Huntington’s treatment safely slows disease over 9 months in early trial
Developer expanding new study of SKY-0515 from Australia to countries worldwide
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Nine months of treatment with Skyhawk Therapeutics’ oral candidate SKY-0515 appears to have slowed disease progression relative to its natural course in people with early-stage Huntington’s disease.
That’s according to new interim data from a substudy, or Part C (ACTRN12624000602527), of an Australia-based Phase 1 clinical trial (ACTRN12623001161617) involving adults with the progressive disorder.
Further, these results showed that a higher dose of the therapy was associated with a 62% reduction in mutant huntingtin (mHTT) levels — the protein that drives Huntington’s — and that both tested doses were generally safe.
“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,” Sergey Paushkin, MD, PhD, head of research and development at Skyhawk, said in a company press release.
A Phase 2/3 clinical trial, called FALCON-HD (NCT06873334), is now testing SKY-0515 versus a placebo in approximately 120 people, ages 25 and older, with early-stage Huntington’s. Skyhawk announced that the study, still actively recruiting participants in Australia and New Zealand, is expanding to sites in other countries worldwide.
In Huntington’s disease, a sequence of three nucleotides — the building blocks of DNA — is excessively repeated in the HTT gene, leading to the production of a mutated version of the huntingtin (HTT) protein, which is thought to be toxic to nerve cells.
Recent studies have also suggested that the repeat expansion that causes Huntington’s becomes longer over time in certain disease-affected nerve cells, in part due to the action of a DNA repair protein called PMS1.
New data come from Phase 1 trial testing SKY-0515
An oral RNA-based therapy, SKY-0515 is designed to simultaneously reduce levels of the HTT and PMS1 proteins. In doing so, the experimental treatment, taken once daily, hopes to slow Huntington’s progression.
“SKY-0515’s ability to reduce both mHTT and PMS1 offers a potent combination for treating Huntington’s disease via two of its core pathogenic [disease-driving] mechanisms,” said Ed Wild, PhD, a professor of neurology at University College London.
The first two parts of the Phase 1 trial showed the therapy had an acceptable safety profile and reduced HTT protein levels in healthy volunteers.
The new findings come from the trial’s Part C, which is testing two doses of SKY-0515 (3 and 9 mg) in people with early-stage Huntington’s. Three-month data, announced last year, showed that the therapy was superior to a placebo at reducing mHTT and PMS1 levels.
SKY-0515 shows signs of effectiveness in adults at early stage
The new trial data, concerning an extension portion in which all participants receive one of the two SKY-0515 doses for a year, show continued reductions in these proteins out to nine months.
In patients given high-dose SKY-0515, average blood mHTT levels were reduced by 62%, while levels of messenger RNA (mRNA) for the gene encoding PMS1 were reduced by 26%. mRNA is an intermediary molecule derived from DNA that guides protein production; a reduction in mRNA usually equates to a decrease in protein levels.
Huntington’s severity is being tracked in participants with the Composite Unified Huntington’s Disease Rating Scale (cUHDRS), a standardized measure in which lower scores indicate more severe disease and disability.
According to Skyhawk, natural history data derived from matched, untreated Huntington’s patients in long-term, observational studies indicate that the Phase 1 trial participants would be expected to experience a decrease in cUHDRS scores of about 0.73 points after nine months. But SKY-0515-treated patients instead showed an average cUHDRS score increase of 0.64 points.
SKY-0515 continues to reduce mHTT protein [which drives Huntington’s] to the greatest extent demonstrated by any therapeutic tested to date in patients, with clinical and biomarker data showing the drug is well tolerated at all doses tested.
The company also said that SKY-0515 has been “generally safe and well tolerated” in the Phase 1 trial, but provided no further safety details.
“I am very encouraged by these safety and early efficacy data from SKY-0515’s Phase 1 Part C trial in patients, showing divergence in cUHDRS away from expected natural history deterioration at the three, six, and nine month prespecified analyses,” Wild said.
According to Wild, “SKY-0515 continues to reduce mHTT protein to the greatest extent demonstrated by any therapeutic tested to date in patients, with clinical and biomarker data showing the drug is well tolerated at all doses tested.”
Developer says its Huntington’s treatment may be best in class
A notable caveat of these data is that, although the first three months of the study involved a placebo group, in the subsequent extension portion, participants knew they were all taking SKY-0515 and it’s impossible to rule out a placebo effect when interpreting the results.
Paushkin said the developer’s objective for the Phase 1 study was “to establish safety and biomarker activity” for the therapy.
“The continued strength of SKY-0515’s biomarker response in our nine month interim data analysis — and the improvement in the potential [outcome measure], cUHDRS, compared to a worsening of the cUHDRS score in the natural history data for patients — underscores SKY-0515’s potential as a best in class disease-modifying therapy for [Huntington’s],” Paushkin said.
The ongoing Phase 2/3 FALCON-HD study is designed to evaluate the safety and effectiveness of SKY-0515 in people with Huntington’s. Participants are randomly assigned to receive either one of three SKY-0515 doses, or a placebo, once daily for a year. The main goal is to evaluate the therapy’s effect on blood mHTT levels, UHDRS scores, and MRI-based measures of brain volume. The trial is expected to end in 2027.
