enrolled over 50% of the proposed study population and it is expected to complete in late 2023 to early 2024.
As part of the major amendment, Amylyx submitted randomized, long-term overall survival information that is intended to highlight a critical and complementary finding to the primary outcome and analyses. “The applicant contends that survival analyses from CENTAUR and the OLE [open-label extension study] can also serve as confirmatory evidence for the effectiveness of AMX0035 in ALS, given that death is an objective assessment,” the reviewers note.
They say there are a “variety of concerns about the reliability of this analysis. Notably, this is a non-randomized comparison to an external control that is subject to potential confounding due to differences between the AMX0035-treated patients and the external controls in unmeasured prognostic factors, measured prognostic factors not accurately measured or captured by the survival prediction model, and/or supportive care/interventions. FDA also notes that patients in the natural history database were not in a clinical trial which could also lead to differences between the groups. Furthermore, there was no pre-specified protocol and/or analysis plan for this comparison and post hoc analyses are challenging to interpret.”
Additionally, FDA is preemptively dismissing consideration of using the accelerated approval pathway for AMX0035. “Accelerated approval concerns the character of the endpoints, not the strength of the results on those endpoints,” the reviewers write in the briefing document. “An effect on an endpoint supporting accelerated approval must be an effect on an endpoint that in its character is reasonably likely to predict clinical benefit and, in its persuasiveness, provides substantial evidence of effectiveness from adequate and well controlled trials, just as substantial evidence of effectiveness on a clinically meaningful endpoint from adequate and well controlled trials supports traditional approval.”
The document further states that in the case of the ALS drug, “we do not have data for an effect of AMX0035 on an endpoint that is reasonably likely to predict clinical benefit for ALS.”