Huntington’s disease (HD) is a rare, inherited neurodegenerative disorder that progressively affects movement, cognition, and functional abilities. Despite advances in clinical research, there are currently no approved therapies demonstrated to slow or halt disease progression.

New twelve-month findings from the Phase 1/2 clinical program of SKY-0515, an investigational oral therapy for Huntington’s disease, showed favorable trends across measures of functional capacity, motor performance, and cognition. The study also reported reductions in biomarkers associated with the underlying biology of the disease.

While these findings are encouraging, SKY-0515 remains an investigational treatment, and larger controlled studies will be needed to determine its clinical efficacy and long-term potential.

Targeting the Molecular Drivers of Huntington’s Disease

SKY-0515 is an orally administered small-molecule RNA splicing modifier developed using Skyhawk Therapeutics’ SKYSTAR® platform. The therapy is designed to reduce both mutant huntingtin (mHTT) and PMS1.

Mutant huntingtin is the primary protein associated with Huntington’s disease pathology, while PMS1 is involved in somatic CAG repeat expansion, a process associated with disease progression. In the Phase 1/2 program, treatment with SKY-0515 produced dose-dependent reductions in blood mHTT protein of up to 69% and reductions in PMS1 mRNA of up to 26%.

These biomarker findings provide an important part of the scientific rationale for continued development of the therapy.

Twelve-Month Trends Across Functional, Motor, and Cognitive Measures

The twelve-month analysis assessed four components of the Composite Unified Huntington’s Disease Rating Scale (cUHDRS):

• Total Functional Capacity (TFC), which evaluates functional abilities
• Total Motor Score (TMS), which measures motor impairment
• Symbol Digit Modalities Test (SDMT), which assesses cognitive processing
• Stroop Word Reading Test (SWRT), which provides an additional measure of cognitive function

Participants receiving SKY-0515 demonstrated favorable mean changes from baseline across all four measures when compared with expected changes derived from propensity score-weighted analyses using Enroll-HD natural history datasets.

At twelve months, the reported mean changes were:

*Expected changes were based on propensity score-weighted analyses using Enroll-HD natural history data.

Together, these findings showed favorable trends across functional, motor, and cognitive measures during the twelve-month period.

Patient and Clinician Assessments Show Disease Stability

The study also included Patient Global Impression (PGI) and Clinician Global Impression (CGI) assessments to provide an additional perspective on changes in disease status.

Among participants for whom Huntington’s disease would be expected to cause considerable worsening over twelve months, no patient or clinician assessed disease progression at the twelve-month assessment. In addition, 65% of participants and 50% of clinicians assessed improvement.

These findings complement the observed trends in functional, motor, and cognitive measures, although they should be interpreted within the context of the study’s design and size.

Implications for Huntington’s Disease Research

The twelve-month results provide encouraging data for the continued investigation of SKY-0515 as a potential disease-modifying approach for Huntington’s disease.

Of particular interest is the consistency between the therapy’s effects on disease-related biomarkers and the favorable trends observed across several clinical measures. The reported reductions in mHTT and PMS1, alongside changes in cUHDRS subcomponents, provide multiple areas for further investigation.

However, these results should not yet be interpreted as definitive evidence that SKY-0515 slows or halts Huntington’s disease. The Phase 1/2 program was designed primarily to assess safety, tolerability, pharmacokinetics, and pharmacodynamics, while also evaluating biomarkers and efficacy endpoints.

The findings therefore represent an important step in clinical development, but additional evidence is necessary to establish the treatment’s efficacy and long-term clinical benefit.

Advancing Toward Larger Clinical Studies

The Phase 1/2 study has completed enrollment. Its Part C component evaluated two doses of SKY-0515 in people with early-stage Huntington’s disease in a randomized, double-blind, placebo-controlled study lasting 84 days, followed by a twelve-month blinded extension in which participants received active treatment.

The program has subsequently advanced to the Phase 2/3 FALCON-HD pivotal program, which is evaluating the pharmacodynamics, efficacy, and safety of SKY-0515 in a larger patient population.

FALCON-HD includes clinical studies across multiple sites and regions, with one study enrolling 144 participants in Australia and New Zealand and another planned to enroll up to an additional 400 participants across more than 40 sites worldwide.

The Next Stage of SKY-0515 Development

The twelve-month findings add to the growing body of clinical data surrounding targeted approaches to Huntington’s disease. The combination of biomarker reductions and favorable trends across functional, motor, and cognitive measures provides a rationale for continued evaluation of SKY-0515.

The larger pivotal studies will be important in determining whether these findings can be replicated in broader populations and whether the treatment can ultimately demonstrate meaningful clinical benefit.

For Huntington’s disease, where disease-modifying treatment remains an unmet need, continued investigation of therapies that target its underlying molecular mechanisms represents an important area of research.