RG6496: checking safety and how the drug works in people with Huntington's disease

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 first-in-human study will test single ascending doses of RG6496 (or placebo) in people who carry the Huntington's disease gene expansion to see if the drug is safe, tolerable, and how it is processed and acts in the body.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 40 (estimated)
• Ages: 25 Years to 65 Years
• Sex: All
• Sponsor: Hoffmann-La Roche (Industry-sponsored)
• Locations: 3 sites (Ciudad Autonoma Bs As and 2 other locations)
• Trial ID: NCT07246941 on ClinicalTrials.gov

What this trial studies

This Phase 1, first-in-human trial gives single ascending doses of RG6496 versus placebo to Huntington's disease gene expansion carriers and then offers an open-label extension for eligible participants. The primary focus is on safety and tolerability, with detailed pharmacokinetic and pharmacodynamic sampling to understand drug exposure and biological effects. Participants must carry the target SNP and meet functional and motor criteria, be able to undergo MRI, and meet weight/BMI limits. The study is being run at regional specialist centers in Argentina, Australia, and New Zealand.

Who should consider this trial

Good fit: Ideal participants are adults who carry the Huntington's disease CAG expansion (>39), carry the target SNP, have relatively preserved function (IS ≥70, TFC ≥10), can walk unassisted, tolerate MRI, and meet weight/BMI requirements.

Not a fit: People who do not carry the target SNP, have more advanced or unstable medical conditions, cannot tolerate MRI, are unable to walk unassisted, or are enrolled in other interventional clinical studies are unlikely to benefit from participation.

Why it matters

Potential benefit: If RG6496 is safe and shows favorable pharmacokinetics and pharmacodynamics, it could move forward as a candidate therapy to be tested for disease-modifying effects in future trials.

How similar studies have performed: This is the first-in-human trial for RG6496; other early-phase huntingtin-lowering or huntingtin-targeted approaches have shown biomarker or target-engagement signals in some cases but have not yet produced consistent, proven clinical benefit.

Eligibility criteria

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.

Where this trial is running

Ciudad Autonoma Bs As and 2 other locations

• Hospital Britanico de Buenos Aires — Ciudad Autonoma Bs As, Argentina (Recruiting)
• Westmead Hospital — Westmead, New South Wales, Australia (Recruiting)
• New Zealand Brain Research Institute — Christchurch, New Zealand (Recruiting)

Study contacts

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

Conditions Huntington's Disease