Skyhawk Therapeutics, a privately held biotech based in Waltham, Massachusetts, announced final 15-month results Monday from its Phase 1/2 trial of SKY-0515, an experimental once-daily pill for Huntington’s disease. Patients who took the drug held steady or slightly improved on a standard measure of disease severity through 15 months. A comparison group of untreated patients, drawn not from the same trial but from outside patient databases, got steadily worse over the same period.
That is a real signal in a disease with no approved treatments that slow its progression. But how Skyhawk built its comparison group matters just as much as the result itself, and it is worth understanding before reading too much into the numbers.
What the Trial Measured
The Phase 1/2 study enrolled patients with early-stage Huntington’s disease and gave them either a 4 mg or 9 mg dose of SKY-0515 once daily, after an initial randomized, placebo-controlled 12-week period. Nearly all patients ended up on the 9 mg dose. Researchers tracked a composite score called the cUHDRS, which blends four measures: a patient’s daily functioning, motor control, processing speed and reading speed. Lower scores mean the disease is getting worse.
At Month 15, treated patients’ composite scores had improved by an average of 0.94 points from where they started. The comparison group, built from patients in the Enroll-HD natural history registry, declined by an average of 0.65 points over the same window. The gap between the two groups was 1.59 points, which Skyhawk says is statistically significant (p<0.001). All four individual components of the cUHDRS also favored treated patients, and the gap widened at nearly every checkpoint from Month 9 onward.
Skyhawk also reported average reductions of more than 60% in mutant huntingtin protein, the toxic protein central to Huntington’s disease, and more than 25% in PMS1 messenger RNA, a driver of the genetic repeat expansion that worsens the disease over time, both at the 9 mg dose. Those are biomarker readings, not proof of clinical benefit by themselves, but the company points to them as a mechanistic explanation for why patients’ scores held up. Skyhawk reported no treatment-related serious adverse events through 15 months.
Why the Comparison Group Is the Real Story
Here is the part that got less attention in Skyhawk’s release: after the first 12 weeks, every patient who finished the Phase 1/2 study was on active drug. No placebo group ran alongside them through Month 15. Instead, Skyhawk compared its patients to untreated people from three outside sources, the Enroll-HD, 2CARE and CREST-E databases, using a statistical method called overlap-weighted ANCOVA to make the two groups look as similar as possible on paper.
That is a common workaround in a rare, slow-moving disease where recruiting a large concurrent placebo group for over a year is difficult. It is also close to the exact kind of evidence the FDA told a competitor, in writing, is not sufficient on its own. In March, the agency told uniQure (Nasdaq: QURE) that data from its own Phase 1/2 gene therapy trial in Huntington’s, compared against an external control group, did not provide enough evidence of effectiveness to support a marketing application, and recommended a randomized, sham-controlled study instead. uniQure’s stock fell more than a third in the days after that news, though it later recovered ground when the FDA agreed to consider a longer follow-up dataset. Skyhawk’s Phase 1/2 comparison in this release rests on the same basic approach the FDA pushed back on there, though Skyhawk’s ongoing Phase 2/3 program, unlike this analysis, is designed from the start as a randomized, placebo-controlled trial.
Skyhawk’s own comparison group also got smaller as the study went on, from 24 patients at Month 3 to 15 by Month 15, as participants missed visits or were excluded under the study’s own rules. Smaller groups make it easier for a handful of outlying scores to move the average.
Skyhawk Is Not Alone in Making This Bet
Skyhawk is not the only company leaning on natural-history comparisons in Huntington’s disease. PTC Therapeutics (Nasdaq: PTCT) reported similar data in April for votoplam, a drug it developed and then handed off to Novartis, showing a 52% slowing of disease progression at the highest dose against a natural-history cohort. Both companies describe their results the same way: encouraging, but not yet confirmed by a randomized comparison. Both are now running, or about to run, placebo-controlled Phase 3 trials meant to settle the question: Novartis’s global INVEST-HD study for votoplam, and Skyhawk’s own FALCON-HD program, which has finished enrolling 144 patients in Australia and New Zealand and is recruiting roughly 600 more worldwide.
Other approaches in the field have fared worse. Roche discontinued its tominersen program in July after a second trial, run at a lower dose specifically to fix problems seen in an earlier failed study, also missed its efficacy goals. None of these are head-to-head comparisons against SKY-0515, since each program enrolls different patients on different scales and timeframes, but together they show a field that keeps reaching for the same kind of early evidence and, in Roche’s case, still coming up short even after a second attempt.
What Is Left Unanswered
Skyhawk’s release does not say whether or when the company might approach the FDA using this Phase 1/2 dataset alone, and given the agency’s recent stance with uniQure, that path looks narrow. The release also does not mention whether SKY-0515 holds any FDA designations, such as Fast Track or Breakthrough Therapy status, that could speed a future review, or say what the company’s Phase 1/2 program cost to run. Skyhawk is privately held and has raised more than $300 million in venture and partnership funding, according to PitchBook, so there is no public stock for investors to trade directly. Anyone tracking this space for investable exposure will need to look at the publicly traded companies working on competing programs instead.
This article covers clinical trial data and is not medical or investment advice.
Sources
Skyhawk Therapeutics: Skyhawk Therapeutics Announces Final Fifteen-Month Results from Phase 1/2 Clinical Trial of SKY-0515 in Huntington’s Disease Patients, PRNewswire, September 15, 2026. Primary source release.
uniQure N.V.: Regulatory Update on AMT-130 for Huntington’s Disease (SEC Form 8-K), cited for the FDA’s stated position that Phase 1/2 data compared to an external control group were not sufficient to support a marketing application, context not addressed in the Skyhawk release.
PTC Therapeutics: Reports Positive Topline Results from Month 24 Interim Analysis of PIVOT-HD Extension Study of Votoplam, cited for comparable natural-history-controlled Huntington’s disease data from a competing program and its move into a randomized Phase 3 trial.
PitchBook: Skyhawk Therapeutics Company Profile, cited for Skyhawk’s private ownership status and total funding raised, neither disclosed in the company’s release.
Roche Discontinues Two Huntington’s Disease Programs After Tominersen Fails Phase II, cited for the July 2026 discontinuation of Roche’s tominersen program, used here for competitive-landscape context.
Editorial Disclosure
This article is based on a press release issued by Skyhawk Therapeutics, Inc. on September 15, 2026. BioTech Stocks Daily was not compensated for this coverage. Additional context on the comparability of natural-history-controlled Huntington’s disease data, the FDA’s recent position on external control groups, and the status of competing Huntington’s disease programs was drawn from public filings by uniQure N.V. (Nasdaq: QURE) and PTC Therapeutics, Inc. (Nasdaq: PTCT), and from independent reporting on Roche’s tominersen program, all cited above, since the original release did not address competing programs or regulatory precedent. Skyhawk Therapeutics is privately held; no ticker or public security is associated with the company. No staff member, principal, or affiliate of BioTech Stocks Daily holds a position, option, or financial interest in Skyhawk Therapeutics or in any of the publicly traded companies mentioned as of the date of publication. Statements regarding future regulatory submissions, the design and outcome of the ongoing FALCON-HD and INVEST-HD trials, and the eventual approval prospects of SKY-0515 or votoplam are forward-looking and involve substantial risks and uncertainties; actual results may differ materially. This article is for informational and educational purposes only, does not constitute investment advice, and is not medical advice. Consult a qualified healthcare professional for medical guidance. See our full DISCLAIMER.
