Wave Life Sciences Ltd. announced positive results from its Phase 1b/2a SELECT-HD clinical trial of WVE-003, which is being developed as a potential disease modifying therapeutic for Huntington?s disease (HD). WVE-003 is a first-in-class, allele-selective antisense oligonucleotide (ASO) designed to lower mutant huntingtin (mHTT) protein and preserve healthy, wild-type huntingtin (wtHTT) protein. In the multidose portion of the SELECT-HD study (n=23), participants received either every-eight-week (Q8W) intrathecal doses of 30 mg WVE-003 (n=16) or placebo (n=7), with 12 weeks of follow up (total study period of 28 weeks).

Key results are as follows: WVE-003 was generally safe and well-tolerated, with no Serious Adverse Events (SAEs) reported; ventricular volume was in line with natural history. Significant mHTT protein lowering was observed throughout the 28-week assessment period. At 24 weeks (8 weeks after last dose), mean mHTT lowering in cerebrospinal fluid (CSF) was 46% versus placebo (p=0.0007).

At 28 weeks (12 weeks after last dose), mean mHTT lowering in CSF was 44% versus placebo (p=0.0002), which supports quarterly or less frequent dosing. wtHTT protein was preserved throughout the 28-week assessment period, validating allele-selective silencing. Additionally, statistically significant increases were observed in wtHTT protein versus placebo.

wtHTT protein supports the health and function of neurons and is crucial for CSF flow in the ventricles. mHTT also has a detrimental effect on wtHTT at the protein level, which further decreases wtHTT?s function. Only selective lowering of mHTT has potential to relieve its negative impact on wtHTT protein function.

Most WVE-003-treated participants had neurofilament light protein (NfL) levels that were in the range of placebo or had NfL levels that increased and returned to the range of placebo. At 24 weeks (the last MRI assessment), mHTT reduction was correlated with slowing of caudate atrophy (R=-0.50; p=0.047). Caudate atrophy is an imaging biomarker that is predictive of clinical outcomes, including clinically meaningful worsening of Total Motor Score (TMS).

While not powered for clinical outcomes, a slowing of decline was observed for TMS for WVE-003 versus placebo (4.25 mean difference at 24 weeks, p=not significant). HD is a debilitating and ultimately fatal autosomal dominant neurological disorder. The HD population is significant ?

in the United States alone, approximately 30,000 people have clinical symptoms of HD and more than 200,000 are at risk of inheriting HD. WVE-003 is expected to address approximately 40% of individuals with HD, and up to 80% of HD may be addressed in the future with other SNP-targeted candidates.