Wave Life Sciences discontinues ALS drug program after early-stage trial fail

A Takeda partner reported an early-stage ALS trial failure Tuesday morning and opted to discontinue the program entirely, serving as a reminder that despite two recent FDA approvals, challenges remain in tackling the universally fatal disease.

Wave Life Sciences said its program, dubbed WVE-004, did not show any clinical benefit when compared to placebo in a subset of ALS patients with specific genetic mutations. The compound additionally failed to show a benefit for patients with frontotemporal dementia in a separate benefit analysis.

Though the Phase Ib/IIa study was designed to measure safety and tolerability, WVE-004 also showed no correlation between changes in an ALS clinical outcome scale and changes in the biomarker known as neurofilament light chain. Biogen used the protein to score an accelerated approval last month for tofersen, an ALS treatment targeting a different genetic mutation.

The Biogen OK marked a few firsts: the first time a biopharma company successfully used the accelerated regulatory pathway to win an ALS approval; the first time the FDA validated a surrogate biomarker for ALS; and the first time any drug won approval using neurofilament as that surrogate, in which it is “reasonably likely to predict clinical benefit” for patients.

Merit Cudkowicz

Tofersen’s approval also potentially opened the door to other ALS drugs, as well as other neurodegenerative diseases that lack clear biomarkers. But Merit Cudkowicz, director of Massachusetts General’s ALS center, said Wave’s results only add to the complicated nature of developing ALS therapies.

Even if it’s still early to try to fully interpret Tuesday’s data (Wave did not disclose hard data figures), it’s likely the field needs more studies that look at how neurofilament affects clinical outcome measures, Cudkowicz said.

“It may turn out that some drugs affect NfL greatly (like ones on gene target like Tofersen) and others do not but still have clinical effects,” Cudkowicz, who consults for Wave, told Endpoints News in an email. She added, “We also need additional biomarkers as NfL isn’t going to be the only relevant one.”

Wave researchers tested multiple dosing cohorts in trying to determine whether WVE-004 would be effective. Some patients received a 10 mg dose or placebo once every four weeks, and some once every 12 weeks. Others received a single 20 mg dose. Wave measured the results out to 24 weeks.

According to the press release, the every-four-week cohort saw a reduction in average scores on the clinical outcome measurement, known as the ALSFRS-R, compared to placebo. But the figures were not statistically significant when compared to a natural history study. The every-12-week cohort also failed to show a statistically significant change in the ALSFRS-R.

Wave did not disclose how much ALSFRS-R scores changed for the single-dose cohort. Across all dosing regimens, however, there were no correlations between changes on the scale and changes in neurofilament. The biotech saw elevations in the protein in the single-dose and every-four-week cohorts, while the 12-week group had “overlapping confidence intervals” with placebo.

The news sent Wave’s stock price $WVE down roughly 10% pre-market, but shares rebounded after the opening bell. During a conference call Tuesday morning, analysts largely wondered how the results would affect Wave’s other programs. The biotech is developing a suite of therapies aiming to impact biomarkers and thus affect disease course, including in Huntington’s disease and Duchenne muscular dystrophy.

Paul Bolno, Wave’s CEO, pointed to WVE-004’s success in reducing levels of a different biomarker, a protein called poly(GP), as evidence it engaged with the right target. Depending on the dosing regimen, patients saw a roughly 50% reduction in poly(GP) levels from baseline.

But the lack of clinical benefit, and not the lack of correlation with neurofilament, ultimately led to the decision to discontinue the program’s development, Bolno told Endpoints after the call. He also said he believes the neurofilament debate remains open-ended, given the complexity and rapidly progressing nature of ALS — particularly in its hereditary forms.

“The challenge with C9-ALS, as we just learned today in running the experiment, is poly(GP) didn’t translate into a clinical benefit,” Bolno said. “The real hunt for biomarkers is going to be indicative of disease progression and being able to really ascertain that biology.”

WVE-004 is an antisense oligonucleotide designed to target genetic mutations associated with the C9orf72 in patients with hereditary, or familial, ALS. C9orf72-mutated ALS is the most common version of familial ALS, making up about 40% to 50% of all hereditary cases. Wave originally partnered with Takeda on WVE-004 and other drug programs in 2018, but the companies revised their pact in 2021, allowing Wave to develop some programs — which were preclinical at the time — on its own.

Biogen’s tofersen, also an antisense drug and branded as Qalsody, targets SOD1-mutated ALS, the second-most common form. Previously approved ALS drugs, including the recently greenlighted Relyvrio from Boston-area biotech Amylyx Pharmaceuticals, showed no correlation between the ALSFRS-R and neurofilament.

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