A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of RG6496 in Huntington's Disease

NCT07246941 | Recruiting Phase 1

• 2 other identifiers: BP453782025-520631-17-00
• Study Type: interventional
• Target: 40
• Locations: 3 countries
• Sites: 3

Brief Summary

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 \[open-label extension (OLE)\].

Conditions

Huntington's Disease

Outcome Measures

Primary Outcomes (8)

• 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 Outcomes (3)

• 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

Study Arms (3)

Part 1: RG6496

EXPERIMENTAL

Participants will receive single dose of RG6496. Participants will be enrolled in planned sequential cohorts associated with ascending dose levels.

Drug: RG6496

Part 1: Placebo

PLACEBO COMPARATOR

Participants will receive a single dose of RG6496 matching placebo.

Drug: Placebo

Part 2: OLE

EXPERIMENTAL

All participants who have completed Part 1 and are eligible for Part 2 will receive one open-label dose of RG6496.

Drug: RG6496

Interventions

RG6496 DRUG

RG6496 will be administered as per the schedule specified in the respective arms.

Part 1: RG6496; Part 2: OLE

Placebo DRUG

RG6496 matching placebo will be administered as per the schedule specified in placebo arm.

Part 1: Placebo

Eligibility Criteria

• Age: 25 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Hoffmann-La Roche: lead

Study Sites (3)

Hospital Britanico de Buenos Aires

Ciudad Autonoma Bs As, C1280AEB, Argentina

RECRUITING

Westmead Hospital

Westmead, New South Wales, 2145, Australia

RECRUITING

New Zealand Brain Research Institute

Christchurch, 8011, New Zealand

RECRUITING

MeSH Terms

Conditions

Huntington Disease

Condition Hierarchy (Ancestors)

Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Dementia; Chorea; Dyskinesias; Movement Disorders; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Cognition Disorders; Neurocognitive Disorders; Mental Disorders

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Central Study Contacts

Reference Study ID Number: BP45378 https://forpatients.roche.com/

CONTACT

888-662-6728 (U.S. Only); global-roche-genentech-trials@gene.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: Part 1: Investigator \& participants will be blinded; Part 2: Open-label
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 19, 2025
• First Posted: November 24, 2025
• Study Start: November 19, 2025
• Primary Completion (Estimated): December 11, 2027
• Study Completion (Estimated): March 5, 2029
• Last Updated: April 27, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

AR (1); NZ (1); AU (1)