Benzinga | Mar 29, 2021 04:14PM EDT

Wave Life Sciences Says mHTT Results From PRECISION-HD Trials Do Not Support Further Development Of WVE-120102 And WVE-120101

Wave Life Sciences Ltd. (NASDAQ:WVE), a clinical-stage genetic medicines company committed to delivering life-changing treatments for people battling devastating diseases, today announced data from the Phase 1b/2a PRECISION-HD2 and PRECISION-HD1 trials evaluating investigational treatments WVE-120102 and WVE-120101, respectively, in Huntington's disease (HD).

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.

In the PRECISION-HD2 open label extension (OLE) trial, results from all participants (n=28) showed modest reductions in mHTT after a mean of 8.1 monthly doses (range: 1-17), but effects were inconsistent over the course of the trial. While there was a correlation between WVE-120102 cerebrospinal fluid (CSF) concentrations and mHTT lowering, pharmacokinetic (PK) modeling suggests that additional dose escalation is unlikely to achieve drug concentrations needed for robust mHTT knockdown. Given the lack of consistent and significant reductions in mHTT and the PK modeling projections, Wave will stop clinical development of WVE-120102. Trial participants will have a final follow-up visit but receive no further doses.

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. Given these and results from Wave's previous clinical trials, as well as current understanding of the limitations of the company's first-generation candidates, Wave will also stop clinical development of WVE-120101. 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.

"We are disappointed not to have better news to share with the HD community and would like to extend our gratitude to the trial participants and their families for their commitment to these programs," said Michael Panzara, MD, MPH, Chief Medical Officer and Head of Therapeutics Discovery and Development at Wave Life Sciences. "However, we have learned an enormous amount from these trials and are encouraged by data that suggest our SNP targeting approach may achieve allele-selectivity. We look forward to continuing our collaboration with our research partners to advance our first HD clinical candidate that incorporates our next-generation PN backbone chemistry, WVE-003, and remain committed to the science of HD and, in particular, selective mutant huntingtin lowering."

WVE-003 is an investigational drug designed to selectively lower mHTT by targeting a specific single nucleotide polymorphism (SNP3) that is commonly found on the expanded CAG allele. This allele-selective approach is guided by the recognition that, in addition to a gain of function of mHTT, people with HD have lost one copy of the wild-type HTT allele, leaving them with a smaller protective reservoir of healthy, wild-type HTT protein (wtHTT) than unaffected individuals. A growing body of scientific evidence suggests that preserving as much of this essential protein as possible is important for favorable health outcomes.

Wave expects to initiate dosing in a Phase 1b/2a clinical trial for WVE-003 in 2021. As people with HD can carry multiple SNPs, participants from the PRECISON-HD trials will be offered the opportunity to undergo screening for potential enrollment in the WVE-003 trial. It is estimated that approximately 40% of adults with HD carry SNP3 in association with the HD mutation.

"Everyone at Wave wishes our PRECISION-HD programs had yielded different results, but we believe our WVE-003 program will enable us to address deficiencies with our first-generation candidates while maintaining our commitment to developing wild-type sparing therapies for HD," said Paul Bolno, MD, MBA, President and Chief Executive Officer of Wave Life Sciences. "Our next generation of investigational clinical candidates, which also includes WVE-004 for amyotrophic lateral sclerosis and frontotemporal dementia and WVE-N531 for Duchenne, as well as our current preclinical and discovery programs, all use novel PN chemistry, which has been shown to increase potency, exposure, and durability across our silencing, splicing, and editing modalities in preclinical studies. Our clinical candidates have also been optimized with pharmacodynamic and pharmacokinetic insights from in vivo models, which were not available for our first-generation compounds. For example, we selected WVE-003 as our next HD candidate after years of optimization and demonstrated target engagement in vivo. Moreover, we are implementing innovative, adaptive designs across our new clinical programs to speed development and help us make data-driven decisions more quickly. These collective advances and learnings will improve our ability to deliver transformative genetic medicines."