Nine months of an investigative treatment appears to slow Huntington’s progression in early-stage patients, interim Phase 1 data from an Australian substudy suggests.
Huntington’s is a progressive disorder caused by a genetic change that produces a toxic form of huntingtin, a protein that harms nerve cells.
New interim results indicate the oral candidate SKY-0515 slowed disease course relative to natural history.
A higher dose was linked with a 62 per cent drop in mutant huntingtin, and both tested doses were generally safe.
Sergey Paushkin, head of research and development at Skyhawk Therapeutics, said: “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.”
A Phase 2/3 trial, FALCON-HD, is now testing SKY-0515 against placebo in about 120 people, aged 25 and older, with early-stage disease.
The study, recruiting in Australia and New Zealand, is expanding to sites worldwide.
In Huntington’s, a repeated DNA sequence in the HTT gene causes production of a mutated huntingtin protein thought to be toxic to neurons.
Research also suggests the repeat expansion can lengthen over time in some affected cells, partly via a DNA repair protein called PMS1.
SKY-0515 is an oral RNA-based therapy designed to reduce both HTT and PMS1. By lowering these targets, once-daily dosing aims to slow progression.
Ed Wild, professor of neurology at University College London, said: “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 mechanisms.”
Earlier parts of the Phase 1 study in healthy volunteers found an acceptable safety profile and reductions in HTT protein.
Part C is testing 3 mg and 9 mg in people with early-stage disease. Three-month data announced last year showed superiority to placebo in lowering mutant huntingtin and PMS1.
Extension data, in which all participants received SKY-0515 for a year, show reductions out to nine months.
With the high dose, average blood mutant huntingtin fell by 62 per cent, while PMS1 messenger RNA fell by 26 per cent.
Messenger RNA carries genetic instructions to make proteins, so a reduction usually means less protein is produced.
Clinical severity is being tracked using the composite Unified Huntington’s Disease Rating Scale, where lower scores reflect more severe disability.
Based on matched natural history cohorts, participants would be expected to decline by about 0.73 points in nine months. Instead, SKY-0515-treated patients improved by an average of 0.64 points.
Skyhawk said SKY-0515 has been generally safe and well tolerated in Phase 1, without further details.
Wild said: “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.
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.”
A key caveat is that, after the initial placebo-controlled period, the extension was open label. As all participants knew they were receiving SKY-0515, a placebo effect cannot be excluded.
Paushkin said the Phase 1 objective was “to establish safety and biomarker activity” for the therapy.
He added that the nine-month analysis, with continued biomarker reductions and improvement on cUHDRS versus natural history, supports further testing.
FALCON-HD will assess safety and effectiveness over a year, randomising participants to one of three doses or placebo.
Outcomes include blood mutant huntingtin, UHDRS scores and MRI measures of brain volume, with completion expected in 2027.
