J005 An update on select-hd, which is evaluating an allele-selective mutant huntingtin lowering approach in Huntington’s disease

SELECT-HD is a phase 1b/2a clinical trial evaluating the investigational antisense oligonucleotide WVE-003 in early manifest Huntington’s disease. WVE-003 is designed to target a single nucleotide polymorphism (SNP3) that is associated with the mutant huntingtin allele (mHTT), enabling allele-selective lowering of mHTT and relative sparing of wild-type HTT (wtHTT). In September 2022, data from the first 18 participants who were administered a single dose of WVE-003 (30 mg, n=4; 60 mg, n=4; 90 mg, n=4; placebo, n=6) were reported. Through September 20, WVE-003 (30, 60, 90 mg) appeared generally safe and well-tolerated, with no serious adverse events or discontinuations. Adverse events were balanced across active and placebo groups, and mild-to-moderate in intensity. For biomarker analyses, the 30 and 60 mg cohorts were pooled, as only these cohorts had reached day 85, and there was no apparent dose response. The mean reduction in CSF mHTT compared with placebo was 35% (22% compared with baseline). Measured CSF wtHTT protein appeared consistent with allele-selectivity. Increases in neurofilament light chain from baseline were observed in some participants, and there were no clinically meaningful elevations in CSF white blood cell counts or protein that would indicate inflammation in the CNS. These data provided early indications of target engagement and a favorable safety profile for WVE-003 and enabled SELECT-HD to be adapted to expand the single-dose cohorts and to initiate a multidose cohort (30 mg dosed every eight weeks, n=24). This presentation will provide updated biomarker and safety data for all ongoing cohorts.