SKY-0515 data suggest slower progression in Huntington’s disease
One-year interim data show improved cUHDRS scores versus expected decline
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Interim clinical trial data suggest people with early-stage Huntington’s disease who were treated with the investigational oral therapy SKY-0515 for up to one year had slower disease progression than would be expected based on natural history data.
That’s according to new interim data from Part C of a Phase 1/2 clinical trial (ACTRN12623001161617) that is testing two doses of SKY-0515 in adults with early-stage Huntington’s.
“The increasing separation of the clinical trajectories of treated participants from natural history expectations at the twelve-month timepoint suggests exciting and sustained benefits for Huntington’s patients,” said Bill Haney, co-founder and CEO of Skyhawk Therapeutics, the therapy’s developer, in a company press release.
Phase 2/3 trial program is underway
Skyhawk is now running a Phase 2/3 trial program called FALCON-HD that is testing SKY-0515 against a placebo in adults with early-stage Huntington’s. Its Australian and New Zealand (ANZ) portion (NCT06873334) has completed enrollment ahead of schedule, with a total of 144 participants. Its worldwide portion (NCT07378644) is still recruiting up to 400 participants and is currently active across eight countries, including Georgia and Argentina.
“With enrollment in the FALCON-HD ANZ pivotal study completed ahead of schedule, we are rapidly advancing toward the next stage of development for SKY-0515 and remain committed to doing all we can to deliver a potentially transformative oral therapy to the Huntington’s disease community at the earliest possible time,” Haney said.
Huntington’s is a progressive neurodegenerative disease caused by mutations in the HTT gene, which result in the production of a mutant form of the huntingtin (HTT) protein that is thought to drive the disease.
SKY-0515 is designed to target RNA — an intermediary molecule produced when genes are read to make protein — and reduce levels of both normal and mutant forms of HTT, as well as PMS1, a DNA-repair protein that has been implicated in the development and progression of Huntington’s.
Data from Parts A and B of the Phase 1/2 trial, which tested the therapy in healthy volunteers, showed an acceptable safety profile and a reduction in HTT mRNA levels. Part C is testing SKY-0515 in early-stage Huntington’s patients.
Clinical scores improved after one year
The progression of Huntington’s is commonly measured with a standardized tool called the Composite Unified Huntington’s Disease Rating Scale (cUHDRS), which includes measures of motor function, cognitive tests, and assessments of overall functional ability in day-to-day life.
Interim Phase 1/2 trial data show that average scores on this measure increased (improved) by 0.31 points after three months on SKY-0515 and then remained elevated: after one year of treatment, average cUHDRS scores had improved by 0.38 points relative to the study’s start. Skyhawk noted that favorable trends were seen in all parts of the cUHDRS.
To put these results in context, the company said that data from similar patients in natural history studies (studies tracking disease progression in the absence of treatment) suggest that average cUHDRS scores would be expected to decrease (worsen) by 0.92 points over one year of follow-up.
Consistent with earlier findings, the newly announced results showed that after a year on SKY-0515, blood mHTT protein levels were decreased by up to 69%, while levels of PMS1 mRNA were reduced by up to 26%.
“The magnitude and durability of lowering of critical biomarkers mHTT and PMS1, as well as encouraging twelve-month clinical findings across all four of the critical cUHDRS subcomponents, reinforce our confidence in SKY-0515’s differentiated mechanism and potential for dramatic therapeutic impact for patients,” Haney said.
Treatment was generally well tolerated
Skyhawk also said the experimental therapy has been generally safe and well tolerated across the dose levels studied thus far.
“I am very encouraged by these continued safety and efficacy data from SKY-0515’s Phase 1/2 trial in patients, including sustained improvement in patients’ cUHDRS when compared with expected … natural history deterioration at each of three, six, nine and twelve-month prespecified analyses,” said Ed Wild, PhD, a professor of neurology at University College London. “SKY-0515 continues to reduce mHTT protein to the greatest extent demonstrated in patients, with clinical and biomarker data showing the drug is well tolerated at all doses tested.”
Wild added that these early data “give an expectation of meaningful therapeutic impact for people living with [Huntington’s] across the world – for whom an orally administered huntingtin-lowering treatment such as SKY-0515 will be truly transformative.”
In FALCON-HD, participants are randomly assigned to receive one of three doses of SKY-0515 or a placebo for up to 1.5 years. The main goals include assessing SKY-0515’s effects on cUHDRS scores, mHTT levels, and brain volume. The ANZ portion is expected to end next year, while the worldwide portion is anticipated to be completed in 2029.
