Skyhawk Therapeutics reports positive 12‑month interim results for SKY‑0515, an oral RNA splicing modifier for Huntington’s disease, showing functional, motor, cognitive, and biomarker improvements ahead of pivotal Phase 2/3 trials.
Wriitten By: Fariha Sameen, PharmD
Reviewed By: Pharmacally Editorial Team
Skyhawk Therapeutics has reported positive 12-month interim results from its ongoing Phase 1/2 trial of SKY-0515, an investigational oral RNA splicing modifier for early-stage Huntington’s disease (HD). The data, presented at the European Academy of Neurology, showed favorable trends across functional, motor, and cognitive assessments, while continued biomarker reductions strengthened evidence of the drug’s potential disease-modifying activity.
The findings come as the company advances SKY-0515 into its global Phase 2/3 FALCON-HD program (NCT06873334 and NCT07378644).
SKY-0515 Targets Two Key Drivers of Huntington’s Disease
Huntington’s disease is a rare, inherited neurodegenerative disorder affecting more than 40,000 symptomatic individuals in the United States and many more worldwide. The disease progressively impairs movement, cognition, and daily functioning, and no approved therapy has demonstrated an ability to slow disease progression.
SKY-0515 is an orally administered small-molecule RNA splicing modifier developed using Skyhawk’s proprietary SKYSTAR® platform. Unlike therapies that target mutant huntingtin (mHTT) alone, SKY-0515 simultaneously reduces mHTT, the toxic protein responsible for Huntington’s disease pathology, and PMS1, a DNA repair protein that contributes to somatic CAG repeat expansion linked to disease progression.
Phase 1/2 Trial Demonstrated Sustained Clinical Benefit at 12 Months
The first-in-human Phase 1/2 study evaluated the safety, pharmacokinetics, pharmacodynamics, biomarkers, and preliminary efficacy of SKY-0515 in healthy volunteers and participants with early-stage Huntington’s disease. Part C enrolled patients with HD-ISS Stage 1, Stage 2, or mild Stage 3 disease in a randomized, double-blind, placebo-controlled study, followed by a 12-month blinded extension in which all participants received active treatment.
At 12 months, participants receiving SKY-0515 demonstrated favorable outcomes across every component of the composite Unified Huntington’s Disease Rating Scale (cUHDRS):
- Total Functional Capacity (TFC): Mean change from baseline of +0.07, compared with an expected decline of -0.87 points based on propensity score-weighted Enroll-HD natural history data.
- Total Motor Score (TMS): Mean improvement of -2.00 points versus an expected worsening of +2.21 points.
- Symbol Digit Modalities Test (SDMT): Mean change of -0.19, compared with an expected decline of -1.78.
- Stroop Word Reading Test (SWRT): Mean improvement of +3.44, versus an expected decline of -3.13.
The company also reported encouraging patient- and clinician-reported outcomes. Over the 12-month treatment period, no clinicians or participants reported disease worsening. Instead, 65% of participants and 50% of clinicians rated overall disease status as improved using the Patient Global Impression (PGI) and Clinician Global Impression (CGI) assessments.
Biomarker analyses further supported the clinical findings. SKY-0515 produced dose-dependent reductions of mutant huntingtin protein of up to 69% in blood and PMS1 mRNA reductions of up to 26%, demonstrating engagement of both intended molecular targets.
Across dose levels studied, SKY-0515 remained generally safe and well tolerated while showing excellent central nervous system exposure. More than 175 participants have now been enrolled across the clinical development program spanning five countries.
Dual Biomarker Effects Support Disease-Modifying Potential
Commenting on the findings, Sergey Paushkin, Head of Research and Development at Skyhawk Therapeutics, said the consistent improvements across functional, motor, cognitive, biomarker, and global impression measures strengthen confidence that simultaneous suppression of mHTT and PMS1 could provide meaningful long-term benefit for people living with Huntington’s disease.
Global Phase 2/3 FALCON-HD Program Continues
Enrollment has been completed in the Australian and New Zealand arm of the pivotal FALCON-HD 004-ANZ study, which recruited 144 patients with Stage 2 and early Stage 3 Huntington’s disease. The companion global study, FALCON-HD 004-WW, plans to enroll up to 400 additional participants across more than 40 international sites and is actively recruiting and treating patients.
The pivotal studies are expected to determine whether the promising biomarker and clinical signals observed in the Phase 1/2 trial translate into confirmed disease-modifying efficacy in a larger Huntington’s disease population.
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About the Writer
Fariha Sameen, PharmD (LinkedIn), is a clinical pharmacy professional with hands-on experience in patient counselling, medication review, therapeutic monitoring, and clinical documentation across multiple departments. She has experience identifying and assessing drug-related problems and supporting medication safety practices. Her interests include pharmacovigilance, ADR reporting, clinical research, and medical writing focused on clear, evidence-based communication.