SKY-0515 Demonstrates Sustained Mutant Huntingtin Lowering in Latest Phase 1/2 Study Update

In a randomized, double-blind, placebo-controlled interim phase 1/2 trial, patients with Huntington disease (HD) treated with the investigational oral RNA-splicing modifier SKY-0515 demonstrated sustained reductions in mutant huntingtin protein (mHTT) of up to 69% and favorable clinical outcomes through 12 months, according to Skyhawk Therapeutics, the drug manufacturer.¹

Notably, treatment with the agent was associated with positive changes from baseline on the Composite Unified Huntington Disease Rating Scale (cUHDRS), a key measure of disease progression in HD. Although the findings have not yet been published in a peer-reviewed journal, the results suggest SKY-0515 may have the potential to influence both disease-related biomarkers and clinical measures in HD, an inherited neurodegenerative disorder for which no disease-modifying therapies have been approved.²

“The increasing separation of the clinical trajectories of treated participants from natural history expectations at the twelve-month timepoint suggests exciting and sustained benefits for Huntington's patients," Bill Haney, Co-founder and Chief Executive Officer of Skyhawk Therapeutics, said in a statement.¹ "The magnitude and durability of lowering of critical biomarkers mHTT and PMS1, as well as encouraging twelve-month clinical findings across all four of the critical cUHDRS subcomponents, reinforce our confidence in SKY-0515's differentiated mechanism and potential for dramatic therapeutic impact for patients.”

Phase 1/2 Trial Overview

SKY-0515 is an orally administered small molecule developed using Skyhawk's proprietary RNA-targeting platform. The therapy is designed to modulate RNA splicing and reduce production of both mutant huntingtin protein and PMS1, a DNA mismatch repair protein implicated in somatic CAG repeat expansion and disease progression.^1,3

The ongoing first-in-human phase 1/2 program includes healthy volunteers and patients with early-stage HD. The patient portion of the study enrolled individuals with HD Integrated Staging System (HD-ISS) stage 1, stage 2, or mild stage 3 disease, followed by a blinded extension period in which all participants receive active treatment.¹

According to the interim analysis, treatment produced dose-dependent reductions in mHTT levels of up to 69% at the 9-mg dose after 12 months. Investigators also reported reductions in PMS1 messenger RNA of up to 26%. Beyond biomarker findings, favorable trends were observed across all cUHDRS component measures, including Total Motor Score, Total Functional Capacity, Symbol Digit Modalities Test, and the Stroop Word Reading Test.¹

Across prespecified analyses conducted at 3, 6, 9, and 12 months, mean cUHDRS scores improved between +0.31 and +0.38 points from baseline, compared with an expected decline of –0.92 points over 12 months based on propensity score-weighted natural history analyses derived from the Enroll-HD and TRACK-HD datasets.¹

Skyhawk stated that SKY-0515 was generally safe and well tolerated across evaluated dose levels and demonstrated central nervous system exposure consistent with its intended mechanism of action. However, detailed safety data, adverse event rates, and discontinuation rates were not disclosed in the announcement.¹

FALCON-HD Program Advances

Alongside the phase 1/2 update, Skyhawk announced that enrollment of 144 participants has been completed 6 months in advance in the Australia and New Zealand portion of the phase 2/3 FALCON-HD 004-ANZ program. In total, FALCON-HD 004-WW plans to enroll 400 participants with Stage 2 and early Stage 3 HD across more than 40 sites worldwide and is still actively recruiting.¹

As reported previously by NeurologyLive, the randomized, double-blind, placebo-controlled FALCON-HD program is designed to evaluate the efficacy, safety, pharmacodynamic effects, and biomarker impact of SKY-0515 across multiple dose levels.Participants are randomized to a once-daily oral dose of SKY-0515 at 1 of 3 dose levels or placebo for a treatment duration of at least 12 months.⁴

In FALCON-HD, investigators will also evaluate SKY-0515’s ability to modulate RNA splicing and reduce production of HTT and PMS1 proteins.⁴ More than 175 participants have now been enrolled across the phase 1/2 and pivotal FALCON-HD studies.¹

Clinical Context and Next Steps

Current approved therapies for HD primarily address symptoms such as chorea and psychiatric manifestations rather than the underlying disease process. As a result, huntingtin-lowering approaches have become a major focus of therapeutic development over the past decade.³

Several investigational strategies, including antisense oligonucleotides, gene therapies, and RNA-targeting approaches, have sought to reduce mutant huntingtin expression. However, development has proven challenging, with several programs failing to demonstrate clinical benefit despite evidence of target engagement.²

Interpretation of the current findings is limited by several factors. The data represent an interim analysis from an ongoing study and have yet to be peer reviewed. Additionally, comparisons of cUHDRS outcomes were made against propensity score-weighted natural history datasets rather than contemporaneous placebo-controlled results from the extension period.

Further evaluation in the ongoing FALCON-HD program will be necessary to determine whether the observed biomarker reductions and clinical trends translate into durable disease-modifying effects for patients with HD.

REFERENCES
1. Skyhawk Therapeutics Announces Twelve-Month Interim Results from Phase 1/2 Clinical Trial of SKY-0515 in Huntington's Disease. Skyhawk Therapeutics. News Release. June 1, 2026. Accessed: June 1, 2026. https://www.prnewswire.co.uk/news-releases/skyhawk-therapeutics-announces-twelve-month-interim-results-from-phase-12-clinical-trial-of-sky-0515-in-huntingtons-disease-302786696.html?tc=eml_cleartime
2. Tabrizi SJ, Ghosh R, Leavitt BR. Huntington disease. Lancet. 2019;394(10197):555-572. doi:10.1016/S0140-6736(19)31280-7.
3. McColgan P, Tabrizi SJ. Huntington's disease: a clinical review. Eur J Neurol. 2018;25(1):24-34. doi:10.1111/ene.13413.
4. Skyhawk Therapeutics Announces First Patient Dosed in Phase 2/3 FALCON-HD Trial of SKY-0515 for Huntington’s Disease. News Release. Skyhawk Therapeutics. Published June 17, 2025. Accessed June 24, 2025. https://www.skyhawktx.com/post/skyhawk-therapeutics-announces-first-patient-dosed-in-phase-2-3-falcon-hd-trial-of-sky-0515-for-hunt