Amylyx Pharmaceuticals has terminated development of AMX0035 for progressive supranuclear palsy (PSP) after the investigational drug failed to demonstrate efficacy in a Phase 2b clinical trial. The company announced Wednesday that AMX0035 showed no significant differences compared to placebo on primary or secondary outcomes at the 24-week follow-up in the ORION study.
The decision marks a significant setback for the Cambridge, Massachusetts-based biotech, which had designed the ORION program as a Phase 2b/3 trial with plans to advance to Phase 3 upon positive results. The study, which targeted enrollment of 110 patients, primarily assessed AMX0035's ability to slow disease progression in adults living with PSP.
Trial Results and Safety Profile
AMX0035 failed to outperform placebo across all measured endpoints, including secondary outcomes such as improvements in motor aspects of activities of daily living. Despite the lack of efficacy, the drug candidate maintained a favorable safety profile consistent with previous studies and was generally well-tolerated by participants.
"We set a high bar for AMX0035 in PSP and made a commitment to base our decision-making on the totality of the data and the potential for clinically meaningful outcomes for those living with PSP," said Camille L. Bedrosian, MD, Chief Medical Officer at Amylyx. "While we are disappointed in these results, we believe these data will inform the PSP trial literature as well as deepen scientific understanding of this devastating disease."
Based on these findings, Amylyx will discontinue both the Phase 2b trial and its open-label extension, while abandoning plans to initiate the Phase 3 portion of the program.
Understanding Progressive Supranuclear Palsy
Progressive supranuclear palsy represents a significant unmet medical need, affecting approximately seven in 100,000 people worldwide. This sporadic, rare, and fatal neurodegenerative disorder impacts multiple neurological functions, including movement, gait, balance, eye movements, swallowing, and speech. Patients typically face a life expectancy of six to eight years following initial diagnosis, with the disease typically beginning in late-middle age and rapidly progressing over time. Currently, no disease-modifying therapies are approved for PSP treatment.
AMX0035 Mechanism and Continued Development
AMX0035 is an oral, fixed-dose combination of sodium phenylbutyrate and taurursodiol designed to target endoplasmic reticulum stress and mitochondrial dysfunction—two interconnected pathways that contribute to cell death and neurodegeneration. Amylyx developed the proprietary combination with the belief that the complementary mechanisms of action would synergistically target abnormal cell death more effectively than treatments addressing either mechanism alone.
Despite the PSP setback, Amylyx will continue evaluating AMX0035 as a potential treatment for Wolfram syndrome, with updates expected later this year.
Strategic Refocus on Avexitide
The company's leadership emphasized that avexitide remains their highest priority moving forward. "Our highest priority and focus remain on the pivotal Phase 3 LUCIDITY trial of avexitide, with enrollment expected to complete in 2025 and topline data anticipated in the first half of 2026," stated co-CEOs Joshua Cohen and Justin Klee.
Avexitide, a first-in-class glucagon-like peptide-1 receptor antagonist, has received FDA Breakthrough Therapy Designation for both post-bariatric hypoglycemia and congenital hyperinsulinism. The drug candidate has demonstrated highly statistically significant reductions in hypoglycemic events in two Phase 2 PBH clinical trials.
The ongoing LUCIDITY trial is an approximately 75-participant, multicenter, randomized, double-blind, placebo-controlled Phase 3 study evaluating avexitide's efficacy and safety in participants with post-bariatric hypoglycemia following Roux-en-Y gastric bypass surgery. Post-bariatric hypoglycemia affects an estimated 8% of people in the U.S. who have undergone the two most common types of bariatric surgery, representing approximately 160,000 people with no currently approved therapies.
Pipeline and Financial Outlook
Beyond avexitide, Amylyx continues advancing AMX0114, an antisense oligonucleotide for amyotrophic lateral sclerosis. Early cohort data from the Phase 1 LUMINA trial are expected in 2025.
The company maintains its financial guidance, expecting its cash runway to extend through the end of 2026, providing sufficient resources to advance its key programs through critical milestones.
