SKY-0515 Demonstrates Dose-Dependent Reductions in Mutant Huntingtin Protein in Phase 1 Update

An update from Part C of Skyhawk Therapeutics’ phase 1 trial revealed that treatment with investigational SKY-0515 led to dose-dependent reductions of mutant huntingtin (mHTT) protein in patients with Huntington disease (HD), further supporting the agent’s development as a potential treatment for HD. Additional topline data from the blinded active treatment extension are expected in mid-2026.¹

The phase 1 first-in-human trial is broken up into 3 parts: Parts A and B evaluated SKY-0515 in healthy volunteers, while Part C is a double-blind, placebo-controlled parallel design study testing 2 doses of SKY-0515 vs placebo in individuals with early-stage HD. After 84 days of treatment, those on 9 mg of SKY-0515, the higher dose, demonstrated a 62% lowering of mHTT protein compared with baseline. Less pronounced effects were observed in the 3 mg group, with mHTT reductions of 29% over that time period.

HD is caused by a CAG trinucleotide repeat expansion in the HTT gene, leading to the production of mHTT with a toxic polyglutamine tract. Unlike symptomatic drugs, reducing mHTT aims to slow or halt progression by targeting the root cause. Research has shown that the accumulation of mHTT is thought to be the primary driver of neuronal dysfunction and death, especially in the striatum and cortex.

"SKY-0515 is reducing mHTT protein to the most impressive extent we've seen so far in patients, and crucially the clinical and biomarker data show no safety concerns so far at any dose tested,” Ed Wild, professor of neurology at University College London, said in a statement.¹ “It is great that we are seeing substantial PMS1 reduction as well, which should be a potent combination for treating Huntington's disease via two of its core pathogenic mechanisms."

Wild added, "This is what success looks like at the 3-month timepoint, setting the stage for meaningful impact for people living with HD across the world – for whom an orally administered huntingtin-lowering treatment such as SKY-0515 would be truly transformative.

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SKY-0515, developed through Skyhawk’s proprietary integrated platform, SKYSTAR, is designed to reduce both HTT protein and PMS1 protein, an additional key driver of somatic CAG repeat expansion and HD pathology. In HD, the somatic instability of CAG repeats worsens in affected tissues, especially striatum, leading to more toxic mHTT. PMS1 itself is not yet a direct drug target, but it represents part of the DNA repair landscape that could be modulated.

"The strength of SKY-0515's biomarker response after just 84 days of treatment underscores its potential as a transformative therapy for HD,” Sergey Paushkin, head of research & development at Skyhawk, said in a statement.¹ "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."

SKY-0515 is currently being assessed in a phase 2/3, double-blind, placebo-controlled trial dubbed FALCON-HD (NCT06873334). The study, which evaluates pharmacodynamics, safety, and efficacy of several doses of the agent in patients with Stage 2 and early Stage 3 HD, had dosing underway earlier this summer. Expected to include 120 participants with HD, the trial will test SKY-0515’s ability to modulate RNA splicing and reduce production of HTT and PMS1 proteins. FALCON-HD, spanning 10 sites across Australia and New Zealand, tests 3 different dose levels of the investigational agent over a 12-month period.²

Skyhawk previously released positive data from the healthy volunteer portion of its phase 1 trial, where SKY-0515 demonstrated a dose-dependent reduction in HTT mRNA. Overall, a mean decrease of 72% was found in the highest dose, with lower reductions of 41% and 19% in the 3 mg and 1 mg cohorts, respectively. In addition to showing preliminary efficacy, the treatment was well tolerated across all dose levels tested.³

REFERENCES
1. Skyhawk Therapeutics Announces Positive First Interim Results in Patients from its Phase 1 Clinical Trial of SKY-0515 as a Treatment for Huntington's Disease. News release. September 17, 2025. Accessed September 17, 2025. https://www.prnewswire.com/news-releases/skyhawk-therapeutics-announces-positive-first-interim-results-in-patients-from-its-phase-1-clinical-trial-of-sky-0515-as-a-treatment-for-huntingtons-disease-302559083.html
2. Skyhawk Therapeutics Announces First Patient Dosed in Phase 2/3 FALCON-HD Trial of SKY-0515 for Huntington’s Disease. News Release. Skyhawk Therapeutics. Published June 17, 2025. Accessed September 17, 2025. https://www.skyhawktx.com/post/skyhawk-therapeutics-announces-first-patient-dosed-in-phase-2-3-falcon-hd-trial-of-sky-0515-for-hunt
3. Skyhawk Therapeutics announces positive topline results from Parts A and B of its phase 1 clinical trial of SKY-0515 as a treatment for Huntington disease, reaching 72% Huntingtin mRNA reduction. News Release. Skyhawk Therapeutics. July 10, 2024. Accessed September 17, 2025. https://finance.yahoo.com/news/skyhawk-therapeutics-announces-positive-topline-123000702.html