A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of RG6496 in Huntington's Disease (POINT-HD)

A Phase I, 2-Part Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single-ascending Doses of Intrathecally Administered RG6496 in a Randomized, Placebo-controlled, Investigator/Participant-blind Study With an Open-label Extension in Huntington's Disease Gene Expansion Carriers

This is a first-in-human (FIH) study of RG6496 that will assess the safety and tolerability of single-ascending doses of RG6496 administered to huntington's disease gene expansion carriers (HDGECs). The study consists of two parts: Part 1 [single-ascending dose] followed by Part 2 [open-label extension (OLE)].

Study Overview

• Status: Recruiting
• Conditions: Huntington's Disease
• Intervention / Treatment: Drug: RG6496; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Reference Study ID Number: BP45378 https://forpatients.roche.com/; Phone Number: 888-662-6728 (U.S. Only); Email: global-roche-genentech-trials@gene.com
• Study Contact Backup: Name: Fastest response: use the inquiry form. No email attachments. https://www.gene.com/contact-us/submit-medical-inquiry

Study Locations

• Argentina
  • Ciudad Autonoma Bs As, Argentina, C1280AEB
    • Recruiting
    • Hospital Britanico de Buenos Aires
• Australia
  • New South Wales
    • Westmead, New South Wales, Australia, 2145
      • Recruiting
      • Westmead Hospital
  • Victoria
    • Parkville, Victoria, Australia, 3050
      • Recruiting
      • Royal Melbourne Hospital
• New Zealand
  • Christchurch, New Zealand, 8011
    • Recruiting
    • New Zealand Brain Research Institute

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

Part 1

• Confirmation of HDGEC status with cytosine-adenine-guanine (CAG) expansion > 39.
• Confirmation of SNP carrier status of the target SNP
• Independence Scale (IS) score of ≥70, total functional capacity (TFC) ≥10, total motor score (TMS) >6.
• Ability to read the words "red," "blue," and "green" and be fluent in the language of the informed consent form (ICF) and the tests used at the study site.
• Ability to walk unassisted.
• Total body weight > 40 kilogram (kg) and body mass index (BMI) within the range 18-32 kilogram per square meter (kg/m^2) (inclusive) at baseline.
• Ability to undergo and tolerate MRI scans.

Part 2

• Completed the post-dose safety follow-up period in the Part 1 of the study.
• In the opinion of the Investigator, the participant has not experienced a worsening in health that precludes their safe continued participation in the study.

Exclusion Criteria:

Part 1

• Concurrent or planned participation in any interventional clinical study, including current use of an ASO or any HTT-lowering therapy or treatment with investigational therapy within 90 days or 5 drug-elimination half-lives, whichever is longer prior to screening
• Pregnant or breastfeeding, or with the intention of becoming pregnant during the study or within the timeframe in which contraception is required
• Malignancy within 5 years prior to screening
• Planned brain surgery during the study
• Positive HIV test, hepatitis B surface antigen and hepatitis B surface antigen at screening
• Active psychosis, confusional state, or violent behavior, including aggression that could cause harm to self or others, over the 12 weeks prior to screening.
• Current or previous history of a primary independent psychotic disorder.
• Scoliosis or spinal deformity or surgery making IT injection not feasible in an outpatient setting
• History of attempted suicide or suicidal ideation with plan (i.e., active suicidal ideation) that required hospital visit and/or change in level of care within 12 months prior to screening.

