RARE Daily

Wave Dumps Two Huntington’s Treatments after Failure to Show Benefit in Studies

March 30, 2021

Rare Daily Staff

Wave Life Sciences is dropping further development of two experimental treatments in Huntington’s disease after data failed to show they had an effect compared to placebo, but says it will move forward with a third candidate that has demonstrated improved preclinical pharmacology.

Shares of Wave Life Sciences dropped 28 percent on the news.

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.

The phase 1b/2a PRECISION-HD2 and PRECISION-HD1 trials evaluated experimental treatments WVE-120102 and WVE-120101, respectively, in 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. Results in all participants through 16 mg (n=51) from the PRECISION-HD1 core trial were similar to those in PRECISION-HD2 at those dose levels.

Wave will move to advance a next-generation candidate, WVE-003 into clinical trials in an effort 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.

The company 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 percent 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, president and CEO 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.”

Photo: Paul Bolno, president and CEO of Wave Life Sciences

Stay Connected

Sign up for updates straight to your inbox.