Despite the positive results demonstrated in a prior phase 2 trial, AMX0035 failed to meet the phase 3 trial’s primary end point in treating patients with amyotrophic lateral sclerosis.
The FDA announced the discontinuation of marketing authorizations for the combination of sodium phenylbutyrate and taurursodial (Relyvrio, AMX0035; Amylyx Pharmaceuticals), a therapy to treat amyotrophic lateral sclerosis (ALS), in the US and Canada. The process was initiated voluntarily by Amylyx Pharmaceuticals and the decision to remove the product from the market was made following results from the phase 3 PHOENIX trial (NCT05021536). Effective immediately, Relyvrio will no longer be available, although patients with ALS who are currently receiving the therapy and want to continue with treatment can be transitioned to a free drug program with their physician’s consultation.1
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Relyvrio is an oral, fixed-dose combination of sodium phenylbutyrate and taurursodiol that was designed to slow or lessen the severity of ALS-related neurodegeneration by targeting endoplasmic reticulum (ER) stress and mitochondrial dysfunction. The drug demonstrated positive results in a prior phase 2 trial.1
“While this is a difficult moment for the ALS community, we reached this path forward in partnership with the stakeholders who will be impacted and in line with our steadfast commitment to people living with ALS and other neurodegenerative diseases. The decision to remove Relyvrio from the market and provide therapy free of charge for those who wish to continue was informed by the PHOENIX trial results, engagement with regulatory authorities, and discussions with the ALS community,” said Joshua Cohen and Justin Klee, co-CEOs of Amylyx, in a press release.1
1. PHOENIX Trial
2. CENTAUR Trial
The PHOENIX trial is a global, randomized, placebo-controlled phase 3 clinical trial that spanned 48 weeks and evaluated Relyvrio versus placebo in 664 patients with ALS. Participants were randomly assigned into groups, but both received standard-of-care in addition to continuing a stable dosing regimen of riluzole with or without edaravone.2
Although Relyvrio maintained a consistent safety and tolerability profile with no new safety signals, it failed to meet the study’s primary end point and demonstrate changes from baseline in ALS Functional Rating Scale-Revised (ALSFRS-R) score at 48 weeks (p = .667). Further, there were no significant differences observed across the secondary end points, which were overall survival, quality of life and patient-reported outcome assessments, and respiratory function as measured by slow vital capacity.2
The PHOENIX trial followed the 6-month, multicenter, placebo-controlled, randomized phase 2 CENTAUR trial that had an open-label, long-term follow-up phase (NCT03127514). This trial evaluated Relyvrio in 137 participants with ALS and demonstrated positive results, meeting the primary efficacy end point of reducing functional decline as measured by the ALSFRS-R scale. Further, reported rates of adverse events and discontinuations were similar between the Relyvrio and placebo groups during the 24-week randomized phase; however, gastrointestinal events occurred with greater frequency (≥2%) in the Relyvrio group.2
“We are surprised and deeply disappointed by the PHOENIX results following the positive data from the CENTAUR trial,” said Klee and Cohen in a previous press release. “Our main priority at the moment is sharing the information with people living with ALS and their treating physicians; this is part of our continued commitment to them and our mission. Over the next 8 weeks, our team will continue to engage with regulatory authorities and the ALS community to discuss the results from PHOENIX.”2
Despite the results from the PHOENIX trial, researchers are continuing to investigate treatment methods for patients with ALS. One potential therapy that has been evaluated in preclinical trials is AMX0114, an antisense oligonucleotide that targets the gene encoding calpain-2, which is a key contributor to the axonal degeneration pathway that is an early contributor to the clinical presentation and pathogenesis of ALS along with other neurogenerative diseases. In the preclinical trials, the drug showed efficacy in reducing extracellular neurofilament light chain levels following neurotoxic insult in iPSC-derived human motor neurons.2
“Our pipeline is supported by compelling clinical and preclinical science demonstrating the potential of AMX0035 and AMX0114 in neurodegenerative diseases…We also remain focused on ALS and believe AMX0114 has strong potential for the treatment of ALS and other diseases,” said Camille L. Bedrosian, MD, chief medical officer of Amylyx. “Calpain-2 is considered an essential protein in the process of axonal degeneration and has been repeatedly linked to neurofilament biology in published studies. In our preclinical studies of AMX0114 and in multiple independent published studies, inhibition of calpain-2 has reduced cell death and degeneration and decreased neurofilament levels. We expect to initiate a clinical trial studying AMX0114 in ALS in the second half of this year.”1
Despite the poor showing in the PHOENIX trial, researchers are continuing to assess the safety and efficacy of Relyvrio in other neurodegenerative conditions. Currently, it is being studied as a potential treatment for Wolfram syndrome and progressive supranuclear palsy, in the open-label phase 2 HELIOS trial (NCT05676034) and the global, randomized, double-blind, placebo-controlled phase 3 ORION trial (NCT06122662), respectively.1,2
“…Together, the work we have accomplished across the world has helped build a vital foundation to achieve our mission of 1 day ending the suffering caused by neurodegenerative diseases, which continue to have critical, unaddressed needs,” said Cohen and Klee in the press release.1
