Objective: Here we describe ORION, a phase 3 trial assessing efficacy and safety of AMX0035 in progressive supranuclear palsy (PSP).

Background: PSP is a rare, progressive, fatal, tauopathy with no available disease-modifying treatments. Amx0035 is an oral, fixed-dose combination of sodium phenylbutyrate (PB) and taurursodiol (TURSO; also known as ursodoxicoltaurine) hypothesized to simultaneously target unfolded protein response and mitochondrial dysfunction. In clinical trials, PB and TURSO altered cerebrospinal fluid (CSF) Alzheimer’s disease biomarkers (tau and markers of synaptic/neuronal degeneration, gliosis, and DNA oxidation) and exhibited an acceptable safety profile (gastrointestinal events occurred with greater frequency with PB and TURSO).

Method: ORION will enroll ~600 participants in Europe, Japan, and North America (≤135 centers). Inclusion criteria include: ambulant adults 40-80 years of age; possible/probable PSP-Richardson syndrome diagnosis (Movement Disorder Society [MDS] 2017 criteria); PSP symptoms for <5 years; score of <40 on the total Progressive Supranuclear Palsy Rating Scale (PSPRS); a score of ≥24 on the Mini Mental State Examination; and on stable dose of antiparkinsonian drugs for 60 days before enrollment. Participants will be followed for 12 months with an optional 12-month open label extension period.  The primary efficacy end point evaluates disease progression from baseline to Week 52 on the total PSPRS score. Safety assessments include the frequency of treatment-emergent adverse events and serious adverse events. Secondary efficacy endpoints include progression of the MDS-Unified Parkinson’s Disease Rating Scale Part II Score. Exploratory outcomes include changes in activities of daily living, cognitive function, quality of life, overall survival, brain volume, fluid biomarkers of neuronal injury/inflammation, and caregiver burden.

Results: Trial sites are activating globally on a rolling basis. The first participant was enrolled in late 2023.

Conclusion: Updated enrollment status will be presented at the MDS annual meeting. This research was previously presented at the AD/PD 2024 Alzheimer’s & Parkinson’s Diseases Conference on March 6, 2024.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/orion-a-global-phase-3-randomized-double-blind-placebo-controlled-trial-of-amx0035-in-progressive-supranuclear-palsy-a35-009/