Skyhawk Therapeutics’ investigational oral treatment SKY-0515 showed a 1.59-point difference in disease progression at 15 months versus an external natural-history control in a Phase 1/2 Huntington’s disease study.

Clinical measures favoured SKY-0515

At the Month 15 primary timepoint, patients treated with SKY-0515 had an average 0.94-point improvement from baseline on the Composite Unified Huntington’s Disease Rating Scale (cUHDRS), while the overlap-weighted external control group declined by an average of 0.65 points.

The resulting difference was 1.59 points (95% CI 1.09–2.09; p<0.001).

The cUHDRS combines four measures of Huntington’s disease progression: Total Functional Capacity, Total Motor Score, Symbol Digit Modalities Test and Stroop Word Reading Test.

Differences between SKY-0515 and the external control group were statistically significant across all four components at Month 15. The difference was 0.98 points for Total Functional Capacity, -9.38 points for Total Motor Score, 4.15 points for Symbol Digit Modalities Test and 4.18 points for Stroop Word Reading Test.

For Total Motor Score, a lower score represents better performance.

The cUHDRS difference favoured SKY-0515 at every prespecified assessment, although the difference was not statistically significant at Month 3 or Month 6. Statistical significance was reached at Month 9 and remained significant at Months 12 and 15.

The Month 15 analysis included 15 participants who had an available assessment. The external control was derived from natural-history datasets including Enroll-HD, 2CARE and CREST-E, with overlap-weighted propensity scoring used to account for differences between the groups.

SKY-0515 reduced mutant huntingtin

The clinical findings were accompanied by reductions in molecular markers associated with Huntington’s disease.

Skyhawk reported average reductions of more than 60% in mutant huntingtin protein (mHTT) at the 9 mg dose throughout the study, alongside average reductions of more than 25% in PMS1 mRNA.

SKY-0515 is an oral small molecule designed to modify RNA splicing and reduce production of both mHTT and PMS1. PMS1 is involved in somatic CAG repeat expansion, a process associated with Huntington’s disease progression.

The company said the treatment demonstrated central nervous system exposure and was generally well tolerated across the doses studied through 15 months, with no treatment-related serious adverse events reported.

The Phase 1/2 study was initially a randomised, double-blind, placebo-controlled study in patients with early-stage Huntington’s disease. Participants received placebo, 3 mg or 9 mg during the first 12 weeks, followed by a 12-month blinded extension in which participants received either 4 mg or 9 mg of SKY-0515.

Because the extension period followed the initial 12-week treatment period, the Month 15 analysis includes participants who had received placebo during the first three months before switching to active treatment. Skyhawk noted that this study design partly affects the Month 15 dataset.

Phase 2/3 FALCON-HD programme continues

Samuel Frank, director of the Huntington’s Disease Society of America Center of Excellence at Beth Israel Deaconess Medical Center, said: “The consistent effects on function, motor and cognitive measures need to be further studied in ongoing placebo-controlled studies but it is an exciting step forward for HD and the program.”

The final Phase 1/2 analysis comes as Skyhawk advances SKY-0515 into the global Phase 2/3 FALCON-HD programme.

The FALCON-HD programme comprises 004-ANZ, which has completed enrolment of 144 participants in Australia and New Zealand, and 004-WW, which is recruiting approximately 600 participants with Stage 2 and Stage 3 Huntington’s disease at more than 40 sites worldwide.

Across the Phase 1/2 and FALCON-HD programmes, more than 200 patients have now been enrolled at 20 trial sites in 10 countries.

The Phase 1/2 findings provide clinical data supporting continued evaluation of SKY-0515, but the study’s small Month 15 population and use of an external natural-history control mean the results will need to be tested in the ongoing placebo-controlled Phase 2/3 programme.

Huntington’s disease is a hereditary neurodegenerative disorder caused by an expanded CAG repeat in the HTT gene. SKY-0515 is being developed as a potential disease-modifying treatment and is not currently an approved therapy.