Allele-Specific Antisense Oligonucleotide Lowers Mutant Huntingtin Protein Selectively in Huntington Disease
In the phase 1b/2a adaptive dose-finding, placebo-controlled SELECT-HD trial (NCT05032196), participants with Huntington disease (HD) treated with stereopure antisense oligonucleotide (ASO) (WVE-003; Wave Life Sciences, Cambridge, MA) had reduced levels of mutant huntingtin (mHTT) protein in cerebrospinal fluid (CSF).
The mean reduction in CSF mHTT from baseline was 22% (median reduction 30%) at 85 days following a single dose with 30 or 60 mg groups. Wild-type HTT was preserved, which is consistent with allele-selectivity. No meaningful changes in clinical outcome measures were observed. In the 30 mg and 60 mg CSF mHTT levels cohorts pooled together, there were no apparent dose response and a 35% mean reduction between CSF mHTT vs placebo at 85 days.
“These preliminary data suggest WVE-003 is working as intended: to selectively reduce the toxic mHTT protein while avoiding targeting the healthy, wild-type huntingtin protein, thereby preserving its beneficial effects in the central nervous system,” said Ralf Reilmann, MD, founder of the George-Huntington Institute, Muenster, Germany and member of the SELECT-HD Clinical Advisory and Dose Escalation Committees. “Additionally, I am encouraged by the safety and tolerability data. Taken together, WVE-003 appears to have a unique profile with the potential to overcome prior therapeutic challenges in this field. Furthermore, as a clinician and researcher focused on HD, it is my hope that innovative adaptive trial designs like SELECT-HD become more commonplace to optimize dosing in early proof-of-concept studies. It is also exciting to finally see an assay measuring wtHTT being developed and used successfully in a clinical trial – a long awaited, big step forward for the HD research community. The availability of this assay has potential to significantly increase our understanding of how best to treat this challenging disease.”
Participants (n=18) were divided into groups who received different doses (30 mg, n=4; 60 mg, n=4; 90 mg, n=4; placebo, n=6) of the ASO. The participants who received 30 mg, 60 mg, or placebo had adequate follow-up to day 85 for biomarker analysis. Adverse events were similar with the ASO vs placebo, and mild to moderate in intensity with no serious adverse events.
The SELECT-HD clinical trial will be adapted to be expand the single dose cohorts and will also continue the 90 mg cohort for biomarker analysis at day 85.