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

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

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

Study Overview

• Status: Completed
• Conditions: Huntington Disease
• Intervention / Treatment: Drug: PTC518; Drug: Placebo

Detailed Description

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.

Participants who complete this study and agree to participate in a long-term extension (LTE) study, will be enrolled in a separate LTE study PTC518-CNS-004-HD (NCT06254482).

• Study Type: Interventional
• Enrollment (Actual): 159
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • Clayton, Australia, 3168
    • Monash Health
  • Sydney, Australia, 2145
    • Westmead Hospital
• Austria
  • Innsbruck, Austria, 6020
    • Medical University Innsbruck
• Canada
  • Ottawa, Canada, K1Y 4E9
    • The Ottawa Hospital, Parkinson's and Movement Disorders Clinic
• France
  • Angers, France, 49100
    • Centre Hospitalier Universitaire d'Angers
  • Marseille, France, 13385
    • Hôpital Universitaire de Marseille Hôpital de la Timone
  • Paris, France, 75013
    • Brain and Spine Institute Paris
• Germany
  • Berlin, Germany, 10117
    • Charité University Medicine Berlin
  • Bochum, Germany, 44791
    • Ruhr-Univ. Bochum St. Joseph-Hospital
  • Münster, Germany, 48149
    • George-Huntington-Institut
  • Ulm, Germany, 89081
    • Ulm University, UKU, Dep. of Neurology
• Italy
  • Bologna, Italy, 40139
    • Irccs Istituto Delle Scienze Neurologiche Di Bologna Uoc Clinica Neurologica
  • Milan, Italy, 20133
    • IRCCS Carlo Besta Neurological Institutte
  • San Giovanni Rotondo, Italy, 71013
    • IRCCS Casa Sollievo della Sofferenza Research Hospital
• Netherlands
  • Leiden, Netherlands, 2333 ZA
    • Leiden University Medical Center
• New Zealand
  • Christchurch, New Zealand, 8011
    • University of Otago, New Zealand Brain Research Institute
• Spain
  • Barakaldo, Spain, 48903
    • Hospital Universitario Cruces
  • Barcelona, Spain, 8025
    • Hospital de la Santa Creu i Sant Pau
  • Burgos, Spain, 90550
    • Hospital Universitario Burgos
  • Madrid, Spain, 28034
    • Hospital Ramon y Cajal
• United Kingdom
  • Birmingham, United Kingdom, B15 2FG
    • The Barbery National Centre for Mental Health
  • Cardiff, United Kingdom, CF10 3AX
    • Cardiff University Schools of Medicine and Biosciences
  • London, United Kingdom, WC1N 3BG
    • UCL Queen Square Institute of Neurology National Hospital for Neurology and Neurosurgery
  • Manchester, United Kingdom, M13 9WL
    • Manchester University NHS Foundation Trust
• United States
  • California
    • La Jolla, California, United States, 92037
      • University of California, San Diego
  • Tennessee
    • Nashville, Tennessee, United States, 37212
      • Vanderbilt University Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • The University of Texas Health Science Center at Houston; McGovern Medical School
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington Department of Neurology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 25 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-emergent Adverse Events (TEAEs)	An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A TEAE was defined as an AE that had an onset date or date of worsening on or after the first dose of study drug. A summary of other non-serious AEs and all serious adverse events (SAEs), regardless of causality is located in the 'Reported AE section'.	Baseline up to Month 18
Percent Change From Baseline in Geometric Mean Blood tHTT Protein at Month 3	Least square (LS) mean and 95% confidence interval (CI) were calculated using mixed-model repeated measures (MMRM). The blood tHTT protein value was log-transformed before fitting the MMRM model. The LS means from MMRM model were back-transformed to present geometric mean percent changes.	Baseline, Month 3

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline in Caudate Volume as Assessed Via Volumetric Magnetic Resonance Imaging (vMRI) at Month 12	LS mean and standard error (SE) were calculated using MMRM.	Baseline, Month 12
Change From Baseline in Composite Unified Huntington's Disease Rating Scale (cUHDRS) Scores at Month 12	cUHDRS includes the Total Functional Capacity (range, 0-13; higher score means better functioning), Total Motor Score (range, 0-124; higher score means worse motor severity), Symbol Digit Modality Test (range, 0-110, correctly paired numbers-symbols in 90 seconds; higher score means better cognitive performance), and Stroop Word Reading (range, 0-no max value, correctly read colour words in 45 seconds; higher score means better cognitive performance) scores. The total score for the cUHDRS ranges from approximately 3 to 18, where higher scores indicated better functioning. LS mean and SE were calculated using analysis of covariance (ANCOVA) model.	Baseline, Month 12
Percent Change From Baseline in Geometric Mean Blood tHTT Protein at Month 12	LS mean and 95% CI were calculated using MMRM. The blood tHTT protein value was log-transformed before fitting the MMRM model. The LS means from MMRM model were back-transformed to present geometric mean percent changes.	Baseline, Month 12
Percent Change From Baseline in Cerebrospinal Fluid (CSF) Mutant Huntingtin Protein (mHTT) at Month 12	LS mean and 95% CI were calculated using MMRM. The CSF mHTT protein value was log-transformed before fitting the MMRM model. The LS means from MMRM model were back-transformed to present geometric mean percent changes.	Baseline, Month 12
Percent Change From Baseline in Blood mHTT Protein at Month 12	LS mean and 95% CI were calculated using MMRM. The blood mHTT protein value was log-transformed before fitting the MMRM model. The LS means from MMRM model were back-transformed to present geometric mean percent changes.	Baseline, Month 12

Collaborators and Investigators

• Sponsor: PTC Therapeutics

Publications and helpful links

General Publications

• Estevez-Fraga C, Tabrizi SJ, Wild EJ. Huntington's Disease Clinical Trials Corner: November 2022. J Huntingtons Dis. 2022;11(4):351-367. doi: 10.3233/JHD-229006.
• Estevez-Fraga C, Tabrizi SJ, Wild EJ. Huntington's Disease Clinical Trials Corner: March 2024. J Huntingtons Dis. 2024;13(1):1-14. doi: 10.3233/JHD-240017.

Study record dates

Study Major Dates

• Study Start (Actual): June 3, 2022
• Primary Completion (Actual): February 7, 2025
• Study Completion (Actual): July 31, 2025

Study Registration Dates

• First Submitted: April 27, 2022
• First Submitted That Met QC Criteria: April 27, 2022
• First Posted (Actual): May 3, 2022

Study Record Updates

• Last Update Posted (Estimated): January 13, 2026
• Last Update Submitted That Met QC Criteria: December 19, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: Neurodegenerative disorder; Rare disease
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Pathologic Processes; Disease Attributes; Genetic Diseases, Inborn; Neurocognitive Disorders; Cognition Disorders; Dementia; Movement Disorders; Heredodegenerative Disorders, Nervous System; Basal Ganglia Diseases; Dyskinesias; Chorea; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Rare Diseases; Neurodegenerative Diseases; Huntington Disease
• Other Study ID Numbers: PTC518-CNS-002-HD; 2021-003852-18 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No