Wave Life Sciences Ltd. announced the initiation of dosing in the company’s Phase 1b/2a SELECT-HD clinical trial evaluating investigational WVE-003 as a treatment for Huntington’s disease (HD). WVE-003 is a stereo pure antisense oligonucleotide designed to target SNP3, a single nucleotide polymorphism on the mutant huntingtin (mHTT) allele, thereby selectively lowering mHTT protein and sparing healthy, wild-type huntingtin (wtHTT) protein. Wave’s approach to HD and the WVE-003 program is guided by the recognition that, in addition to a gain of function of the mHTT protein, people with this disease have lost one copy of the wtHTT allele, leaving them with a smaller protective reservoir of healthy protein than unaffected individuals. A growing body of scientific evidence suggests that preserving as much of this essential wtHTT protein as possible, when in the setting of stress from the toxic mHTT protein, may be important for favorable clinical outcomes. WVE-003 incorporates the company’s novel PN backbone chemistry modifications (PN chemistry), which have been shown in preclinical studies to enhance potency, exposure, and durability. In preclinical studies, WVE-003 demonstrated dose-dependent and selective reduction of mHTT mRNA in vitro and potent and durable knockdown of mHTT mRNA in vivo, in both the cortex and striatum. Data from several preclinical models evaluating pharmacokinetic to pharmacodynamic relationships for WVE-003 have informed the starting dose for the SELECT-HD trial. The SELECT-HD trial is a global, multicenter, randomized, double-blind, placebo-controlled Phase 1b/2a clinical trial to assess the safety and tolerability of single- and multiple-ascending intrathecal doses of WVE-003 in people with a confirmed diagnosis of HD who are in the early stages of the disease and carry SNP3 in association with their cytosine-adenine-guanine (CAG) expansion. It is estimated that approximately 40 % of adults with HD carry SNP3 in association with the HD mutation. Additional objectives include assessing the plasma pharmacokinetic profile and exposure in the cerebrospinal fluid, as well as exploratory pharmacodynamic (mHTT, wtHTT and neurofilament light chain) and clinical endpoints. The SELECT-HD trial is expected to enroll approximately 36 patients. It is designed to be adaptive, with dose escalation and dosing frequency being guided by an independent committee.