Part 2

• Prematurely discontinued from Part 1 for any reason (i.e., before the completion of the postdose safety follow-up period of Part 1).
• Pregnant or breastfeeding, or with the intention of becoming pregnant during the study or within the timeframe in which contraception is required.
• Concurrent or planned participation in any interventional clinical study, including current use of an ASO or any HTT-lowering therapy
• Received any active investigational treatment other than RG6496 during or since completion of Part 1 of the study.
• Had confirmed Dose-Limiting Adverse Event (DLAE)(s) in Part 1 of the study.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1: RG6496; Participants will receive single dose of RG6496. Participants will be enrolled in planned sequential cohorts associated with ascending dose levels.	Drug: RG6496; RG6496 will be administered as per the schedule specified in the respective arms.
Placebo Comparator: Part 1: Placebo; Participants will receive a single dose of RG6496 matching placebo.	Drug: Placebo; RG6496 matching placebo will be administered as per the schedule specified in placebo arm.
Experimental: Part 2: OLE; All participants who have completed Part 1 and are eligible for Part 2 will receive one open-label dose of RG6496.	Drug: RG6496; RG6496 will be administered as per the schedule specified in the respective arms.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1: Number of Participants With Adverse Events (AEs)		Up to approximately 24 months
Part 1: Change From Baseline in Neurological Assessment	A neurologic examination including fundoscopy, will be performed by a neurologist or an ophthalmologist depending on local practice. A neurologic examination will include an assessment of mental status, level of consciousness, cranial nerve function, motor function, sensory function, reflexes, gait, and coordination.	Up to approximately 24 months
Part 1: Percentage of Participants With Suicidal Ideation or Behavior, as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score	C-SSRS measures 4 constructs as follows: severity of ideation, intensity of ideation, behavior, and lethality of actual suicide attempts. Binary (yes/no) data are collected for 10 categories. Numeric ratings are provided for intensity of ideation (if present), from 1 to 5, with 1 being the least severe and 5 being the most severe.	Up to approximately 24 months
Part 1: Change from Baseline in Montreal Cognitive Assessment (MoCA)	MoCA is a rater-administered, participant completed assessment (PerfO instrument) used to detect cognitive impairment. It contains a series of basic assessments, including attention and visuospatial tasks. The total score ranges from 0 to 30, where lower scores indicate greater impairment.	Up to approximately 24 months
Part 2: Number of Participants With AEs		Up to approximately 38 months
Part 2: Change From Baseline in Neurological Assessment	A neurologic examination including fundoscopy, will be performed by a neurologist or an ophthalmologist depending on local practice. A neurologic examination will include an assessment of mental status, level of consciousness, cranial nerve function, motor function, sensory function, reflexes, gait, and coordination.	Up to approximately 38 months
Part 2: Number of Participants With Suicidal Ideation or Behavior, as Assessed by C-SSRS Score	C-SSRS measures 4 constructs as follows: severity of ideation, intensity of ideation, behavior, and lethality of actual suicide attempts. Binary (yes/no) data are collected for 10 categories. Numeric ratings are provided for intensity of ideation (if present), from 1 to 5, with 1 being the least severe and 5 being the most severe.	Up to approximately 38 months
Part 2: Change from Baseline in MoCA	MoCA is a rater-administered, participant completed assessment (PerfO instrument) used to detect cognitive impairment. It contains a series of basic assessments, including attention and visuospatial tasks. The total score ranges from 0 to 30, where lower scores indicate greater impairment.	Up to approximately 38 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Part 1: Plasma Concentration of RG6496	Up to approximately 24 months
Part 1 and Part 2: Number of Participants With Anti-drug Antibody (ADA) in Plasma to RG6496	Part 1: Up to approximately 24 months; Part 2: Up to approximately 38 months
Part 1 and Part 2: Change From Baseline of Mutant Huntingtin Protein (mHTT) Concentrations in Cerebrospinal Fluid (CSF) Over Time	Part 1: Up to approximately 24 months; Part 2: Up to approximately 38 months

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche
• Investigators: Study Director: Clinical Trials, Hoffmann-La Roche

Publications and helpful links

Helpful Links

• Please use this form to submit your questions for a faster response: https://www.gene.com/contact-us/submit-medical-inquiry. Do not include or attach any medical records when emailing or completing the form. A nurse will respond within 24 business hours.

Study record dates

Study Major Dates

• Study Start (Actual): November 19, 2025
• Primary Completion (Estimated): February 28, 2028
• Study Completion (Estimated): May 23, 2029

Study Registration Dates

• First Submitted: November 19, 2025
• First Submitted That Met QC Criteria: November 19, 2025
• First Posted (Actual): November 24, 2025

Study Record Updates

• Last Update Posted (Actual): June 2, 2026
• Last Update Submitted That Met QC Criteria: May 29, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Genetic Diseases, Inborn; Neurocognitive Disorders; Cognition Disorders; Dementia; Neurodegenerative Diseases; Movement Disorders; Heredodegenerative Disorders, Nervous System; Basal Ganglia Diseases; Dyskinesias; Chorea; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Huntington Disease
• Other Study ID Numbers: BP45378; 2025-520631-17-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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