A PHASE II, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, DOSE-FINDING STUDY TO EVALUATE THE SAFETY, BIOMARKERS, AND EFFICACY OF TOMINERSEN IN INDIVIDUALS WITH PRODROMAL AND EARLY MANIFEST HUNTINGTON’S DISEASE

Signed Informed Consent Form Age 25-50 years, inclusive, at the time of signing the Informed Consent Form HD gene expansion mutation carrier status: CAP score of 400-500, inclusive, where CAP is calculated as follows: Age x (CAG repeat length - 33.66) Prodromal HD, defined as DCL 2 to 3, Total Motor Score (TMS) > 6, Independence Scale (IS) > 100 (broadly equivalent to HD-ISS Stage 2), or early manifest HD, defined as DCL 4, TMS > 6, 100 >IS >/= 70, and TFC >/= 8 (broadly equivalent to HD-ISS Stage 3) Estimated glomerular filtration rate >/= 60 mL/min/1.73 m2 in at least one out of two maximum screening samples Total body weight > 40 kg and a body mass index within the range of 18-32 kg/m2 Ability to read the words "red," "blue," and "green" in native language Ability to walk unassisted without a cane or walker and move about without a wheelchair on a daily basis as determined at screening and baseline visit (Day 1) Long-distance (e.g., > 50 meters) use of wheelchairs for convenience or transfer is permitted. Ability to undergo and tolerate MRI scans (e.g., no claustrophobia, no severe chorea or other condition that precludes MRI scans or renders scanning intolerable for the participant, no MRI-incompatible intrauterine devices, metallic dental braces, or other metal implants) Ability to tolerate blood draws and lumbar punctures (LPs) Ability and willingness, in the investigator's judgement, to comply with all aspects of the protocol including completion of interviews and questionnaires for the duration of the study Stable medical, psychiatric, and neurologic status as assessed by physician (including anxiety, depression, irritability) for at least 12 weeks prior to screening and at the time of enrollment Signed study companion consent form for person who fulfills all of the required criteria Negative hepatitis B surface antigen test at screening Negative hepatitis C virus (HCV) antibody test at screening, or a positive HCV antibody test followed by a negative HCV RNA test at screening. The HCV RNA test must be performed for individuals who have a positive HCV antibody test. For female participants of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception and agree to refrain from donating eggs as defined For male participants: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agree to refrain from donating sperm, as defined

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 Active psychosis, confusional state, or violent behavior, including aggression that could cause harm to self or others, over the 12 weeks prior to screening Any serious medical condition or clinically significant laboratory or vital sign abnormality or claustrophobia at screening that, in the investigator's judgement, precludes the individual's safe participation in and completion of the study History known to the investigator or presence of an abnormal ECG that is clinically significant in the investigator's opinion, including complete left bundle branch block, second- or third-degree atrioventricular heart block, or evidence of prior myocardial infarction Clinical diagnosis of chronic migraines as per the International Headache Society Classification of Headache Disorders (third edition) (a headache occurring on 15 or more days/month for more than 3 months, which on at least 8 days/month has the features of migraine headache) Pregnancy or breastfeeding, or intention of becoming pregnant during the study or within 5 months after the final dose of study drug Presence of an implanted shunt for the drainage of CSF or an implanted CNS catheter Hydrocephalus History of deep brain stimulation Known HIV infection An infection requiring oral or IV antibiotics within 14 days prior to screening, during screening and prior to randomization Anti-retroviral medications, including anti-retroviral medication taken as prophylaxis within 12 months of study enrollment Current or previous use of an ASO (including small interfering RNA) or any HTT lowering therapy (including tominersen) Treatment with investigational therapy within 4 weeks or 5 drug-elimination half-lives, whichever is longer, prior to screening Current or previous history of a primary independent psychotic disorder (i.e., schizophrenia, schizoaffective disorder, bipolar disorder type I, severe with psychotic features) Current use of anti-psychotics for motor symptoms or mood stabilization (i.e., irritability or aggressive behavior) and/or tetrabenazine, valbenazine, or deutetrabenazine at a dose that has not been stable for at least 12 weeks prior to screening or is anticipated to change between screening and initiation of study treatment Cholinesterase inhibitors, memantine, amantadine, or riluzole use within 12 weeks from initiation of study treatment Current use of an anti-depressant or benzodiazepine at a dose that has not been stable for at least 12 weeks prior to screening or is anticipated to change between screening and initiation of study treatment Current use of supplements (e.g., coenzyme Q10, vitamins, creatine) used to treat HD symptoms, including in an experimental setting, at a dose that has not been stable for at least 6 weeks prior to screening or is anticipated to change during the study 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 mg/day), clopidogrel, dipyridamole, warfarin, dabigatran, rivaroxaban, apixaban, and heparin History of bleeding diathesis or coagulopathy Platelet count less than the lower limit of normal History of gene therapy, cell transplantation, or brain surgery Planned brain surgery during the study Concurrent or planned participation in any interventional clinical study, including explicit pharmacological and non-pharmacological interventions. Observational studies (e.g., ENROLL-HD prospective study) are acceptable, however data collection is not permitted between screening and baseline visits or within the 8 weeks before a study clinic visit. Drug (i.e., cannabis, opioid, stimulant, hallucinogen, designer) and/or alcohol abuse or psychological or physiological dependency within 12 months prior to screening, as per the investigator's judgement Poor peripheral venous access Scoliosis or spinal deformity or surgery making IT injection not feasible in an outpatient setting and potentially interfering with distribution of tominersen up the neuraxis Malignancy within 5 years prior to screening, except basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated Preexisting intra-axial or extra-axial lesions (e.g., tumor, arterio-venous malformation, meningiomas) as assessed by a centrally read MRI scan during the screening period