Patient Dosing Underway in Phase 2/3 FALCON-HD Trial of SKY-0515 for Huntington Disease

Bill Haney

(Credit: Global Genes)

Recently, Skyhawk Therapeutics announced that their first patient has been dosed in its phase 2/3 FALCON-HD trial (NCT06873334) evaluating investigational agent SKY-0515, an oral RNA splicing modulator, for the treatment of Huntington disease (HD).¹

FALCON-HD is a phase 2/3 randomized, double-blind, placebo-controlled study to evaluate the pharmacodynamics, safety, and efficacy of several doses of SKY-0515 in participants with Stage 2 and early Stage 3 HD. The trial includes 10 sites across Australia and New Zealand and the initial dosing recently took place at Flinders Medical Center in Adelaide, Australia.

The study is expected to enroll approximately 120 participants, randomizing participants to a once-daily oral dose of SKY-0515 at 1 of 3 dose levels or placebo for a treatment duration of at least 12 months. In FALCON-HD, investigators will also evaluate SKY-0515’s ability to modulate RNA splicing and reduce production of huntingtin (HTT) and PMS1 proteins, both of which are imperative in the pathology of HD.

In a phase 1 trial with healthy participants, SKY-0515 produced a dose-dependent reduction in HTT mRNA, with a mean decrease of 72% observed at the highest dose. Lower dosages, including the 3 mg and 1 mg cohorts, also produced reductions of 41% and 19%, respectively, in treated patients. Above all, the treatment was well tolerated across all tested dose levels.²

"Dosing the first patient in our FALCON-HD trial marks a significant milestone in our mission to develop a disease-modifying therapy for Huntington's patients," Bill Haney, founder and chief executive officer of Skyhawk Therapeutics, said in a statement.¹ "Building on our compelling Phase 1 data, we are eager to assess SKY-0515's potential to make a meaningful difference in the lives of patients affected by this devastating condition."

READ MORE: Antidopaminergic Medications Worsen Outcomes in Huntington Disease, Study Shows

HD is a fully penetrant, autosomal dominant neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the HTT gene on chromosome 4p16.3. Recognized in 1993, this gene encodes the huntingtin protein, which is believed to play a critical role in neuronal function and embryonic development, though its exact biological role is still unclear. Despite decades of research, therapeutic progress has been limited, and current treatments are symptomatic.

"Given the lack of approved disease-modifying treatments for Huntington's disease, we are hopeful that SKY-0515 could offer a new therapeutic option for patients," neurologist Karyn Boundy, MBBS, FRACP, principal investigator at Flinders Medical Centre, said in a statement.¹

According to Boundy, the initiation of the phase 2/3 FALCON-HD trial could be a leap in the right direction toward new disease-modifying therapies in HD. Experts noted that SKY-0515’s dual-target mechanism may bring meaningful advantages; targeting PMS1 in addition to HTT could slow expansion-driven neurotoxicity, something HTT-lowering alone may not do.¹

Skyhawk developed the compound using its proprietary platform, led by the same scientists behind risdiplam, the first approved small molecule splicing modifier approved for spinal muscular atrophy. The agent is designed to cross the blood-brain barrier and act in both the central nervous system and peripheral tissues, potentially offering better tissue distribution than any prior drugs.

“We’ve become one of the world’s experts in the chemistry of splicing modification, which is differentiated from traditional protein-targeting chemistry," Maura McCarthy, head of corporate development at Skyhawk, told NeurologyLive^® in a previous interview. “Not many pharmaceutical companies or chemical libraries have a large portion of chemistry useful for this type of targeting.”

This splicing-based mechanism differs from antisense oligonucleotide approaches and may allow broader accessibility and sustained benefit. Skyhawk noted that the company hopes it can support the development of lower-cost, large scale therapy for patients with HD around the world.

REFERENCES
1. 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 June 24, 2025. https://www.skyhawktx.com/post/skyhawk-therapeutics-announces-first-patient-dosed-in-phase-2-3-falcon-hd-trial-of-sky-0515-for-hunt
2. 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 Jun 24, 2025. https://finance.yahoo.com/news/skyhawk-therapeutics-announces-positive-topline-123000702.html