28-Day Study of SAGE-718 on Functioning Capacity in Participants With Huntington's Disease

A 28-Day Randomized, Placebo-Controlled, Double-Blind, Parallel Groups and Normative Comparison Study to Evaluate the Effect of SAGE-718 on Functioning Capacity in Participants With Huntington's Disease

The primary purpose of this study is to assess the magnitude of the baseline difference between participants with early Huntington's Disease (HD) and healthy participants (HP) with respect to measures of cognitive performance.

Participants will receive SAGE-718 1.2 mg softgel lipid capsule orally once daily in the morning for up to 28 days.

Participants will receive SAGE-718-matching placebo capsule orally once daily in the morning for up to 28 days.

Difference in Huntington's Disease Cognitive Assessment Battery (HD-CAB) Composite Score Between Participants With HD vs HP at Baseline

The HD-CAB evaluates cognitive function via the following subtests: Symbol Digit Modalities Test; One Touch Stockings of Cambridge; Trail Making; Hopkins Verbal Learning Test Revised; Paced Tapping Test; and the Emotion Recognition Test. The HD-CAB composite is derived by transforming individual participants' scores on each of the 6 subtests to z-scores, and averaging z-scores to represent global performance relative to the reference sample (HP). A negative HD-CAB composite score of participants with HD will indicate a decline in cognitive function relative to HP.

An AE is any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An SAE is any untoward medical occurrence that at any dose results in death, places the participant at immediate risk of death (a life-threatening event); however, this does not include an event that, had it occurred in a more severe form, might have caused death, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, results in a congenital abnormality or birth defect.

The CANTAB evaluates cognitive function via following subtests: N-Back Test (optional) Multitasking Test (optional) Spatial Working Memory Task Test Spatial Span Test (optional) Paired Associates Learning (optional) This outcome measure will compare the CANTAB test results between participants with HD vs HP at Baseline.

The VRFCAT is a tablet-based measure that assesses ability to perform instrumental activities of daily living serve as a measure of functional improvement. Participants complete a series of tasks corresponding to functional capacity for meal preparation, use of public transportation, shopping, and managing currency. The total completion time is recorded for these activities, which ranges from 0 - 60000 milliseconds. Lesser time required to complete activity indicates better function.

Change From Baseline in the Huntington's Disease Cognitive Assessment Battery (HD-CAB) Composite Score

The HD-CAB evaluates cognitive function via the following subtests: Symbol Digit Modalities Test; One Touch Stockings of Cambridge; Trail Making; Hopkins Verbal Learning Test Revised; Paced Tapping Test; and the Emotion Recognition Test. The HD-CAB composite is derived by transforming individual participants' scores on each of the 6 subtests to z-scores, and averaging z-scores to represent global performance relative to the reference sample with an expected z-score distribution of approximately -3 to +3, with higher score indicating improvement. A positive HD-CAB composite at follow-up indicates improvement in cognitive function; a negative composite score indicates worsening in cognitive function; and a composite of "0" would reflect no change relative to baseline. This outcome measure will compare the HD-CAB composite change from baseline scores between participants with HD in SAGE-718 and placebo arms.

The CANTAB evaluates cognitive function via following subtests: N-Back Test (optional) Multitasking Test (optional) Spatial Working Memory Task Test Spatial Span Test (optional) Paired Associates Learning (optional)

The VRFCAT is a tablet-based measure that assesses ability to perform instrumental activities of daily living serve as a measure of functional improvement. Participants complete a series of tasks corresponding to functional capacity for meal preparation, use of public transportation, shopping, and managing currency. The total completion time is recorded for these activities, which ranges from 0 - 60000 milliseconds. Lesser time required to complete activity indicates better function.

Inclusion Criteria: For all Agree to refrain from drugs of abuse for the duration of the study and from alcohol during the 48 hours preceding each study visit Additional criteria for participants with HD only: Be ambulatory, able to travel to the study center, and, judged by the investigator, is likely to be able to continue to travel to the study center to complete study visits for the duration of the study. Have: Genetically confirmed disease with cytosine, adenine, and guanine (CAG) expansion ≥36 At screening, Unified Huntington's Disease Rating Scale (UHDRS) Total Functional Capacity (TFC) >6 and <13, suggesting no more than a moderate level of functional impairment. No features of juvenile HD CAG-Age-Product (CAP) score >70, as calculated using the CAP formula: Age × (CAG - 30) / 6.49. Score of 15 to 25 (inclusive) on the Montreal Cognitive Assessment (MoCA) at Screening, indicating the presence of cognitive impairment. Additional criteria for HP only: Score ≥26 on the MoCA at Screening. Have no known family history of HD; or, have known family history of HD but have genetic test results available that show a normal CAG repeat length for both Huntingtin (HTT) alleles (<36). Exclusion Criteria: For All Receive any prohibited medications within 30 days of Screening and during participation in the study Have participated in a previous clinical study of SAGE-718, have previous exposure to gene therapy; or have participated in any HD investigational drug, biologic, or device trial within 180 days, or a non-HD drug, biologic, or device trial within 30 days or 5 half-lives (whichever is longer). (Note: Participants with confirmation of enrolment in the placebo arm of these trials would not be excluded.) Is known to be allergic to any of SAGE-718 excipients, including soy lecithin. Additional criteria for participants with HD only Had gastric bypass surgery, has a gastric sleeve or lap band, or has had any related procedures that interfere with gastrointestinal transit. Receive any prohibited medications within 30 days of Screening and during participation in the Study.