A Study to Evaluate the Safety and Efficacy of PTC518 in Participants With Huntington's Disease (HD)

Study Overview
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Brief Summary
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The primary goal of this study is to evaluate the safety and pharmacodynamic effects of PTC518 compared with placebo in participants with HD.

Detailed Description
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Participants will first be randomized to Part A or Part B or Parts D or E in a 1:1 randomization ratio, depending on their Huntington's disease Integrated Staging System (HD-ISS) staging criteria and then to active treatment (PTC518 5 mg in Parts A and D and 10 mg in Parts B and E) or matching placebo within each part in a 2:1 ratio of active treatment to placebo. A Drug Safety Monitoring Board (DSMB) Charter will undertake an unblinded review of safety data from the 5 and 10 mg dosing groups and provide a recommendation on when Parts C and F (with a 20 mg active treatment arm) can be initiated. At that time, participants will be randomized to any study Part that is currently open for enrollment, and then to either active treatment or placebo (in a 2:1 ratio) within that Part.

Official Title
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A Phase 2A, Randomized, Placebo-Controlled, Dose-Ranging Study to Evaluate the Safety and Efficacy of PTC518 in Subjects With Huntington's Disease

Conditions
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Huntington Disease

Intervention / Treatment
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* Drug: PTC518
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Genetically confirmed HD diagnosis with a cytosine-adenine-guanine (CAG) repeat length from 40 to 50, inclusive Eligibility for HD-ISS Stage 2 Group (Parts A, B, and C): A Unified Huntington's Disease Rating Scale (UHDRS)-Independence Scale (IS) score of 100 A UHDRS Total Functional Capacity (TFC) score of 13 A score between 0.18 and 4.93 inclusive on the normed version of the HD prognostic index (PINHD) Eligibility for HD-ISS Mild Stage 3 Group (Parts D, E, and F): A UHDRS Total Functional Capacity (TFC) score of 11 or 12, or a UHDRS TFC score of 13 with an UHDRS IS score of <100 Key Exclusion Criteria: Receipt of an experimental agent within 90 days or 5 half-lives prior to Screening or anytime over the duration of this study, ribonucleic acid (RNA)- or deoxyribonucleic acid (DNA)-targeted HD-specific investigational agents such as antisense oligonucleotides, cell transplantation, or any other experimental brain surgery Any history of gene therapy exposure for the treatment of HD Participation in an investigational study or investigational paradigm (such as exercise/physical activity, cognitive therapy, brain stimulation, etc) within 90 days prior to Screening or anytime over the duration of this study Any medical history of brain or spinal disease that would interfere with the lumbar puncture process safety assessments Any medical history or condition that would interfere with the ability to complete the protocol-specified assessments (for example, implanted shunt, conditions precluding magnetic resonance imaging [MRI] scans) Pregnancy, planning on becoming pregnant during the course of the study or within 6 months of end of treatment, or currently breastfeeding Note: Other inclusion and exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 25 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
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PTC518 5 mg<br>Participants will receive PTC518 5 milligrams (mg) tablets once daily orally for 12 months. | Drug: PTC518<br>* PTC518 will be administered per dose and schedule specified in the arm.<br>|
| Experimental: PTC518 10 mg<br>Participants will receive PTC518 10 mg tablets once daily orally for 12 months. | Drug: PTC518<br>* PTC518 will be administered per dose and schedule specified in the arm.<br>|
| Experimental: PTC518 20 mg<br>Participants will receive PTC518 20 mg tablets once daily orally for 12 months. | Drug: PTC518<br>* PTC518 will be administered per dose and schedule specified in the arm.<br>|
| Placebo Comparator: Placebo<br>Participants will receive placebo matching to PTC518 tablets once daily orally for 12 months. | Drug: Placebo<br>* Placebo matching to PTC518 will be administered per schedule specified in the arm.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs) |  | Baseline up to Month 18 | 
| Change From Baseline in Blood Total Huntingtin Protein (tHTT) at Month 3 |  | Baseline, Month 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Caudate Volume as Assessed Via Volumetric Magnetic Resonance Imaging (vMRI) at Month 12 |  | Baseline, Month 12 | 
| Change From Baseline in Composite Unified Huntington's Disease Rating Scale (cUHDRS) Scores at Month 12 |  | Baseline, Month 12 | 
| Change From Baseline in Blood tHTT Protein at Month 12 |  | Baseline, Month 12 | 
| Change From Baseline in Cerebrospinal Fluid (CSF) Mutant Huntingtin Protein (mHTT) at Month 12 |  | Baseline, Month 12 | 
| Change From Baseline in Blood mHTT Protein at Month 12 |  | Baseline, Month 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neurodegenerative disorder, Rare disease