Wave Life Sciences announced data from the Phase 1b/2a PRECISION-HD2 and PRECISION-HD1 trials evaluating WVE-120102 and WVE-120101, respectively, in Huntington’s disease (HD). Neither trial met the endpoints required to move forward with development, and hence the WVE-120102 and WVE-120101 programs for Huntington’s disease will be discontinued.
The multicenter, randomized, double-blind, placebo-controlled PRECISION-HD2 and PRECISION-HD1 trials evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of WVE-120101 and WVE-120102 in adults with early manifest HD who carried a targeted single nucleotide polymorphism (SNP) rs362307 (SNP1) and rs362331 (SNP2), respectively. The trials included both single and multi-dose portions where participants were randomized to either active drug or placebo, with five cohorts in the multi-dose portion, ranging from 2-32 mg dosed intrathecally every four weeks.
In the PRECISION-HD2 core trial, results from all participants (n=88) showed no statistically significant change in mutant huntingtin protein (mHTT) versus placebo after single or multiple doses of WVE-120102 up to and including 32 mg monthly. There was no evidence of a dose response across the dose levels tested.
Results in all participants through 16 mg (n=51) from the PRECISION-HD1 core trial are similar to those in PRECISION-HD2 at those dose levels. Dosing in the 32 mg cohort of the PRECISION-HD1 core trial is complete, and core and OLE trial participants will have a final follow-up visit but receive no further doses. Wave expects to complete analysis of the 32 mg cohort in the second quarter of 2021.
A third Huntington’s disease candidate is also under development. Site activation and enrollment in a phase 1b/2a clinical trial of WVE-003 for adults with HD that carry SNP3 are currently underway, and Wave expects to begin dosing in 2021.
About WVE-120102 and WVE-120101
WVE-120101 is an antisense oligonucleotide. It works by interfering with the mutant mRNA copy of the HTT gene. It does this by binding to the mutant mRNA, preventing the cell’s protein-making machinery from reading it. This prevents abnormal Huntingtin protein from being produced. WVE-120102 is designed to prevent the production of faulty Huntingtin protein by stopping its corresponding mRNA from being read. It specifically targets the mRNA produced from the mutant HTT gene, but not the mRNA produced from the normal HTT gene.
About Huntington’s Disease
Huntington’s disease (HD) is a debilitating and ultimately fatal autosomal dominant neurological disorder, characterized by cognitive decline, psychiatric illness, and chorea. HD causes nerve cells in the brain to deteriorate over time, affecting thinking ability, emotions, and movement. HD is caused by an expanded cytosine-adenine-guanine (CAG) triplet repeat in the huntingtin (HTT) gene that results in production of mutant HTT protein (mHTT). Accumulation of mHTT causes progressive loss of neurons in the brain. Wild-type, or healthy, HTT protein (wtHTT) is critical for neuronal function and suppression may have detrimental long-term consequences. Approximately 30,000 people in the United States have symptomatic HD and more than 200,000 others are at risk for inheriting the disease. There are currently no approved disease-modifying therapies available. Wave’s allele-selective approach may also enable treatment in the premanifest setting, before onset of clinical disease.