Amylyx Discontinues AMX0035 Program in Supranuclear Palsy Following Disappointing Phase 2b Data

Camille L. Bedrosian, MD

Newly reported findings from the phase 2b ORION program revealed that AMX0035, an investigational agent of sodium phenylbutyrate and taurursodiol, did not meet its primary end point in adults with progressive supranuclear palsy (PSP). Based on these data, Amylyx Pharmaceuticals, the drug manufacturer, has decided to discontinue to the drug’s program in PSP, with no future phase 3 trial expected.¹

ORION, a trial of nearly 600 patients with PSP, was originally started in 2023 to test the efficacy and safety of AMX0035 as a potential treatment for PSP. After 24 weeks of double-blind treatment, results revealed no statistically significant differences on primary or secondary outcomes, which included Total Progressive Supranuclear Palsy Rating Scale, brain atrophy, quality of life, overall survival, and relevant biomarkers.

"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. 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," Camille L. Bedrosian, MD, chief medical officer at Amylyx, said in a statement. "We extend our gratitude to the participants, their families and care partners, the ORION sites, and the entire PSP community for their collaboration on this study."

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AMX0035, a combination therapy, was first approved as a treatment for amyotrophic lateral sclerosis (ALS) in 2022, but was voluntarily withdrawn from the market in 2024 based on negative confirmatory data.² The idea behind studying the agent in PSP came from its ability to mitigate tau pathology through multiple pathways, with preclinical evidence and data from the PEGASUS trial, a study of AMX0035 in Alzheimer disease (AD), to support this theory.

PEGASUS, a randomized, double-blind trial, included 95 patients with early-stage AD who were randomly assigned to AMX0035 (n = 51) or placebo (n = 45) for a 24-week period. While there was no difference in clinical outcomes on the primary end point of change in GST (between-group difference, 0.07; 95% CI, –0.08 to 0.21; P = .36), there were statistically significant lowering of both phosphorylated tau (p-tau)181 (P <.0001) and total tau (P <.0001), the hallmark protein of PSP, in the intent-to-treat cohort.³

Within this group, the study also revealed reductions in other neurodegeneration biomarkers of neurogranin (P <.0001) and FABP3 (P = .0004), as well as gliosis biomarker YKL-40 (P = .0005). In addition, there were trends of increasing amyloid-ß42/40 ratio (P = .07) and increases in 8-OHdG (P = .007), a marker of oxidative stress.

Justin Klee

"Amylyx remains committed to advancing potential new treatments for communities with high unmet needs. 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,” Joshua Cohen and Justin Klee, co-chief executive officers at Amylyx, said in a statement.¹ "We are also continuing development of AMX0035 in Wolfram syndrome and progressing AMX0114 in ALS, with early cohort data from the Phase 1 LUMINA trial expected in 2025."

Joshua Cohen

AMX0114 is a unique agent, designed as an antisense oligonucleotide targeting calpain-2. Calpain-2 is increasingly viewed as a therapeutic target for ALS because inhibiting it may reduce TDP-43 fragmentation, stabilize neuronal structures, and protect motor neurons. LUMINA, a randomized phase 1 study, includes 48 patients with ALS testing up to 4 doses of the investigational agent. The study primarily focuses on safety, however, includes other secondary outcomes like change in calpain-2 levels, neurofilament light levels, and other pharmacodynamic biomarkers of ALS.⁴

REFERENCES
1. Amylyx Pharmaceuticals to Discontinue ORION Program of AMX0035 for Progressive Supranuclear Palsy (PSP). News release. Amylyx Pharmaceuticals. August 27, 2025. Accessed August 28, 2025. https://www.businesswire.com/news/home/20250827304923/en/Amylyx-Pharmaceuticals-to-Discontinue-ORION-Program-of-AMX0035-for-Progressive-Supranuclear-Palsy-PSP
2. Amylyx Pharmaceuticals Announces Formal Intention to Remove RELYVRIO®/ALBRIOZA™ from the Market; Provides Updates on Access to Therapy, Pipeline, Corporate Restructuring, and Strategy. News Release. Amylyx Pharmaceuticals. Published April 4, 2024. Accessed August 28, 2025. https://www.businesswire.com/news/home/20240404501040/en/Amylyx-Pharmaceuticals-Announces-Formal-Intention-to-Remove-RELYVRIO%C2%AEALBRIOZA%E2%84%A2-from-the-Market-Provides-Updates-on-Access-to-Therapy-Pipeline-Corporate-Restructuring-and-Strategy
3. Arnold SE, Hendrix S, Nicodemus-Johnson J, et al. Biological effects of sodium phenylbutyrate and taurursodiol in Alzheimer’s disease. Alzheim Assoc. 2024;10(3):e12487. doi:10.1002/trc2.12487
4. Amylyx Pharmaceuticals Announces First Participant Dosed in Phase 1, Multiple Ascending Dose LUMINA Trial of AMX0114 in People Living with Amyotrophic Lateral Sclerosis. News release. Amylyx Pharmaceuticals. April 9, 2025. Accessed August 28, 2025. https://www.biospace.com/press-releases/amylyx-pharmaceuticals-announces-first-participant-dosed-in-phase-1-multiple-ascending-dose-lumina-trial-of-amx0114-in-people-living-with-amyotrophic-lateral-sclerosis