SKY-0515 Shows Sustained Biomarker Reductions in Huntington’s Disease
Key Clinical Summary
- SKY-0515, an investigational oral RNA splicing modifier, reduced mutant huntingtin (mHTT) protein levels in blood by up to 69% and PMS1 mRNA by up to 26% in a phase 1/2 Huntington’s disease (HD) trial.
- Twelve-month interim data showed positive mean changes from baseline in Composite Unified Huntington’s Disease Rating Scale (cUHDRS) scores ranging from +0.31 to +0.38, compared with an expected decline of -0.92 points based on natural history analyses.
- SKY-0515 was reported to be generally safe and well tolerated, with ongoing global phase 2/3 studies evaluating efficacy and safety.
In a phase 1/2 clinical trial, SKY-0515, an investigational oral small-molecule therapy for Huntington’s disease (HD), demonstrated sustained reductions in key disease-related biomarkers in patients with early-stage HD, reported manufacturer Skyhawk Therapeutics. The 12-month interim data also found that the treatment was associated with improved clinical outcomes.
Study Findings
The phase 1/2 study evaluated SKY-0515, a small-molecule RNA splicing modifier designed to reduce both mutant huntingtin (mHTT) and PMS1 proteins, targets implicated in Huntington’s disease pathology and progression.
At the 12-month interim analysis, treatment produced dose-dependent reductions in mHTT protein levels in blood of up to 69% and reductions in PMS1 mRNA of up to 26%. The company reported that SKY-0515 was generally safe and well tolerated across all dose levels studied.
Clinical outcomes were assessed using the Composite Unified Huntington’s Disease Rating Scale (cUHDRS). Mean changes from baseline ranged from +0.31 to +0.38 at 3, 6, 9, and 12 months. These results compared favorably with an expected 12-month worsening of -0.92 points derived from propensity score-weighted analyses using Enroll-HD and TRACK-HD natural history datasets.
Positive trends were also observed across all 4 cUHDRS subcomponents, including Total Motor Score, Total Functional Capacity, Symbol Digit Modalities Test, and Stroop Word Reading Test.
Clinical Implications
Huntington’s disease is a rare, inherited neurodegenerative disorder affecting more than 40,000 symptomatic individuals in the United States, with no approved therapies proven to slow or halt disease progression.
The sustained biomarker reductions observed through 12 months of treatment with SKY-0515, coupled with favorable cUHDRS trends, provide preliminary evidence supporting continued clinical development. However, the findings remain interim and will require confirmation in larger, placebo-controlled pivotal studies.
Expert Commentary
"I am very encouraged by these continued safety and efficacy data from SKY-0515's phase 1/2 trial in patients, including sustained improvement in patients' cUHDRS when compared with expected propensity-weighted natural history deterioration at each of 3, 6, 9, and 12-month prespecified analyses," said Ed Wild, MRCP, PhD, professor of neurology, University College London. "SKY-0515 continues to reduce mHTT protein to the greatest extent demonstrated in patients, with clinical and biomarker data showing the drug is well tolerated at all doses tested.”
Wild added that the ability of SKY-0515 to reduce both mHTT and PMS1 “appears to be a potent combination for treating Huntington’s disease via 2 of its core pathogenic mechanisms.” He noted that an ongoing phase 2/3 trial, the FALCON-HD program, seeks to validate the results of these initial data.
