Amylyx's ALS therapy in limbo after confirmatory trial fails

08 Mar 2024
firstwordpharma.com
Phase 2Phase 3OligonucleotideDrug Approval
A confirmatory study of Amylyx Pharmaceuticals' amyotrophic lateral sclerosis (ALS) therapy Relyvrio (sodium phenylbutyrate/taurursodiol) failed to meet its primary endpoint, casting doubt on the fate of a drug controversially approved by the FDA in 2022 despite uncertainty about its effectiveness. The news sent company shares crashing as much as 86% on Friday, leaving Amylyx with a market value below $280 million.
The failure of Amylyx's drug is likely to fuel more questions about whether the FDA should continue to approve treatments for debilitating conditions such as ALS on the basis of limited trial evidence.
"We are surprised and deeply disappointed by the PHOENIX results," remarked Justin Klee and Joshua Cohen, joint CEOs of Amylyx. In light of the trial failure, the company said it will voluntarily pause promotion of Relyvrio while it weighs its options, which include withdrawing the $158,000-a-year treatment from the market.
Missed all endpoints
"We will be led in our decisions by two key principles: doing what is right for people living with ALS, informed by regulatory authorities and the ALS community, and by what the science tells us," Klee and Cohen said. The company added that it will be gathering feedback from various stakeholders within the next eight weeks.
In the 664-patient PHOENIX study, results showed that there was no significant difference between Relyvrio and placebo in ALS Functional Rating Scale-Revised (ALSFRS-R) total score at 48 weeks. Further, no significant difference was observed in the subset of participants who had met the Phase II CENTAUR trial criteria, nor were there any across the study's secondary endpoints.
Controversial call
Approval of Relyvrio came after it faced two advisory committee meetings as the FDA looked to make sense of the CENTAUR data, which drew persistent scepticism from the agency’s scientists. At the second AdCom meeting, Klee had also committed to withdrawing the drug should it ultimately show no significant benefit in the PHOENIX trial.
Despite the lingering questions, and amid pressure from patient-advocacy groups including the ALS Association, the regulator went ahead and approved the medicine instead of waiting two years for the PHOENIX results, noting at the time that it exercised its "regulatory flexibility" in reaching its decision. Since then, some 4000 patients in the US have received the treatment.
Meanwhile, European regulators have remained steadfast in denying approval of Amylyx’s drug, reaffirming late last year a decision not to authorise the fixed-dose combination. For related analysis, see Spotlight On: Amylyx tea leaf-readers may be seeing mixed messages.
"We are certain there will be important learnings that will help inform future ALS research," the co-CEOs said, indicating that they may pursue the drug, also known as AMX0035, as a potential treatment for other neurodegenerative diseases such as Wolfram syndrome (WS) and progressive supranuclear palsy (PSP). Amylyx completed enrolling the Phase II HELIOS trial in WS last month, and recently kicked off the Phase III ORION study of the drug in PSP. It is also working on the investigational antisense oligonucleotide AMX0114, which targets calpain-2, as a possible ALS therapy.
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