Skyhawk's Oral SKY-0515 Shows First-of-Its-Kind Clinical Signals in Huntington's Disease: +1.59 cUHDRS vs External Control at 15 Months, >60% mHTT Knockdown
On September 15, 2026, Skyhawk Therapeutics announced final fifteen-month results from its Phase 1/2 trial of SKY-0515, an investigational once-daily oral RNA-splicing modifier designed to lower both mutant huntingtin (mHTT) and PMS1 — two core drivers of Huntington's disease pathology. There are currently no approved therapies shown to slow or halt HD progression.
The headline numbers (Month 15, vs overlap-weighted external control drawn from Enroll-HD/2CARE/CREST-E):
- cUHDRS: treated patients improved +0.94 from baseline while external controls declined −0.65 — a +1.59-point difference (95% CI 1.09–2.09; p<0.001)
- All four cUHDRS components favored treatment: daily function (TFC +0.98), movement (TMS −9.38, lower is better), processing speed (SDMT +4.15), reading speed (SWRT +4.18) — all statistically significant
- Consistent average reductions of >60% mHTT protein and >25% PMS1 mRNA at the 9 mg dose throughout the study
- Generally well tolerated with no treatment-related serious adverse events through 15 months
- The cUHDRS gap was statistically significant from Month 9 onward and widened through Month 15
Dr. Samuel Frank (Director, HDSA Center of Excellence, Beth Israel Deaconess): "A 1.59-point cUHDRS difference versus a rigorously weighted natural history control at fifteen months is exactly the type of signal the field looks for in early studies of a potentially effective therapeutic agent... If these findings are confirmed in the ongoing Phase 2/3 FALCON-HD pivotal program, the impact on people living with HD across the world could be profound."
Caveats: this is a small open-label-extension dataset (n=15 at Month 15) compared against a weighted external control rather than concurrent placebo — the design the HD field has repeatedly seen produce overoptimistic early signals. The pivotal test is the Phase 2/3 FALCON-HD program (NCT06873334 / NCT07378644): 004-ANZ fully enrolled with 144 participants in Australia/New Zealand, and 004-WW actively recruiting ~600 participants across 40+ sites worldwide.
The readout also sharpens the contrast with uniQure's AMT-130, the gene-therapy contender on an FDA accelerated-approval path for HD: SKY-0515's pitch is a noninvasive daily pill that could reach patients outside specialized centers — "a therapy that is noninvasive and does not require care in a specialized center has the potential to reach so many more patients," said Katie Jackson, CEO of Help 4 HD International. See uniQure Secures FDA Path for Accelerated Approval of AMT-130 in Huntington's Disease.