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Skyhawk’s SKY-0515 Shows Significant Lowering of Huntingtin mRNA in Phase 1 Study
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Recruitment has begun for Part C of the study, with topline data from this part of the trial expected to report in Q2 2025.
Ed Wild
Newly announced data from Parts A and B of a phase 1 clinical trial showed that treatment with investigational SKY-0515 (Skyhawk Therapeutics) resulted in significant reduction of mutant huntingtin (HTT) mRNA in healthy volunteers. Given these positive topline results, the company anticipates dosing in Part C of the study, which includes patients with Huntington disease (HD), in Q3 2024 and initiation of a phase 2 study early next year.1
After 14 days of treatment with SKY-0515, patients in the 9 mg daily group in Part B of the study, otherwise known as the multiple-ascending dose (MAD) cohort, demonstrated an average HTT mRNA reduction of 72%. Less pronounced effects were seen in the lower dosed groups, with reductions of 41% and 19% in the 3 mg and 1 mg groups, respectively. For context, those on placebo saw average HTT mRNA increases of 2% throughout the study.
Part A of the study, a double-blind, placebo-controlled, single-ascending dose phase, included 5 cohorts of healthy participants who were dosed with escalating single doses of SKY-0515 ranging from 1 mg to 16 mg or placebo. Part B, a MAD study, included 3 cohorts of participants who were randomly assigned multiple ascending doses of SKY-0515 ranging from 1 mg to 9 mg or placebo administered daily from days 1 to 14 (inclusive). Dose levels of the agent, identified in Parts A and B, will be evaluated in Part C of the study, which will include patients with early-stage HD.
SKY-0515, a small molecule RNA splicing modifier developed through Skyhawk’s novel RNA-splicing platform, resulted in a maximum 67% reduction in HTT mRNA level in blood within 24 hours after a single dose of 16 mg. Maximum reduction in HTT mRNA level in blood reached 33% in the 8 mg SAD group and 15% in the 2 mg SAD cohort. For reference, the placebo group showed a 2% increase in HTT mRNA.
"Huntingtin-lowering and somatic expansion have been two of the hottest targets in HD research in the past decade. Reducing both HTT and PMS1 could have greater therapeutic benefit than lowering HTT alone,” Ed Wild, professor of neurology at the University College London, said in a statement.1 "Huntington’s disease is a rare hereditary neurodegenerative disease affecting over 40,000 patients in the United States. There are no approved treatments that can reverse or slow its course of progression. SKY-0515’s HTT reduction has the highest dynamic range I’ve seen from any therapeutic modality and gives me great hope for SKY-0515’s potential to one day help those patients in need."
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SKY-0515 is designed to reduce both HTT protein and PMS1 protein, an additional key driver of somatic CAG repeat expansion and HD pathology. In Part C of the study, investigators will test efficacy and safety of 2 dose levels of the agent in comparison with placebo, preceded by an observational period lasting a minimum of 28 days. In that period, pharmacokinetic parameters such as mutant HTT protein and mRNA levels will be observed. Recruitment for Part C has already begun, with topline data expected in Q2 of 2025.
HD, an autosomal dominant, neurodegenerative disorder with complete penetrance caused by CAG trinucleotide repeat expansion in the HTT gene, has seen little drug success in recent years. The HTT gene, located on chromosome 4p16.3, was first identified in 1993. It encodes for the HTT protein. Though the precise function of the protein remains unknown, it apparently plays an important role in neurons and is essential for normal embryogenesis.
"We believe that, with these impressive HTT mRNA lowering results and the drug’s predicted suppression of the PMS1 protein, SKY-0515, if approved, could make a meaningful difference in patients with Huntington disease lives’,” Douglas V. Faller, MD, PhD, chief medical officer at Skyhawk, said in a statement. “The Safety Review Committee has determined that SKY-0515 has been generally well tolerated at all tested doses with a dose proportional increase in systemic exposure and, given these favorable safety results, approved this study to move into the patient arm. Recruitment has begun, and topline data from this part of the trial are expected to report in Q2 2025."
