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

What this trial studies

This clinical trial aims to evaluate the safety, pharmacodynamics, and efficacy of SKY-0515, a novel, orally-administered small molecule mRNA-splicing modulator for treating Huntington's Disease (HD). 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 by lowering of HTT messenger RNA (mRNA) through a splicing mechanism, 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. In early studies, SKY-0515 has reduced HTT and PMS1 mRNA levels in a dose-dependent manner, with favorable safety and tolerability profiles in healthy volunteers. This study is a randomized, double-blind, placebo-controlled, trial conducted at multiple sites. 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) in a 1:1:1:1 ratio. The study is composed of three periods: 1. Screening Period (up to 4 weeks): Participants will undergo eligibility assessments. 2. Double-Blind …

Who can join: the full rules

Inclusion Criteria:

* You must be 25 years or older.
* You must have Huntington's Disease confirmed through genetic testing, with a specific gene change (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.
* You must agree to sign a consent form and follow the study's rules and schedule.

Exclusion Criteria:

* You have other serious health problems or brain/spinal issues that could interfere with the study or make procedures unsafe.
* You have a condition that interferes with protocol-specified assessments, like an implanted medical device or difficulty getting an MRI.
* You have cancer, except for some types of skin cancer, or a history of cancer in the last five years.
* You have severe allergies or have reacted badly to similar drugs in the past.
* You are taking medications or treatments that might interfere with the study.
* You've been in another study or taken experimental drugs in the last two months (or longer for some drugs).
* You have had any kind of gene therapy.
* You have a history of suicidal thoughts, severe depression, or have attempted suicide in the past year.
* Your liver function tests show significant abnormalities.
* You have tested positive for hepatitis B, hepatitis C, or HIV.
* You are pregnant, breastfeeding, or planning to become pregnant during the study.

Where it's running

• John Hunter Hospital
  New Lambton Heights, New South Wales, Australia
• Westmead Hospital
  Westmead, New South Wales, Australia
• The University of Queensland
  Herston, Queensland, Australia
• Flinders Medical Centre
  Adelaide, South Australia, Australia
• Launceston General Hospital
  Launceston, Tasmania, Australia
• Calvary Health Care Bethlehem
  Caulfield South, Victoria, Australia

Study contacts

• Principal investigator: Masoud Mokhtarani, MD — Skyhawk Therapeutics, Inc.

How to take part

1. Review the eligibility criteria above with your treating physician.
2. Check the official listing on ClinicalTrials.gov for the latest contact details and recruitment status.
3. Contact the study coordinator or principal investigator to ask for pre-screening. Pre-screening is free and never obligates you to enroll.