Boston-based Skyhawk Therapeutics, Inc. reported final Phase I/II data for SKY-0515 in Huntington's disease, with treated patients showing a statistically significant 1.59-point advantage on the composite Unified Huntington's Disease Rating Scale (cUHDRS) versus an external natural history control at 15 months. The oral RNA-splicing modifier also showed differences favoring treatment across all four components of the cUHDRS, although the analysis was based on 15 treated patients and used an external comparator rather than a concurrent placebo group. Skyhawk is advancing SKY-0515 into the global Phase II/III FALCON-HD program.
The Phase I/II study enrolled patients with early-stage Huntington's disease and began with a 12-week randomized, double-blind, placebo-controlled period, followed by a 12-month blinded extension in which all participants received SKY-0515 at 4 mg or 9 mg once daily. At month 15, treated patients improved by a mean 0.94 points from baseline on the cUHDRS, while an overlap-weighted comparator cohort drawn from the Enroll-HD, 2CARE, and CREST-E natural history datasets declined by 0.65 points, producing a treatment difference of 1.59 points (95% CI 1.09–2.09; p<0.001). Significant differences also favored SKY-0515 on Total Functional Capacity, Total Motor Score, Symbol Digit Modalities Test, and Stroop Word Reading Test.
SKY-0515 is designed to modify RNA splicing of the huntingtin gene, reducing production of both mutant huntingtin protein (mHTT) — the primary driver of HD pathology — and PMS1, a mismatch repair protein whose activity promotes somatic expansion of the CAG repeat tract associated with disease progression. At the 9 mg dose, the drug produced average mHTT reductions exceeding 60% and PMS1 mRNA reductions exceeding 25% throughout the study. No treatment-related serious adverse events were reported across 15 months of follow-up. The dual-target approach distinguishes SKY-0515 from antisense oligonucleotide programs that have advanced in HD; Roche's intrathecally administered tominersen lowered mHTT in cerebrospinal fluid in a Phase I/II study but had its Phase III trial halted due to worse-than-placebo outcomes at higher-frequency dosing, while Wave Life Sciences' allele-selective mHTT-lowering agent WVE-003 demonstrated target engagement in Phase Ib/IIa data but has not advanced to a registrational study.