Key Details of Phase 3 ORION Study of AMX0035 in Progressive Supranuclear Palsy: Gunter Hoglinger, MD

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The professor of neurology and translational neuroscientist at Ludwig-Maximillian’s University Munich discussed the reasons behind specific inclusion criteria and outcomes used in the phase 3 ORION study of AMX0035 in progressive supranuclear palsy. [WATCH TIME: 4 minutes]

WATCH TIME: 4 minutes

"The most important aspects when choosing patients for this trial is to have specificity for the underlying neurobiology. We know that possible and probably patients with Richardson syndrome, as diagnosed by the MDS criteria, have a high specificity of more than 90% to have an underlying tau pathology."

Progressive supranuclear palsy (PSP) is a rare, progressive, and fatal tauopathy that affects body movements, walking and balance, and eye movement. Associated with tau dysfunction, tau aggregation, and widespread neurodegeneration, patients with the disease typically live 6-8 years after being diagnosed. Above all, there remains no approved disease-modifying therapies available and many of the symptoms usually do not respond well to off-label medications.

In May, Amylyx Pharmaceuticals announced a global, phase 3 trial to assess AMX0035 (Relyvrio), a coformulation of sodium phenylbutyrate and taurursodiol, as a potential treatment for PSP, with intentions of launch before the end of 2023. Otherwise known as ORION, the study is expected to enroll 600 adult participants with PSP who will be assessed over a 52-week double-blind period, followed by an optional 52-week open-label extension. AMX0035, which became the third FDA-approved therapy for amyotrophic lateral sclerosis (ALS) in September 2022, is thought to mitigate tau pathology in PSP through multiple pathways, with preclinical evidence and data from the PEGASUS trial, a study of AMX0035 in Alzheimer disease (AD), to support this theory.

In the PEGASUS study of AMX0035, treatment with the agent demonstrated a statistically significant lowering of both phospho-tau181 and total tau in the CSF of people living with AD, the hallmark protein of PSP. Not only was there an effect on tau biomarkers, but in a proteomics analysis of the PEGASUS data, of 288 measured proteins, tau was the most changed with highly significant differences vs. placebo. Of note, AMX0035 is not approved in any country for use in AD.

The trial will use change in Total Progressive Supranuclear Palsy Rating Scale (PSPRS), a 28-item assessment, as the primary end point, with other additional end points of brain atrophy, quality of life, overall survival, and relevant biomarkers. To learn more about the reasons behind the inclusion criteria and outcomes used in ORION, NeurologyLive® sat down with Gunter Hoglinger, MD, principal investigator of the study. Hoglinger, who also serves as a professor of neurology and translational neuroscientist at Ludwig-Maximillian’s University Munich, discussed the importance of identifying patients with PSP without other underlying disease pathologies.

REFERENCES
1. Progressive supranuclear palsy (PSP) investor and analyst conference call. News release. Amylyx Pharmaceuticals. July 26, 2023. Accessed September 20, 2023. https://investors.amylyx.com/static-files/4a2e66ce-8516-488c-9745-29164875869f
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