First Huntington’s patient dosed in Phase 2/3 trial testing SKY-0515
Oral therapy aimed at slowing or halting disease progression
The first Huntington’s disease patient has been dosed in a Phase 2/3 clinical trial testing SKY-0515, Skyhawk Therapeutics‘ oral disease-modifying therapy, in adults with the neurodegenerative condition.
The study, dubbed FALCON-HD (NCT06873334), is expected to enroll up to 120 adults with Huntington’s, ages 25 and older, at 10 sites across Australia and New Zealand. Participants will randomly receive one of three daily doses of SKY-0515, or a placebo, for at least one year.
“Dosing the first patient in our FALCON-HD trial marks a significant milestone in our mission to develop a disease-modifying therapy for Huntington’s patients,” Bill Haney, founder and CEO of Skyhawk, said in a company press release.
“As Skyhawk kicks off their Phase 2/3 FALCON-HD trial in Australia and New Zealand, the international Huntington’s community looks forward to expansion worldwide,” said Ed Wild, PhD, a professor of neurology and the associate director of the Huntington’s Disease Center at University College London in the U.K.
SKY-0515 targets production of two key proteins
Huntington’s is caused by excessive repeats of a sequence of three DNA building blocks — CAG — in the HTT gene. Too many CAG repeats leads to the production of an abnormally long version of the huntingtin (HTT) protein, which is thought to form toxic clumps in nerve cells.
The repeats can progressively lengthen over time, a process called somatic CAG repeat expansion, with longer repeats associated with earlier onset and more severe disease. This may explain why most people with Huntington’s, who are born with HTT defects, don’t develop symptoms until well into adulthood.
Recent studies suggest a DNA-repair protein called PMS1 contributes to Huntington’s by promoting somatic CAG repeat expansion. Deleting the gene that encodes PMS1 from a Huntington’s mouse model prevented further CAG expansion and the formation of the mutant HTT clumps.
SKY-0515’s unique ability to reduce both HTT and PMS1 could meaningfully enhance therapeutic impact beyond that of lowering HTT alone.
Developed through Skyhawk’s proprietary platform, SKY-0515 is an oral small molecule designed to reduce the production of both HTT and PMS1. By lowering these two proteins, the experimental therapy is expected to prevent somatic CAG repeat expansion, reduce levels of mutant HTT and its toxic clumps, and slow or halt Huntington’s progression.
“SKY-0515’s unique ability to reduce both HTT and PMS1 could meaningfully enhance therapeutic impact beyond that of lowering HTT alone,” Wild said.
A previous Phase 1 trial (ACTRN12623001161617) was designed to evaluate the safety, tolerability, and pharmacological properties of single and multiple ascending doses of SKY-0515 against a placebo in healthy volunteers. Data showed the therapy reduced HTT by up to 72% in a dose-dependent manner, with favorable safety and tolerability, according to the company.
“Building on our compelling Phase 1 data, we are eager to assess SKY-0515’s potential to make a meaningful difference in the lives of patients affected by this devastating condition,” Haney said.
Study to assess therapy’s safety, efficacy, effects on body
A Phase 1 trial’s sub-study (ACTRN12624000602527), meant to test SKY-0515 against a placebo in up to 50 adults with Huntington’s, ages 25 to 70, began in January and completed enrollment in March, according to Skyhawk.
The ongoing Phase 2/3 FALCON-HD study is assessing SKY-0515’s safety, pharmacodynamics, which refers to the effects on the body, and efficacy in adults with stage 2 and early stage 3 Huntington’s, when people experience impairments to daily activities and further symptom worsening.
The study’s primary goals are to assess changes in blood levels of the mutant HTT protein and PMS1 protein, as well as in brain volume, as assessed by MRI. Changes in scores of the Unified Huntington’s Disease Rating Scale, a tool incorporating several standardized tests of movement, cognitive abilities, behavior, and functional independence, will also be evaluated.
“We are pleased to participate in this important clinical trial and to have dosed the first patient here at Flinders,” said Karyn Boundy, the trial’s principal investigator and a neurologist at Flinders Medical Centre in Australia. “Given the lack of approved disease-modifying treatments for Huntington’s disease, we are hopeful that SKY-0515 could offer a new therapeutic option for patients.”
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