This study will evaluate the safety, biomarkers, and efficacy of tominersen compared with placebo in participants with prodromal and early manifest Huntington's Disease (HD).

Inclusion Criteria:

DB Period:

• HD gene expansion mutation carrier status with a cytosine-adenine-guanine-age product (CAP) score of 400-500 inclusive

• Either:

  • Prodromal HD (defined as Diagnostic Confidence Level (DCL) 2 to 3, Independence Scale (IS) ≥70, and TFC ≥8); Or
  • Early manifest HD (defined as DCL 4, IS ≥70, and TFC ≥8)

• Total body weight > 40 kilograms (kg) and a body mass index (BMI) within the range of 18-32 kilograms per meter square (kg/m^2)

• Study companion

OLE Period:

• Participants must have completed the DB treatment period
• Participants must remain in the DB Safety follow-up period until OLE period starts

Exclusion Criteria:

DB Period:

• Current or previous use of an antisense oligonucleotide (ASO) (including small interfering ribonucleic acid [RNA]) or any HTT lowering therapy (including tominersen)
• Anti-platelet or anticoagulant therapy within 14 days prior to screening or anticipated use during the study, including, but not limited to, aspirin (unless ≤ 81 milligrams per day [mg/day]), clopidogrel, dipyridamole, warfarin, dabigatran, rivaroxaban, apixaban, and heparin
• History of gene therapy, cell transplantation, or brain surgery
• Hydrocephalus
• Pregnancy or breastfeeding, or intention of becoming pregnant during the study or within 5 months after the final dose of study drug
• 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

OLE Period:

• Early discontinuation from the DB treatment and the safety follow-up (SFU) periods
• Pregnant or breastfeeding, or with the intention of becoming pregnant during the study or within the timeframe in which contraception is required
• Current or previous use of an ASO other than tominersen (including small interfering RNA) or any other HTT-lowering therapy
• Hydrocephalus
• Received any active investigational treatment other than tominersen during or since completion of the DB treatment period

Key inclusions/exclusion criteria are listed here. Other protocol-defined I/E criteria may apply.

For eligible studies, qualified researchers may request access to individual patient level clinical data. See Roche's commitment to transparency of clinical study information here: https://go.roche.com/data\_sharing