Huntington Agent SKY-0515 Shows Favorable Trends Across cUHDRS Subcomponents in 12-Month Findings

Skyhawk Therapeutics released 12-month composite Unified Huntington’s Disease Rating Scale (cUHDRS) subcomponent data from its ongoing phase 1/2 trial of SKY-0515, an investigational oral RNA-splicing modifier for Huntington disease (HD), presented at the European Academy of Neurology annual meeting on June 30, 2026.¹ The data build on prior interim readouts and represent the most granular clinical efficacy update released to date for the program, covering all four cUHDRS subcomponents alongside Clinician and Patient Global Impression (CGI and PGI) survey data.

For context, SKY-0515 is designed to modulate RNA splicing to simultaneously reduce mutant huntingtin protein (mHTT) and PMS1, a DNA mismatch repair protein implicated in somatic CAG repeat expansion, the latter a mechanism increasingly recognized as a driver of HD progression independent of inherited CAG repeat length. The drug is orally administered once daily and has demonstrated CNS penetration across dose levels studied.

12-Month cUHDRS Subcomponent Results

Across all four cUHDRS subcomponents, SKY-0515-treated participants showed trends in the direction of improvement or stabilization at 12 months, compared with expected worsening based on propensity score-weighted natural history data from Enroll-HD datasets. The analysis pooled participants receiving 4 mg and 9 mg SKY-0515 and included patients who received placebo for three months before switching to active treatment.

On Total Functional Capacity (TFC), participants demonstrated a mean change from baseline of +0.07 at 12 months, compared with an expected decline of −0.87 points from natural history analyses. On Total Motor Score (TMS), treated participants showed a mean change of −2.00 (indicating improvement, as lower scores reflect less motor dysfunction), compared with an expected worsening of +2.21 points.¹

Cognitive endpoints followed the same pattern. On the Symbol Digit Modalities Test (SDMT), participants showed a mean change of −0.19, compared with an expected decline of −1.78 points. On the Stroop Word Reading Test (SWRT), treated participants showed a mean improvement of +3.44 points versus an expected worsening of −3.13 points.¹

The magnitude of divergence from natural history expectations widened progressively between months 3 and 12 across all four measures, suggesting a compounding benefit over time rather than a plateauing effect.

CGI and PGI Data

Skyhawk also released interim Clinician and Patient Global Impression of Change (CGI-C and PGI-C) data assessed monthly over 12 months among participants for whom HD was expected to produce considerable disease worsening. At 12 months, no clinician and no patient assessed any disease worsening. Among participants, 65% assessed that their disease had improved; 50% of clinicians assessed improvement in their patients.¹

"We are excited by the fact that participants and their clinicians, for whom Huntington's disease is expected to cause considerable disease worsening, see no worsening at twelve months, and 65% of participants and 50% of clinicians assessed that there had been improvement," Sergey Paushkin, MD, PhD, Head of R&D at Skyhawk Therapeutics, said in a statement.¹

Biomarker Context

The clinical data are accompanied by sustained biomarker findings reported in prior readouts. 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%.¹ These results were first reported at the six-month interim analysis in June 2026 and are now confirmed to have been sustained through 12 months of follow-up.²

The dual-target mechanism distinguishes SKY-0515 from huntingtin-lowering approaches that target mHTT alone. Reducing PMS1 is hypothesized to slow somatic CAG repeat expansion, a process that occurs in neurons after birth and is increasingly understood to accelerate disease onset and progression beyond what the germline CAG length would predict alone.

FALCON-HD and Program Status

The phase 2/3 FALCON-HD pivotal program is actively advancing on two tracks. FALCON-HD 004-ANZ, enrolling patients in Australia and New Zealand, has completed enrollment of 144 participants. FALCON-HD 004-WW, a global study, plans to enroll up to 400 additional participants with stage 2 and early stage 3 HD across more than 40 sites worldwide and is actively treating patients at multiple sites.¹ As previously reported, the first patient was dosed in the FALCON-HD program in June 2025.³ More than 175 participants are now enrolled across the phase 1/2 and pivotal programs in five countries.

REFERENCES
1. Skyhawk Therapeutics releases twelve-month cUHDRS subcomponent results from its phase 1/2 clinical trial of SKY-0515 in Huntington's disease. News release. Skyhawk Therapeutics. June 30, 2026. Accessed June 30, 2026. https://www.prnewswire.com/news-releases/skyhawk-therapeutics-releases-twelve-month-cuhdrs-subcomponent-results-from-its-phase-12-clinical-trial-of-sky-0515-in-huntingtons-disease
2. Skyhawk Therapeutics announces twelve-month interim results from phase 1/2 clinical trial of SKY-0515 in Huntington's disease. News release. Skyhawk Therapeutics. June 1, 2026. Accessed June 30, 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
3. Skyhawk Therapeutics announces first patient dosed in phase 2/3 FALCON-HD trial of SKY-0515 for Huntington's disease. News release. Skyhawk Therapeutics. June 17, 2025. Accessed June 30, 2025. https://www.skyhawktx.com/post/skyhawk-therapeutics-announces-first-patient-dosed-in-phase-2-3-falcon-hd-trial-of-sky-0515-for-hunt