SAGE-718

The WAIS-IV coding test is a valid and sensitive measure of cognitive dysfunction that correlates with real-world functional outcomes (e.g., the ability to accomplish everyday tasks) and recovery from functional disability, used to assess processing speed. The participant is required to identify the symbols matched to numbers using a key and write in the symbol beneath the associated number. The total score ranges from 0 to 135 and is based on the total number of codes correctly completed over a 120-second time limit. Higher scores indicate better processing speed. Positive change from baseline indicates better processing speed. Least Squares (LS) Means were calculated using a mixed-effects model for repeated measures (MMRM) approach.

HD-CAB assesses cognitive function using 6 subtests:Symbol Digit Modalities Test-correctly coded items(0-110); One Touch Stockings of Cambridge(OTS)-mean time to reach correct response(range not defined); Trail Making Test Trail B (TMT-B)-time to complete task(0-240 sec); Hopkins Verbal Learning Test Revised-total correct recall trials(0-48); Paced Tapping Test-reciprocal of standard deviation(SD) of intertap intervals (range not defined); Emotion Recognition Test-negative emotions correctly identified(0-24). Values of OTS \& TMT B are multiplied by -1 to represent higher is better direction as other tests. Each of 6 subtests scores was transformed to z-score(range not defined;low negative value represents cognitive impairment), which is calculated by subtracting mean and dividing by SD of HP at baseline. HD-CAB composite=average of 6 z-scores. Negative HD-CAB of HD participants=decline in cognitive function relative to HP. Assessment is relative to reference group(healthy population).

The SDMT evaluates the tracking of cognitive function over time and for the early detection of cognitive impairment. The test assesses sustained attention, processing speed, visual scanning, and psychomotor speed, with the total score reflecting the number of correct pairings (out of 110 possible) completed within 90 seconds. Scores range from 0 to 110, with higher scores indicating better cognitive performance.

An adverse event (AE) was any untoward medical occurrence in a participant administered with a pharmaceutical product and that does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an IP whether or not related to the product. An AE can include any undesirable medical condition, even if no study treatment has been administered. TEAEs were defined as an AE with an onset date on or after the date of the first dose of IP or any worsening of a pre-existing medical condition/AE with onset after the start of IP and throughout the study.

An adverse event (AE) was any untoward medical occurrence in a participant administered with a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an IP whether or not related to the product. An AE can include any undesirable medical condition, even if no study treatment has been administered. TEAEs were defined as an AE with an onset date on or after the date of the first dose of IP or any worsening of a pre-existing medical condition/AE with onset after the start of IP and throughout the study. Percentages are rounded off to the nearest single decimal.

An AE was any untoward medical occurrence in a participant administered with a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an IP whether or not related to the product. An AE can include any undesirable medical condition, even if no study treatment has been administered. TEAEs were defined as an AE with an onset date on or after the date of the first dose of IP or any worsening of a pre-existing medical condition/AE with onset after the start of IP and throughout the study. Percentages are rounded off to the nearest single decimal.