AMX0035 and Progressive Supranuclear Palsy (ORION)

A Phase 2b/3 Study of the Safety and Efficacy of AMX0035 in Progressive Supranuclear Palsy (ORION)

A35-009 (ORION) is a Phase 2b/3 trial to evaluate the efficacy and safety of AMX0035 in participants with Progressive Supranuclear Palsy (PSP), consisting of randomized, double blind placebo controlled phases, followed by an optional open-label extension phase.

Study Overview

• Status: Completed
• Conditions: Neurodegenerative Diseases; Progressive Supranuclear Palsy; Atypical Parkinsonism; PSP
• Intervention / Treatment: Other: Placebo; Drug: AMX0035

Detailed Description

AMX0035 is a fixed dose combination therapy designed to reduce neuronal death through blockade of key cellular death pathways originating in the endoplasmic reticulum (ER) and mitochondria. This clinical trial is designed to demonstrate that AMX0035 is safe and tolerable, and to assess its effect on disease progression as measured by the Progressive Supranuclear Palsy (PSP) Rating Scale (PSPRS) over a 52-week double-blind phase. The Phase 2b and Phase 3 study portions are planned to feature an identical design: a randomized, double-blind, placebo-controlled phase that is followed by an optional open-label extension (OLE) phase. The phase 3 portion of ORION may be initiated based on results of the phase 2b Interim Analysis and/or the Primary Analysis and the totality of data from the Phase 2b study portion.

