A Randomized, Placebo-Controlled, Double-Blind Study to Evaluate the Effect of SAGE-718 on Cognitive Function in Participants with Huntington’s Disease

Participants must meet all the following criteria to qualify for participation in this study: 1. Be capable of providing informed consent, in the opinion of the investigator. 2. Have signed an informed consent form (ICF) prior to any study-specific procedures being performed. 3. Agree to adhere to the study requirements. 4. Be capable of complying with study procedures, in the opinion of the investigator. 5. Be at least 25 years old but no older than 65 years of age at Screening. 6. Meet all the following criteria for HD: a. Genetically confirmed disease with CAG expansion ≥ 36. b. UHDRS-TFC score > 6 and < 13. c. No features of juvenile HD (ie, UHDRS Diagnostic Confidence Level (DCL) = 4 before age 25). 7. CAP score > 70, as calculated using the CAP formula: AGE × (CAG – 30) / 6.49. 8. Score < 26 on the Montreal Cognitive Assessment (MoCA) at Screening. 9. Be willing to invite a study partner, if available, who is reliable, competent, and at least 18 years of age to participate in the study. 10. Be ambulatory (use of assistance devices such as a walker or cane is acceptable; individuals requiring a wheelchair are excluded), able to travel to the study center, and, judged by the investigator, is likely to be able to continue to travel to the study centre to complete study visits for the duration of the study. 11. Agree, if female, to use one of the following methods of highly effective contraception during participation in the study and for 30 days following the last dose of study drug, unless they are postmenopausal (defined as no menses for 12 months without an alternative medical cause and confirmed by follicular stimulation hormone [FSH] > 40 mIU/mL), surgically sterile (hysterectomy or bilateral oophorectomy), or does not engage in sexual relations which carry a risk of pregnancy (does not include abstinence): • Combined (estrogen and progestogen containing) oral, intravaginal, or transdermal hormonal contraception associated with inhibition of ovulation. • Oral, injectable, or implantable progestogen-only hormonal contraception associated with inhibition of ovulation. • Intrauterine device. • Intrauterine hormone-releasing system. • Bilateral tubal ligation/occlusion. • Vasectomized partner. 12. Agree, if male, to use an acceptable method of effective contraception for the duration of study and for 21 days after receiving the last dose of the study drug, unless the subject does not engage in sexual relations which carry a risk of pregnancy (does not include abstinence). Acceptable methods of effective contraception for males includes vasectomy, or a condom used together with highly effective female contraception methods if the female partner(s) is of child-bearing potential (see Inclusion Criteria #11 for acceptable contraception methods). 13. Agree, if male, to abstain from sperm donation during the treatment period and for 21 days after receiving the last dose of IP. 14. Agree to refrain from drugs of abuse for the duration of the study and from alcohol during the 48 hours preceding each study visit.

Participants who meet any of the following criteria are disqualified from participation in this study: 1. Have participated in a previous clinical study of SAGE-718, have participated in a previous gene therapy study, or have participated in any other drug, biologic, or device trial within 180 days or 5 half-lives (whichever is longer), unless the patient participated solely in the placebo arm of the study. 2. Have a diagnosis of an ongoing neurodegenerative condition other than HD, including but not limited to, Alzheimer’s Disease, vascular dementia, dementia with Lewy bodies, or Parkinson’s Disease. 3. Have been diagnosed with and/or treated for any type of cancer (excluding basal cell carcinoma and melanoma in situ) within the past year prior to screening. 4. Had gastric bypass surgery, has a gastric sleeve or lap band, or has had any related procedures that interfere with gastrointestinal transit. 5. Plans to undergo elective surgery during participation in the study. 6. Receive any of the following prohibited medications within 30 days of screening and during participation in the study: a. Medications with potent effects at the N-methyl-D-aspartate (NMDA) receptor, including amantadine, ketamine, cycloserine, or related compounds. b. Medications that inhibit cholesterol absorption (eg, ezetimibe). c. Bile acid sequestrants (eg, colesevelam, colestipol, cholestyramine). d. Other medications given at doses or in combinations that are likely to have a deleterious effect on cognitive performance, as determined by the investigator. e. Cannabis or other tetrahydrocannabinol (THC)-containing substances (any route of administration). 7. Have current or recent suicidality, defined as follows: a. Suicidal ideation within the past month, as evidenced by a score of 4 (active suicidal ideation with some intent to act, without specific plan) or 5 (active suicidal ideation with specific plan and intent) on the C-SSRS. b. Suicidal behaviour within the past year, as evidenced by a "Yes" on any of the 5 C-SSRS Suicidal Behaviour items (actual attempt, interrupted attempt, aborted attempt, preparatory acts, or behaviour) on the C-SSRS. c. Presenting a serious risk of suicide in the opinion of the investigator. 8. Take any psychotropic medications, including antidepressants and anxiolytics, unless the dose and frequency have been stable for at least 8 weeks prior to the first IP administration and are expected to remain stable for the duration of the study. 9. Have an ongoing medical or psychiatric condition that, in the opinion of the investigator, may compromise the participant’s safety or compliance with study requirements. 10. Have supine vital signs outside of the following ranges at Screening or Baseline (vital sign measurements may be repeated once for initial values outside these ranges): − Heart rate < 50 or > 100 bpm, − Systolic blood pressure < 100 or > 160 mmHg, − Diastolic blood pressure < 60 or > 100 mmHg. 11. Have an alcohol or drug use disorder within the past 2 years, as assessed by the investigator. A positive urine drug screen is exclusionary unless deemed by the investigator to reflect a prescribed medication. 12. Have a history of significant hand injury that would preclude either writing or rapid bimanual computerized responding. 13. Have a history of seizures or epilepsy, with the exception of a single episode of febrile seizures in childhood. 14. Have a history, presence, and/or current evidence of serologic positive results for human immunodeficiency virus (HIV)-1 or HIV-2 and hepatitis B and C. 15. Have a history of brain surgery, a significant head injury causing loss of consciousness greater than 30 minutes, or hospitalization due to a brain injury. 16. Have a history, presence, and/or current evidence of intracranial abnormality (eg, stroke, haemorrhage, space-occupying lesion). 17. Have a positive pregnancy test, or be lactating, or intend to breastfeed during the study. 18. Be investigative site personnel, sponsor personnel, or an immediate member of their family (spouse, parent, child, or sibling whether biological or legally adopted).