Imagine slashing the toxic protein that fuels Huntington's disease by more than half in just three months. That’s the headline coming out of Skyhawk Therapeutics after its Phase 1 trial of SKY-0515 showed a 62% drop in mutant huntingtin (mHTT) levels with a 9 mg daily dose.
Why SKY-0515 matters in Huntington's disease
Huntington's is driven by an expanded CAG repeat in the HTT gene, which creates an abnormally long huntingtin protein. That protein aggregates in neurons, leading to the movement, cognitive and psychiatric symptoms that define the disease. SKY-0515 takes a two‑pronged approach: it curtails the production of both the mutant and normal huntingtin proteins and also suppresses PMS1, a DNA‑repair enzyme linked to CAG repeat expansion.
The Phase 1 data painted a clear picture of dose‑dependent activity. Doses ranging from 1 mg up to 16 mg trimmed mHTT levels by as much as 72% in healthy volunteers, with the 9 mg cohort hitting the 62% mark after 84 days. Importantly, the drug crossed the blood‑brain barrier efficiently, meaning it reaches the very tissue that needs it most.
Safety was another strong point. Across all dose groups, participants reported only mild, transient side effects, and no serious adverse events surfaced. Dr. Sergey Paushkin, Skyhawk’s R&D chief, called the biomarker shifts “remarkable for a 3‑month window,” underscoring the therapy’s potential to change the disease trajectory.
What the next phase looks like
With those encouraging signals, Skyhawk has kicked off the Phase 2/3 FALCON‑HD trial. The study is recruiting adults 25 and older who are in stage 2 or early stage 3 of Huntington's disease, primarily across sites in Australia and New Zealand. Up to 120 participants will be randomized to receive either placebo or one of three SKY‑0515 dose levels for a full year.
The trial’s primary endpoints focus on three pillars:
- Blood biomarkers – tracking reductions in mutant huntingtin and PMS1 mRNA.
- Neuroimaging – measuring changes in brain volume via MRI to gauge neurodegeneration.
- Clinical outcomes – using the Unified Huntington's Disease Rating Scale (UHDRS) to assess motor function, cognition, behavior and daily living abilities.
Secondary measures will look at quality‑of‑life questionnaires and extra safety labs, ensuring a comprehensive view of how the drug performs over a longer period.
Professor Ed Wild of University College London highlighted that seeing a clear biomarker response at 84 days sets a high bar for what success can look like later on. If the Phase 2/3 data mirror the early reductions, SKY‑0515 could become the first oral agent that truly modifies the disease course rather than just managing symptoms.
For patients and families watching the horizon for disease‑altering therapies, the FALCON‑HD trial offers a tangible glimpse of hope. The next milestones – interim analysis at six months and the final read‑out at year‑end – will be closely watched by investors, clinicians and, most importantly, the Huntington’s community.
