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

Phase 2

Not yet recruiting

• Conditions: Huntington Disease; Huntingtons Disease
• Interventions: Drug: SKY-0515; Drug: SKY-0515 Placebo

• Registration Number: NCT06873334
• Lead Sponsor: Skyhawk Therapeutics, Inc.

Brief Summary

The goal of this clinical trial is to test if the drug SKY-0515, an oral medication, can lower harmful proteins linked to Huntington's Disease (HD) and improve the symptoms of participants with HD.

This study includes men and women aged 25 and older who have HD confirmed by genetic testing and meet certain requirements for physical ability and independence.

Detailed Description

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 Treatment Period (12 months): Participants will take SKY-0515 or a placebo once daily and undergo regular clinic visits for monitoring. Safety and efficacy will be evaluated through blood tests, imaging (MRI), and clinical assessments, including the Unified Huntington's Disease Rating Scale (UHDRS).

3. Follow-Up Period (4 weeks): After completing treatment, participants will be monitored for any remaining effects.

An independent Data Safety Monitoring Board (DSMB) will oversee the trial to ensure participant safety.

This study will assess:

* Changes in levels of HTT proteins and other HD-related biomarkers.

* Effects on HD-related brain atrophy and clinical features.

* Long-term safety of SKY-0515.

Study Timeline

• Study First Submitted: 2025-03-06
• Study First Submitted QC: 2025-03-06
• Study First Posted: 2025-03-12
• Status Verified: 2025-05
• Study Start: 2025-05
• Last Update Submitted: 2025-05-04
• Last Update Posted: 2025-05-07
• Primary Completion: 2027-05
• Study Completion: 2027-12

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 120

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
1 (Active)	SKY-0515	Dosage Level(s): Low dose once daily oral
2 (Active)	SKY-0515	Dosage Level(s): Mid dose once daily oral
3 (Active)	SKY-0515	Dosage Level(s): High dose once daily oral
4 (Control)	SKY-0515 Placebo	Matching placebo once daily oral

Primary Outcome Measures

Name	Time	Method
Changes in blood mHTT protein levels	12 months
Changes in brain volume measured through MRI	12 months
Changes in UHDRS	12 months

Trial Locations

Locations (10)

John Hunter Hospital; 🇦🇺 New Lambton Heights, New South Wales, Australia

Westmead Hospital; 🇦🇺 Westmead, New South Wales, Australia

The University of Queensland - Royal Brisbane Womens Hospital; 🇦🇺 Herston, Queensland, Australia

Flinders Medical Centre; 🇦🇺 Adelaide, South Australia, Australia

Calvary Health Care Bethlehem; 🇦🇺 Caulfield South, Victoria, Australia

The Royal Melbourne Hospital; 🇦🇺 Parkville, Victoria, Australia

The Perron Institute for Neurology and Translational Science (Perron Institute); 🇦🇺 Nedlands, Western Australia, Australia

Auckland City Hospital; 🇳🇿 Auckland, New Zealand

Christchurch Neurology Trials Limited; 🇳🇿 Christchurch, New Zealand

Wellington Hospital; 🇳🇿 Wellington, New Zealand