• Study Type: Interventional
• Enrollment (Actual): 139
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• France
  • Paris, France, 75013
    • Groupe Hospitalier Pitie-Salpetriere
  • Bouches-du-Rhône
    • Marseille, Bouches-du-Rhône, France, 13385
      • Hopital de la Timone
  • Gard
    • Nîmes, Gard, France, 30029
      • Hopital Caremeau
  • Gironde
    • Bordeaux, Gironde, France, 30076
      • Groupe Hospitalier Pellegrin - Hôpital Pellegrin
  • Haute Vienne
    • Limoges, Haute Vienne, France, 87042
      • CHU de Limoges - Hôpital Dupuytren
  • Ille Et Vilaine
    • Rennes, Ille Et Vilaine, France, 35033
      • CHU Rennes - Hôpital Pontchaillou
  • Nord
    • Lille, Nord, France, 59037
      • Hopital Roger Salengro - CHU Lille
• Germany
  • Baden-Wurttemberg
    • Ulm, Baden-Wurttemberg, Germany, 89081
      • Universitaetsklinikum Ulm
    • Ulm, Baden-Wurttemberg, Germany, 89081
      • Universitaetsklinikum Duesseldorf AoeR
  • Bavaria
    • Hausham, Bavaria, Germany, 83734
      • Krankenhaus Agatharied
    • Munich, Bavaria, Germany
      • Klinikum der Universitat Munchen
  • Hesse
    • Kassel, Hesse, Germany, 34128
      • Paracelsus-Elena-Klinik Kassel
  • Saxony
    • Dresden, Saxony, Germany, 1307
      • Universitaetsklinikum Carl Gustav Carus TU Dresden
  • Thuringia
    • Stadtroda, Thuringia, Germany, 7646
      • Asklepios Fachklinikum Stadtroda
• Italy
  • Milan, Italy, 20122
    • Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
  • Milan, Italy, 20133
    • Fondazione IRCCS Istituto Neurologico Carlo Besta
  • Padova, Italy, 35128
    • Azienda Ospedale-Università di Padova
  • Roma, Italy, 168
    • Fondazione Policlinico Universitario Agostino Gemelli IRCCS
  • Roma, Italy, 185
    • Azienda Ospedaliera Universitaria Policlinico Umberto I - Università di Roma La Sapienza
  • Salerno, Italy, 84131
    • Azienda Ospedaliera Universitaria OO. RR. S. Giovanni di Dio e Ruggi D'Aragona
• Spain
  • Barcelona, Spain, 8036
    • Hospital Clinic de Barcelona
  • Madrid, Spain, 28034
    • Hospital Universitario Ramon y Cajal
  • Madrid, Spain, 28006
    • Hospital Universitario de La Princesa
  • Seville, Spain, 41013
    • Hospital Universitario Virgen del Rocio
  • Bizkaia
    • Barakaldo, Bizkaia, Spain, 48903
      • Hospital de Cruces
  • Navarre
    • Pamplona, Navarre, Spain, 31008
      • Clinica Universidad de Navarra
  • València
    • Valencia, València, Spain, 46026
      • Hospital Universitari i Politecnic La Fe
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85259
      • Mayo Clinic
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • University of Arkansas for Medical Sciences
  • California
    • Fountain Valley, California, United States, 92708
      • Parkinson's & Movement Disorder Institute
    • Los Angeles, California, United States, 90033
      • University of Southern California
    • Los Angeles, California, United States, 90048
      • Cedars Sinai Medical Center
    • Palo Alto, California, United States, 94304
      • Stanford Movement Disorder Center
    • San Francisco, California, United States, 94158
      • University of California, San Francisco (UCSF)
  • Colorado
    • Aurora, Colorado, United States, 80045
      • UC Health Anschutz Outpatient Pavilion Anschutz Medical Campus
  • Florida
    • Boca Raton, Florida, United States, 33486
      • Parkinson's Disease and Movement Disorders Center of Boca Raton
    • Gainesville, Florida, United States, 32608
      • UF Health Dorothy Mangurian Neuroimaging Suite
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Florida
  • Georgia
    • Augusta, Georgia, United States, 30912
      • Augusta University
  • Hawaii
    • Honolulu, Hawaii, United States, 96813
      • Parkinsons and Movement Disorder Center at the Queens Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University PD and Movement Disorders Center
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center Research Institute, Inc.
  • Kentucky
    • Lexington, Kentucky, United States, 40536-0274
      • University of Kentucky Medical Center
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Burlington, Massachusetts, United States, 01805
      • Lahey Hospital and Medical Center
  • Michigan
    • Farmington Hills, Michigan, United States, 48334
      • Quest Research Institute
  • Minnesota
    • Minneapolis, Minnesota, United States, 55414
      • University of Minnesota, CTSI
  • Missouri
    • Rochester, Missouri, United States, 55905
      • Mayo Clinic - Rochester
  • Nevada
    • Las Vegas, Nevada, United States, 89106
      • Cleveland Clinic Lou Ruvo Center for Brain Health
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • University of Cincinnati
    • Cleveland, Ohio, United States, 44195
      • The Cleveland Clinic Foundation
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Pennsylvania Hospital
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina (MUSC)
  • Tennessee
    • Memphis, Tennessee, United States, 38157
      • Veracity Neuroscience, LLC
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Dallas, Texas, United States, 75231
      • Kerwin Medical Center
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
    • Round Rock, Texas, United States, 78681
      • Central Texas Neurology Consultants
  • Utah
    • Salt Lake City, Utah, United States, 84108
      • University of Utah Movement Disorders Center
  • Virginia
    • Richmond, Virginia, United States, 23298-0059
      • Virginia Commonwealth University Department of Neurology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male or female 40 to 80 years of age, inclusive
• Diagnosis of possible or probable PSP Richardson Syndrome
• Presence of PSP symptoms for <5 years
• Score of <40 on the total (28-item) Progressive Supranuclear Palsy Rating Scale (PSPRS)
• Able to walk independently or with minimal assistance
• Minimum score of 24 on the Mini Mental State Examination (MMSE)
• Must reside outside a skilled nursing facility or dementia care facility at the time of screening. Residence in an assisted living facility is allowed
• Must have a study partner willing to attend study visits and provide information on participant's status
• Capable of providing informed consent
• Capable and willing to comply with trial procedures including visits to the trial clinic, visit requirements and treatment schedule, including MRI scans
• Female participants of childbearing potential must agree to use effective birth control for the duration of the study and for 6 months after last dose of study drug.
• Males must agree to use effective birth control method for the duration of the study and for 6 months after the last dose of study drug. Men must not plan to donate sperm.

