Skyhawk Therapeutics has reported positive nine-month interim results from its Phase 1 clinical trial of SKY-0515, an investigational oral small molecule for Huntington’s disease (HD). The data show improvement in the Composite Unified Huntington’s Disease Rating Scale (cUHDRS) compared to expected natural history decline and highlight biomarker activity relevant to disease modification.

In the Phase 1 Part C cohort, patients receiving SKY-0515 demonstrated mean cUHDRS improvement from baseline of +0.64 points at nine months. This contrasts with the expected nine-month worsening of -0.73 points in symptomatic patients, based on propensity score weighting using Enroll-HD and TRACK-HD datasets.

Treatment with SKY-0515 also produced dose-dependent reductions in mutant huntingtin (mHTT) protein, achieving 62% reduction at the 9 mg dose, and reduced PMS1 mRNA by 26%. PMS1 is a key driver of somatic CAG repeat expansion and HD pathology. The drug demonstrated strong central nervous system exposure and was generally safe and well tolerated.

Ed Wild, professor of neurology at University College London, said: “I am very encouraged by these safety and early efficacy data from SKY-0515’s Phase 1 Part C trial in patients, showing divergence in cUHDRS away from expected natural history deterioration at the three, six, and nine month prespecified analyses. SKY-0515 continues to reduce mHTT protein to the greatest extent demonstrated by any therapeutic tested to date in patients, with clinical and biomarker data showing the drug is well tolerated at all doses tested. SKY-0515’s ability to reduce both mHTT and PMS1 offers a potent combination for treating Huntington’s disease via two of its core pathogenic mechanisms. These open-label trial results, due to be validated in the ongoing placebo-controlled FALCON-HD trial, give an expectation of meaningful impact for people living with HD across the world – for whom an orally administered huntingtin-lowering treatment such as SKY-0515 will be truly transformative.”

Sergey Paushkin, head of R&D at Skyhawk Therapeutics, added: “Our goal for our Phase 1 study was to establish safety and biomarker activity, and the continued strength of SKY-0515’s biomarker response in our nine month interim data analysis – and the improvement in the potential endpoint, cUHDRS, compared to a worsening of the cUHDRS score in the natural history data for patients – underscores SKY-0515’s potential as a best-in-class disease-modifying therapy for HD. These interim data represent an important milestone for SKY-0515 and highlight the power of Skyhawk’s platform to deliver first-in-class small molecules for devastating diseases with no approved disease-modifying therapies.”

Skyhawk also announced expansion of its Phase 2/3 FALCON-HD trial, which now spans more than 40 sites worldwide, with over 90 patients dosed. FALCON-HD is a randomized, double-blind, placebo-controlled study evaluating safety, pharmacodynamics and efficacy of SKY-0515 in patients with Stage 2 and early Stage 3 HD. Participants will receive once-daily oral doses of SKY-0515 or placebo for at least 12 months.

Huntington’s disease is a rare, hereditary, fatal neurodegenerative disorder affecting over 40,000 symptomatic patients in the United States and hundreds of thousands globally. No approved therapies currently slow or halt disease progression. SKY-0515 targets both HTT protein and PMS1, addressing two key pathogenic mechanisms implicated in HD progression.