AMX0035 and Progressive Supranuclear Palsy

Study Overview
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Brief Summary
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ORION Trial is a trial to evaluate the efficacy and safety of AMX0035 in participants with Progressive Supranuclear Palsy (PSP), consisting of a randomized double blind placebo controlled phase, followed by an optional open-label extension phase.

Detailed Description
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AMX0035 is a 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.

Official Title
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A Phase 3 Study of Safety and Efficacy of AMX0035 in Progressive Supranuclear Palsy (ORION)

Conditions
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Progressive Supranuclear Palsy, PSP, Neurodegenerative Diseases, Atypical Parkinsonism

Intervention / Treatment
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* Drug: AMX0035
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A 52-week double-blind, placebo-controlled phase followed by an optional 52-week open-label extension phase
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AMX0035<br>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 administered by mouth: twice daily for an additional 52 weeks | Drug: AMX0035<br>* Proprietary formulation of sodium phenylbutyrate and taurursodiol<br>|
| Placebo Comparator: Placebo<br>Placebo administered by mouth for 52 weeks: once daily for first 2 weeks and then twice daily for remainder of study | Other: Placebo<br>* Matching Placebo Comparator<br>|

What is the study measuring?
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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 |
| --- | --- | --- |
| 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 (MDS-PDRS) Scale Part II; Total scores range from 0-52 with lower scores indicating better function | 52 weeks | 
| Frequency of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) | Safety and tolerability of AMX0035 in participants with PSP | 52 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Progressive Supranuclear Palsy, PSP, Steele-Richardson-Olszewski Syndrome, ORION, Amylyx