Phase 2/3 Randomized, Double‑Blind, Placebo‑Controlled, Dose‑Ranging Study of SKY‑0515 in Adults with Huntington’s Disease

Primary objective: To evaluate the efficacy of SKY-0515 on the clinical manifestations of Huntington’s disease.

• Further assessment of efficacy on disease characteristics.
• Characterization of the pharmacodynamic effects of SKY-0515 using biomarker endpoints.
• Evaluation of the safety and tolerability of oral SKY-0515 across dose groups.

The trial enrolled 346 participants diagnosed with Huntington’s Disease who met genetically confirmed criteria (CAG repeat >40). Eligible individuals were adults aged 25 years or older, inclusive of both male and female participants. Enrollment required classification as stage 2 or stage 3 (mild) based on Unified Huntington’s Disease Rating Scale assessments (total functional capacity ≥10, motor score ≤6, independence score ≥70). Participants were required to have the cognitive capacity to provide informed consent and to be able to comply with the study schedule. Reproductive‑health considerations mandated appropriate contraception for participants of childbearing potential and their partners, or confirmation of sterility/post‑menopausal status. General health status was otherwise unrestricted aside from the disease‑specific criteria, and subjects were expected to maintain their usual diet and physical activity levels throughout the study. Selection was based on documented genetic confirmation, clinical staging, and compliance with consent and contraception requirements.

The study is a Phase 2/3, randomized, double‑blind, placebo‑controlled, dose‑ranging trial evaluating SKY‑0515 in adults with genetically confirmed Huntington’s disease. Participants are allocated in a concealed manner to receive SKY‑0515 tablets at 4 mg, 6 mg, or 9 mg daily, or a matching placebo, and remain blinded to treatment throughout the 72‑week treatment period. The trial timeline spans approximately two years, with recruitment projected to begin on 14 August 2026 and conclude on 14 August 2028. The visit schedule includes an initial screening visit to verify eligibility criteria, a baseline visit (Day 0) to obtain pre‑dose assessments, and subsequent follow‑up visits at weeks 4, 12, 24, 36, 48, 60, and 72, the latter constituting the end‑of‑study visit. At each visit, safety evaluations, vital signs, laboratory tests, and efficacy assessments—including the primary endpoint of change from baseline to week 72 in the composite Unified Huntington’s Disease Rating Scale (cUHDRS)—are performed. Participants are expected to be involved for roughly 78 weeks, encompassing the treatment phase and a final safety follow‑up. Early termination may occur if a participant experiences a serious adverse event, fails to comply with study procedures, withdraws consent, requires prohibited medication, or meets predefined clinical deterioration criteria, in which case the participant will discontinue study medication and complete the end‑of‑study assessments as feasible.

The investigational product is SKY-0515, supplied as immediate‑release tablets in three dose strengths: 4 mg, 6 mg, and 9 mg. Each tablet contains the active substance SKY‑0515 and is administered orally. Participants are randomized to receive one of the three dosage levels throughout the treatment period.

The control arm utilizes a matching placebo composed of micronized methylcellulose spray‑dried intermediate formulated in enteric‑coated tablets. The placebo tablets are identical in appearance to the active tablets and are also administered orally.

All study medications are dispensed in blinded packaging according to the assigned treatment arm. Dosing is scheduled according to the study protocol, with participants instructed to take the assigned tablet once daily. Compliance is assessed by pill count at each study visit and reinforced through participant diaries and verbal reminders. Safety and pharmacodynamic assessments are conducted at predefined intervals to monitor the effects of the investigational product in individuals with Huntington’s disease.

The efficacy of SKY-0515 will be evaluated in participants with Huntington’s Disease by measuring changes from baseline to Week 72 in predefined clinical scales.

The primary efficacy endpoint is the change from baseline to Week 72 in the composite Unified Huntington’s Disease Rating Scale (cUHDRS). Secondary efficacy endpoints comprise the change from baseline to Week 72 in the Total Motor Score (TMS), Total Functional Capacity (TFC), Independence Scale (IS), Stroop Color and Word Test (SCWT), and Symbol Digit Modalities Test (SDTM).

All assessments will be conducted using validated instruments administered by trained evaluators at baseline and at the Week 72 visit. Efficacy data will be analyzed by comparing mean changes from baseline between treatment groups using appropriate statistical methods for continuous outcomes.