SKY-0515 Shows Sustained Benefit at 15 Months in Huntington Disease

Skyhawk Therapeutics reported final 15-month results from its phase 1/2 trial of SKY-0515, an oral RNA splicing modifier, showing improvement on the Composite Unified Huntington Disease Rating Scale (cUHDRS) and sustained reduction of mutant huntingtin protein in patients with early-stage Huntington disease (HD). The results come as the company's pivotal phase 2/3 FALCON-HD trial continues to expand into new countries and enroll additional patients.¹

The randomized, double-blind, placebo-controlled trial enrolled patients with HD-ISS stage 1, stage 2, or mild stage 3 HD, treating them with SKY-0515 3 mg or 9 mg or placebo for an initial 12 weeks before all participants entered a blinded extension on active drug (4 mg or 9 mg, with most on the 9-mg dose); the final analysis reflects 15 patients assessed at month 15.

At month 15, the cUHDRS composite score improved by 0.94 points with SKY-0515 versus a 0.65-point decline in an external natural history control, a treatment difference of 1.59 points (95% CI, 1.09-2.09; P <.001). All 4 cUHDRS subcomponents also favored treatment, building on the favorable trends reported at the 12-month assessment: Total Functional Capacity improved 0.98 points, Total Motor Score improved 9.38 points, and both the Symbol Digit Modalities Test and Stroop Word Reading Test improved more than 4 points.

At the 9-mg dose, mutant huntingtin protein was reduced by more than 60% and PMS1 messenger RNA by more than 25%, extending the sustained huntingtin lowering observed at earlier study time points. SKY-0515 was generally well tolerated through 15 months, with no treatment-related serious adverse events (AEs) reported.

“A 1.59-point cUHDRS difference versus a rigorously weighted natural history control at fifteen months is exactly the type of signal the field looks for,” Samuel Frank, MD, director of the Huntington Study Group Center of Excellence at Beth Israel Deaconess Medical Center, said in a statement.¹

“What makes SKY-0515 especially exciting is that it is a pill, taken once a day at home,” said Katie Jackson, chief executive officer of Help 4 HD International, said in a statement.¹

FALCON-HD phase 2/3 program update

The pivotal FALCON-HD program (NCT06873334, NCT07378644) is an ongoing, randomized, double-blind, placebo-controlled, dose-ranging study testing 3 SKY-0515 dose levels against placebo. It began in Australia and New Zealand, where the first patient was dosed at Flinders Medical Centre in Adelaide in June 2025; that regional study, FALCON-HD 004-ANZ, has since completed enrollment at 144 participants.^2,3

In July 2026, Skyhawk announced it had received regulatory clearances, an IND acceptance in the United States and clinical trial authorizations in Canada and the United Kingdom, to expand the global arm of the program, FALCON-HD 004-WW, into those countries.⁴ As of the September 2026 update, 004-WW is targeting approximately 600 participants across more than 40 sites worldwide, and the combined phase 1/2 and FALCON-HD program has enrolled more than 200 patients across 20 sites in 10 countries.¹

“Clinician and patient assessments done at twelve months of treatment support what SKY-0515's compelling and consistent effects on critical biomarkers demonstrate,” Sergey Paushkin, PhD, co-founder and head of research and development at Skyhawk, said in a statement.⁴

REFERENCES
1. Skyhawk Therapeutics announces final fifteen-month results from phase 1/2 clinical trial of SKY-0515 in Huntington's disease patients. News release. Published September 15, 2026. Accessed September 23, 2026. https://www.skyhawktx.com/article/skyhawk-therapeutics-announces-final-fifteen-month-results-from-phase-1-2-clinical-trial-of-sky-0515-in-huntingtons-disease-patients
2. A study of SKY-0515 in participants with Huntington's disease (FALCON-HD). ClinicalTrials.gov identifiers: NCT06873334, NCT07378644. Accessed September 23, 2026. https://clinicaltrials.gov/study/NCT06873334
3. Skyhawk Therapeutics announces first patient dosed in phase 2/3 FALCON-HD trial of SKY-0515 for Huntington's disease. News release. Published June 17, 2025. Accessed September 23, 2026. https://www.prnewswire.com/news-releases/skyhawk-therapeutics-announces-first-patient-dosed-in-phase-23-falcon-hd-trial-of-sky-0515-for-huntingtons-disease-302483907.html
4. Skyhawk Therapeutics announces expansion of its global pivotal FALCON-HD clinical trial for SKY-0515 in Huntington's disease to the United States, Canada and the United Kingdom. News release. Published July 14, 2026. Accessed September 23, 2026. https://www.prnewswire.com/news-releases/skyhawk-therapeutics-announces-expansion-of-its-global-pivotal-falcon-hd-clinical-trial-for-sky-0515-in-huntingtons-disease-to-the-united-states-canada-and-the-united-kingdom-302825053.html