Study to Evaluate the Pharmacodynamics, Safety and Efficacy of SKY-0515 in Participants With Huntington's Disease

This study is a randomized, double-blind, placebo-controlled trial conducted across multiple sites. This clinical trial aims to evaluate the safety, pharmacodynamics, and efficacy of SKY-0515, a novel, orally administered small molecule. Huntington's Disease (HD) is a rare, inherited neurodegenerative condition caused by a mutation in the huntingtin (HTT) gene, resulting in excessive production of mutant huntingtin (mHTT) protein, which damages nerve cells and leads to progressive motor, cognitive, and psychiatric symptoms. SKY-0515 is designed to reduce mHTT protein levels, leading to a decrease in both wild-type and mutant forms of HTT protein. Additionally, the drug lowers postmeiotic segregation 1 (PMS1) protein, which plays a role in somatic CAG repeat expansion-a key driver of HD progression. Participants must be aged 25 or older, have genetically confirmed HD (CAG repeat length ≥ 40), and meet specific functional and motor criteria. They will be assigned randomly to one of four treatment arms (three doses of SKY-0515 and one placebo group). Safety and efficacy will be evaluated through blood tests, imaging (MRI), and clinical assessments, including the Unified Huntington's Disease Rating Scale (UHDRS).

Inclusion criteria

• 25 years or older.
• Huntington's Disease confirmed through genetic testing, with a specific change in exon 1 of the HTT gene (CAG repeat of 40 or more).
• Total Functional Capacity (TFC) score of 10 or more).
• Total Motor Score (TMS) of 6 or more).
• Independence Score (IS) of 70 or more).
• Women who can have children must have a negative pregnancy test before starting and use two types of birth control during the study and for 30 days after the last dose of the study drug.
• Men must agree to use birth control during the study and for 90 days after the last dose.
• Agree to sign a consent form and follow the study's rules and schedule.

Exclusion criteria

• Other Serious health problems or brain/spinal issues that could interfere with the study or make procedures unsafe.
• Conditions that interfere with protocol-specified assessments, like an implanted medical device or difficulty getting an MRI.
• Cancer, except for some types of skin cancer, or a history of cancer in the last five years.
• Severe allergies or have reacted badly to similar drugs in the past.
• Taking medications or treatments that might interfere with the study.
• Participated in another study or taken experimental drugs in the last two months (or longer for some drugs).
• Any kind of gene therapy.
• History of suicidal thoughts, severe depression, or have attempted suicide in the past year.
• Liver function tests show significant abnormalities.
• Positive for hepatitis B, hepatitis C, or HIV.
• Pregnancy, breastfeeding, or planning to become pregnant during the study.