Executive Summary
This report documents the complete FDA regulatory chronology for Relyvrio (AMX0035), developed by Amylyx Pharmaceuticals for the treatment of amyotrophic lateral sclerosis (ALS). The timeline spans 22 interactions between March 2016 and July 2021, covering the progression from a Pre-IND letter through IND submission, multiple designation setbacks, and pre-NDA planning ahead of Amylyx's target NDA submission in late 2021.
The early regulatory trajectory was marked by friction. Two consecutive Fast Track designation denials in 2018, and a Breakthrough Therapy Designation denial in March 2020, were grounded in FDA's insistence on a joint rank primary analysis of function and survival and on evidence of superiority over both approved ALS therapies (riluzole and edaravone), signaling the agency's heightened evidentiary bar for a field where prior drugs had set a modest benchmark. A pivotal Type C meeting in March 2020 nonetheless established that Amylyx had communicated a statistically significant Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) joint rank result to the Division (FDA's Division of Neurology 1, the neurological drug reviewing office within the Center for Drug Evaluation and Research), which became a foundation for subsequent NDA discussions.
By mid-2021, the regulatory posture had shifted toward pre-NDA alignment. The July 2021 Type B Pre-NDA meeting confirmed FDA's acceptance of interim data from the ongoing Phase 3 PHOENIX study (A35-004) as a post-submission supplement rather than a filing requirement, deferred carcinogenicity and DDI studies post-approval, and confirmed that those omissions would not constitute filing issues, with Amylyx committing to an NDA submission target of end of November 2021.
Relyvrio received FDA approval on September 29, 2022. The drug was subsequently withdrawn from the US and Canadian markets on April 4, 2024, after Amylyx voluntarily discontinued its marketing authorizations following negative topline results from the Phase 3 PHOENIX trial. PHOENIX was the large confirmatory study that had been a central planning topic throughout Amylyx's pre-NDA discussions with FDA, and its failure to replicate the functional improvements seen in the Phase 2 CENTAUR study left Relyvrio without the confirmatory evidence of clinical benefit that had been a condition of its regulatory acceptance. Specific outcome data from the PHOENIX trial are not available in the source files accompanying this report.
Below is a timeline of key regulatory events that took place leading up to Relyvrio's initial FDA approval.