Wave Life Sciences said Tuesday that its experimental Huntington’s disease therapy effectively lowered the mutant huntingtin protein (mHTT) levels associated with the disease in a Phase 1b/2a trial, and it now plans to seek accelerated approval.
In a small study of 23 patients, Wave said WVE-003 induced a 46% reduction in mHTT levels in patients’ cerebrospinal fluid compared to placebo. Patients were dosed with spinal canal injections every eight weeks and Wave observed their CSF mHTT levels after 24 weeks. The result was statistically significant with a p-value of p=0.0007.
Wave also measured mHTT levels out to 28 weeks and saw a 44% reduction, good for a p-value of p=0.0002. The company, which has partnered with Takeda on the program, enrolled 16 patients in the active arm and seven in the placebo arm.
Wave’s stock price $WVE initially jumped about 55% premarket, but since Tuesday’s opening bell, it has fallen roughly 9%. The 46% and 44% reductions in mHTT levels are higher than the 30% that Wave set as a benchmark for success, analysts said.
The data are similar to Phase 1/2a results from another prominent Huntington’s program: Roche and Ionis’ tominersen, which reported an approximate 40% reduction in average mHTT levels back in 2018. However, those results did not translate to success in a larger Phase 3 study. In early 2021, Roche halted that trial, and full results published last year in the New England Journal of Medicine indicated the placebo group outperformed the active arm.
(Roche and Ionis have since launched a new Phase 2 study, which began enrolling patients in early 2023.)
Wave CEO Paul Bolno told Endpoints News that he’s optimistic WVE-003 won’t encounter a similar fate. Unlike tominersen, WVE-003 only targets (or, more precisely, silences) the mutant huntingtin protein and not the wild-type huntingtin protein, which plays a role in brain development and helps regulate the central nervous system.
“We’re actually proving a different hypothesis, not the hypothesis of all the pan-silencing medicines,” Bolno said. “We’re proving the thesis that, ‘Here’s the example of what happens if you only take out the bad protein and you actually allow the reserve of this healthy protein to be present.’”
Anne-Marie Li-Kwai-CheungWith the data, Wave intends to seek an accelerated approval for WVE-003. Though the company will have to sort out the plan with the FDA, chief development officer Anne-Marie Li-Kwai-Cheung said that another trial is “likely.”
The next step will be figuring out which endpoint to use for a pivotal study. Li-Kwai-Cheung said Wave is looking at a biomarker called caudate atrophy that doctors can detect on MRI scans. The Phase 1/2a study was not powered to measure caudate atrophy, but Wave observed a statistically significant correlation between the biomarker and mHTT reduction (p=0.047).
Li-Kwai-Cheung said she expects the correlation to hold up in a larger study, because Wave expects to run it for longer than 28 weeks and it could serve as the primary endpoint.
“We saw that there’s the slowing of it; now you power the study around that so you de-risk the translation,” Li-Kwai-Cheung said. “We’ll obviously look at all of the regular clinical outcomes.”
Wave also reported results from three dose levels of single-dose cohorts of the trial, but did not see a dose response.