SKY-0515 reduces disease-related proteins in early Huntington’s trial
Results underscore its potential as a transformative therapy, developer says
Three months of daily treatment with Skyhawk Therapeutics’ oral candidate SKY-0515 safely and effectively reduced blood levels of Huntington’s disease-associated proteins in people with the neurodegenerative condition.
That’s according to interim results from a substudy of a Phase 1 clinical trial that specifically showed a greater reduction with SKY-0515 relative to a placebo in mutant huntingtin, the faulty protein that drives Huntington’s, and PMS1, a protein that promotes the genetic mutation that causes Huntington’s.
“The strength of SKY-0515’s biomarker response after just 84 days of treatment underscores its potential as a transformative therapy for HD [Huntington’s disease],” Sergey Paushkin, MD, PhD, head of research and development at Skyhawk, said in a company press release.
Ed Wild, PhD, a professor of neurology at University College London, added: “This is what success looks like at the 3-month timepoint, setting the stage for meaningful impact for people living with HD across the world — for whom an orally administered huntingtin-lowering treatment such as SKY-0515 would be truly transformative.”
KY-0515 designed to reduce levels of both healthy and mutant HTT and PMS1
Huntington’s is caused by excessive repeats of a specific sequence of nucleotides — the building blocks of DNA — in the HTT gene, which provides instructions to produce a protein called huntingtin (HTT). This leads to the production of an mHTT protein, which is thought to be toxic to nerve cells and drive disease. Recent studies have also suggested that a DNA repair protein called PMS1 promotes the repeat expansion mutation that causes Huntington’s.
SKY-0515 is an oral therapy designed to reduce levels of both healthy and mutant HTT and PMS1, which is expected to reduce nerve cell damage and ultimately slow Huntington’s progression.
A first-in-human Phase 1 clinical trial (ACTRN12623001161617) tested SKY-0515 in healthy volunteers, with findings indicating an acceptable safety profile and reductions in huntingtin levels by up to 72%.
The new results come from a substudy of that trial (ACTRN12624000602527) that is testing the therapy against a placebo in people with early-stage Huntington’s.
Participants are randomly assigned to receive either one of two doses of SKY-0515 (3 mg or 9 mg) or a placebo daily for 84 days, or about three months. The main goals are to assess the therapy’s safety and its pharmacological effects, including its impact on mHTT and PMS1 protein levels in the blood.
Oral therapy found to effectively reach central nervous system
According to Skyhawk, results from 26 participants showed that the higher dose of SKY-0515 led to a 62% reduction in blood mHTT levels. The lower dose also reduced blood mHTT levels by about 29%, while the placebo was not associated with a pronounced change in blood mHTT levels.
SKY-0515 was also associated with a dose-dependent reduction in blood PMS1 levels, and was found to effectively reach the central nervous system, or the brain and spinal cord. Safety data showed that both doses of the therapy were well-tolerated, according to Skyhawk. The company didn’t give further specifics.
“SKY-0515 is reducing mHTT protein to the most impressive extent we’ve seen so far in patients, and crucially, the clinical and biomarker data show no safety concerns so far at any dose tested,” Wild said. “It is great that we are seeing substantial PMS1 reduction as well, which should be a potent combination for treating Huntington’s disease via two of its core [disease-driving] mechanisms.”
Participants who complete the three-month treatment period will have the option to enter an extension portion, where all will be randomly assigned to receive a low or high dose of SKY-0515 for a year. Top-line results from th e extension are expected by mid-2026.
“These interim data represent an important milestone for SKY-0515 and highlight the power of Skyhawk’s platform to deliver first-in-class small molecules for devastating diseases with no approved disease-modifying therapies,” Paushkin said.
The therapy is also being tested in a Phase 2/3 trial called FALCON-HD (NCT06873334). The study, which may still be enrolling at sites in Australia and New Zealand, is expected to include about 120 adults, 25 years and older, with stage 2 and early stage 3 Huntington’s marked by impairments to daily activities and further symptom worsening.
Participants will be randomly assigned to receive SKY-0515 at one of three doses, or a placebo, for a year. FALCON-HD’s goals are to assess changes in blood levels of mHTT and PMS1 proteins, brain volume as measured by MRI scans, and disease severity, as assessed with the Unified Huntington’s Disease Rating Scale.
The trial started dosing a few months ago and is expected to end in 2027.
About the Author