Exclusion Criteria:

• Require use of a feeding tube
• Evidence of any neurological disorder that could explain signs of PSP
• Evidence of any clinically significant neurological disorder other than PSP, including significant cerebrovascular abnormalities, vascular dementia, motor neuron disease or ALS, Huntington's disease, normal pressure hydrocephalus, brain tumor, seizure disorder, multiple sclerosis, or known structural brain abnormalities.
• History of autosomal dominant PSP due to a Microtubule Associated Protein Tau (MAPT) mutation
• History of an autosomal dominant mutation associated with Frontotemporal Lobar Degeneration (FTLD)
• Prior or current diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder
• Presence of unstable psychiatric disease, cognitive impairment (e.g., major cognitive dysfunction), dementia, major depression, or substance abuse that would impair ability of the participant to provide informed consent and follow instructions
• Abnormal liver function
• Renal insufficiency
• Ongoing anemia
• History of Class III/IV heart failure per New York Heart Association (NYHA)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Placebo administered by mouth for 52 weeks: once daily for first 2 weeks and then twice daily for remainder of study	Other: Placebo; Matching Placebo Comparator
Experimental: AMX0035; AMX0035 administered by mouth for 52 weeks: once daily for first 2 weeks and then twice daily for remainder of study For participants electing to continue into the open-label phase at Week 52; AMX0035 will be administered once daily for first 2 weeks and then twice daily for remainder of open-label phase	Drug: AMX0035; Proprietary formulation of sodium phenylbutyrate and taurursodiol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in total (28-item) Progressive Supranuclear Palsy Rating Scale (PSPRS) Score	Assess the impact of AMX0035 on disease progression as measured by the Progressive Supranuclear Palsy (PSP) Rating Scale (PSPRS); Total scores range from 0-96 with higher scores indicating more progressed disease	52 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs)	Safety and tolerability of AMX0035 in participants with PSP	52 weeks
Change in total (10-item) Progressive Supranuclear Palsy Rating Scale (PSPRS) Score	Assess the impact of AMX0035 on disease progression as measured by the Progressive Supranuclear Palsy (PSP) Rating Scale (PSPRS); Total scores range from 0-30 with higher scores indicating more progressed disease	52 weeks
Change in MDS-UPDRS Part II Score	To evaluate the efficacy of AMX0035 on motor aspects of activities of daily living as measured on the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-PDRS) Part II; Total scores range from 0-52 with lower scores indicating better function	52 weeks

Collaborators and Investigators

• Sponsor: Amylyx Pharmaceuticals Inc.
• Investigators: Study Director: Study Director, Amylyx Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): December 21, 2023
• Primary Completion (Actual): September 30, 2025
• Study Completion (Actual): October 21, 2025

Study Registration Dates

• First Submitted: November 3, 2023
• First Submitted That Met QC Criteria: November 3, 2023
• First Posted (Actual): November 8, 2023

Study Record Updates

• Last Update Posted (Actual): April 30, 2026
• Last Update Submitted That Met QC Criteria: April 27, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Progressive Supranuclear Palsy; PSP; Steele-Richardson-Olszewski Syndrome; ORION; Amylyx
• Additional Relevant MeSH Terms: Neurologic Manifestations; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Eye Diseases; Tauopathies; Movement Disorders; Basal Ganglia Diseases; Cranial Nerve Diseases; Ophthalmoplegia; Ocular Motility Disorders; Paralysis; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Neurodegenerative Diseases; Supranuclear Palsy, Progressive; sodium phenylbutyrate and taurursodiol
• Other Study ID Numbers: A35-009

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No