Oral therapy may slow progression in early-stage Huntington’s disease

In final 15-month study data, people with early-stage Huntington’s disease treated with SKY-0515, Skyhawk Therapeutics’ investigational oral therapy, showed improvements in function, movement, and cognition.

That’s according to final results from Skyhawk’s Phase 1/2 clinical program, which included the registered Phase 1 trial (ACTRN12624000602527). The study included about two dozen Huntington’s patients, with assessments reported through month 15. Changes in disease severity measures suggested slower disease progression compared with untreated patients in natural history studies.

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These findings “are extremely encouraging clinical data,” Samuel Frank, MD, director of the Huntington’s Disease Society of America Center of Excellence at Beth Israel Deaconess Medical Center, said in a press release from Skyhawk. “The consistent effects on function, motor and cognitive measures need to be further studied in ongoing placebo-controlled studies but it is an exciting step forward for [Huntington’s disease] and the program.”

SKY-0515 is now being tested against a placebo in people with early-stage Huntington’s in a Phase 2/3 trial program called FALCON-HD. The program includes an Australian and New Zealand portion (NCT06873334), which has completed enrollment, and a worldwide portion (NCT07378644) that is recruiting at sites in Brazil, Argentina, Georgia, Colombia, Chile, and Canada. Sites in the U.S., Germany, and Spain have not yet begun recruiting.

“What makes SKY-0515 especially exciting is that it is a pill, taken once a day at home,” said Katie Jackson, CEO of Help 4 HD International. “Every step forward in [Huntington’s disease] matters and we celebrate all of them, but a therapy that is noninvasive and does not require care in a specialized center has the potential to reach so many more patients – in rural communities, in families who can’t travel, and across the world where care is hard to come by.”

Huntington’s is caused by mutations in the HTT gene, resulting in the production of an abnormal version of the huntingtin protein.

SKY-0515 targets mutant huntingtin and PMS1 through RNA splicing

SKY-0515 is an oral therapy designed to reduce production of both the mutant huntingtin protein and PMS1, a DNA-repair protein that has been implicated in Huntington’s development. The therapy works by modulating RNA splicing, a process that helps prepare genetic instructions for protein production.

In the patient study within Skyhawk’s Phase 1/2 clinical program, adults with early-stage Huntington’s were given either SKY-0515 at 3 or 9 mg, or a placebo, for about three months. Then, all participants received SKY-0515 at 4 or 9 mg for a year, with most receiving the 9-mg dose.

Disease severity was measured using a standardized tool called the Composite Unified Huntington’s Disease Rating Scale (cUHDRS). Typically, cUHDRS scores decrease (worsen) over time as Huntington’s progresses and symptoms get worse.

At month 15, 15 participants were included in the analysis. Trial results showed that, at every timepoint through 15 months, average cUHDRS scores in SKY-0515-treated patients remained at or above their levels before treatment.

To put that in perspective, results were compared with data from similar untreated Huntington’s patients in natural history studies that tracked the disease over time. In those studies, average cUHDRS scores started to decline from month six onward.

After 15 months, the average cUHDRS score in SKY-0515-treated patients increased by 0.94 points. In contrast, the average score in the natural-history control group fell by 0.65 points, for a difference of 1.59 points. The difference between the groups became statistically significant at month nine.

“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,” Frank said. “If these findings are confirmed in the ongoing Phase 2/3 FALCON-HD pivotal program, the impact on people living with [Huntington’s disease] across the world could be profound.”

Benefits seen across function, movement, and cognition

The cUHDRS contains four components: a measure of functional capacity, a measure of motor symptoms, and two tests of cognitive function. At 15 months, patients given SKY-0515 improved on all four measures, with statistically significant differences compared with natural-history controls.

“The completion of this Phase 1/2 study with SKY-0515, showing statistically significant clinical benefit across every cUHDRS component, is a powerful demonstration of what Skyhawk’s SKYSTAR platform can achieve: a daily pill, taken at home, that modifies RNA splicing to lower disease-causing proteins,” said Sergey Paushkin, MD, PhD, co-founder and head of research and development at Skyhawk.

In line with previous one-year trial data, SKY-0515 was generally well tolerated, with no treatment-related serious adverse events reported.

“For almost two decades, I have fought as an advocate for Huntington’s disease patients, bearing witness to countless heartbreaking trial setbacks that have let our families down,” Jackson said. “To finally see results like these—patients experiencing improvements in function, movement, and cognition — is what we have been hoping and waiting for.”