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 \[open-label extension (OLE)\].
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.
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
Parallel
RG6496
DrugRG6496 will be administered as per the schedule specified in the respective arms.
Placebo
DrugRG6496 matching placebo will be administered as per the schedule specified in placebo arm.
Part 1: Number of Participants With Adverse Events (AEs)
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.
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.
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.
Part 1: Plasma Concentration of RG6496
Part 1 and Part 2: Number of Participants With Anti-drug Antibody (ADA) in Plasma to RG6496
Part 1 and Part 2: Change From Baseline of Mutant Huntingtin Protein (mHTT) Concentrations in Cerebrospinal Fluid (CSF) Over Time
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