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Wave Life Sciences announced a positive update to the ongoing Phase 1b/2a SELECT-HD clinical trial of WVE-003, the company's clinical candidate for Huntington's disease. SELECT-HD is an adaptive trial designed to rapidly optimize dose level and frequency based on early indicators of target engagement. The trial update announced is being driven by the observation of reductions in mutant huntingtin protein in cerebrospinal fluid after study participants received either a single 30 or 60 mg dose of WVE-003. Additionally, wild-type huntingtin protein was preserved, which appears consistent with allele-selectivity. Eighteen participants have been dosed in the SELECT-HD trial. Participants enrolled at 30 mg, 60 mg and placebo had adequate follow-up to day 85 for biomarker analysis. At the time of analysis, none of the participants dosed with 90 mg had reached day 85 so this cohort is not included in the biomarker analysis. Key observations include:Single doses of WVE-003 up to 90 mg appeared generally safe and well-tolerated; Adverse events were balanced across treatment groups, including placebo, and all were mild to moderate in intensity; No serious adverse events were observed; No participants discontinued from the study; Among participants in the 30 and 60 mg WVE-003 cohorts, the mean reduction in CSF mHTT from baseline was 22% at 85 days following a single dose ; The difference in the mean reduction in CSF mHTT compared to placebo was 35% at 85 days post-single dose; For these analyses, the 30 and 60 mg single dose cohorts were pooled as there was no apparent dose response between these two cohorts; In the 30 and 60 mg cohorts, wtHTT protein was preserved, which appears consistent with allele-selectivity; Increases in neurofilament light chain from baseline were observed in some participants; There were no clinically meaningful elevations in CSF white blood cell counts or protein that would indicate inflammation in the CNS; There were no meaningful changes in clinical outcome measures, although the dataset and duration were not sufficient to assess clinical effects. "These SELECT-HD data are the first to support the feasibility of allele-selective mHTT knockdown in the clinic - a precision approach enabled by our PRISM discovery and drug development platform," said Paul Bolno, MD, MBA, President and Chief Executive Officer at Wave Life Sciences. "SELECT-HD is the second clinical trial this year to demonstrate clinical translation of Wave's PN backbone chemistry modifications, as well as the impact of rational design through control of stereochemistry, increasing our conviction in our platform. We look forward to sharing data from our splicing clinical program in muscle - WVE-N531 for exon 53 skipping in Duchenne muscular dystrophy - in the fourth quarter of 2022."