Dive Brief:

• Wave Life Sciences on Tuesday said it will meet with regulators to discuss what kind of evidence would be needed to support an accelerated approval application for an experimental drug it’s developing for Huntington’s disease.
• The biotechnology company shared its plans alongside results from a placebo-controlled clinical trial testing the drug, dubbed WVE-003. Data showed treatment significantly lowered levels of a mutant protein that causes the neuron death behind Huntington’s. Wave also said this mutant protein lowering correlated with slowing of “caudate atrophy,” a biomarker the company says is predictive of clinical outcomes.
• “[W]e have been working diligently to establish caudate volume as a biomarker for clinical development,” said Anne-Marie Li-Kwai-Cheung, Wave’s chief development officer, in a statement. “We believe these strong data compel a case for accelerated approval for WVE-003, which we plan to discuss with regulators.”

Dive Insight:

WVE-003 is Wave’s second attempt at designing an effective drug for Huntington’s, after the company in 2021 shelved two prior candidates that weren’t potent enough in testing. All three candidates are meant to silence expression of mutated forms of the “HTT” gene, thereby reducing levels of mutant “huntingtin” protein that’s toxic to neurons. (The resulting dysfunction and death of neurons is what causes the movement and thinking problems associated with Huntington’s.)

However, WVE-003 was designed using different chemistry modifications, and targets another nucleotide in the RNA transcript produced by mutant HTT. The idea is the drug will selectively degrade mutant HTT protein while sparing the wild-type HTT protein thought to be helpful to normal brain function.

The trial data Wave disclosed Tuesday are evidence of this desired “allele selectivity,” the company said. Participants in the study given three doses of WVE-003 had, on average, 46% lowering in mutant HTT protein levels in the cerebrospinal fluid, compared to placebo. Yet wild-type HTT protein levels were preserved and even increased, according to Wave.

“Wild-type huntingtin plays such a critical role in the central nervous system, and it’s very exciting to finally have an opportunity to evaluate mHTT lowering in the context of allele-selectivity and to see positive signals emerging,” Ralf Reilmann, founder of the George-Huntington Institute in Germany and lead investigator in Wave’s study, said in the company’s statement.

Researchers measured mutant HTT protein levels at week 24 of the study, two months after participants’ last dose, and at week 28. Average protein lowering was maintained, at 44%, through the additional four weeks, Wave said.

The protein reductions surpassed analysts expectations of what would WVE-003 would need to show at this phase of testing.

Participants on treatment also “trended towards” less caudate atrophy, which is imaged using MRI scans. In a presentation to Wave investors, the company pitched caudate atrophy as a sort of intermediate measure between mutant HTT protein lowering and functional benefits. It also outlined a 12- to 18-month study of 150 Huntington’s disease patients and measuring caudate atrophy as an “efficient pathway” to an accelerated approval.

But there were less positive signs in Wave’s data, too. Cerebrospinal fluid levels of another protein, called neurofilament light chain or NfL, generally increased in participants given WVE-003, although Wave described the change as “in line” with the placebo group. NfL has become an increasingly important biomarker in certain neurological diseases and is thought to be indicative of nerve cell damage.

The Huntington’s field has also been disappointed before with drugs that reduced mutant HTT protein, but didn’t lead to clear benefits in motor function or cognition. Wave has emphasized “allele selectivity” as a reason why it’s drug could be different.

Shares in the company fell by as much as 11% in Tuesday morning trading.

PTC Therapeutics and Roche are also working on Huntington’s drugs designed to silence mutant HTT expression, while UniQure is developing a gene therapy. Last week, the Food and Drug Administration lifted a partial clinical hold it had imposed on a study of PTC’s treatment.

Takeda Pharmaceuticals previously partnered with Wave on WVE-003, and holds an option to co-develop and co-market the drug. Wave said it will submit its “opt-in package” to Takeda.