Wave's ALS-dementia drug crashes out after early-phase flop, dealing further blow to target

Wave Life Sciences’ antisense oligonucleotide WVE-004 has come up short in a phase 1/2 trial. A year after Biogen and Ionis Pharmaceuticals killed off a similar asset, the biotech is waving goodbye to WVE-004 after getting a look at early-phase clinical trial data in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).

WVE-004 is designed to lower levels of a form of C9orf72, a protein implicated in ALS and FTD. The good news for Wave is the antisense oligonucleotide appears to engage its target as hoped. In a phase 1b/2a trial, levels of poly(GP), a biomarker for the potentially disease-driving C9orf72 hexanucleotide repeat expansion transcripts, fell by around 50% in recipients of WVE-004.

The problem? The decline in the biomarker had no effect on clinical outcomes. Wave saw no benefit in WVE-004-treated subjects compared with placebo on any exploratory clinical outcome measure. Across the ALS and FTD scales used in the trial, the biotech failed to drum up evidence the drug helps patients.

Wave responded to the setback by discontinuing development of WVE-004. The biotech cited the lack of efficacy and “absence of biomarkers reasonably likely to predict clinical outcomes” as the reasons for its decision to pull the plug on the program.

The setback is a further blow to the idea of treating ALS and FTD by using antisense oligonucleotides to target C9orf72. Biogen and Ionis were developing a candidate with the same mechanism but cut their losses last year after failing to uncover evidence of efficacy in an early-phase ALS clinical trial.

Wave kept advancing its candidate after the setback to its rivals in the belief WVE-004’s “potency and differentiated pharmacology” may yield a better result, Paul Bolno, M.D., said in a statement. But reality has now caught up with Wave’s hopes and put paid to the idea that WVE-004 can succeed where Biogen and Ionis' BIIB078 failed.   

The news, which sent Wave’s stock down 15% to $3.16 in premarket trading, leaves the biotech looking to data on the Takeda-partnered Huntington’s disease candidate WVE-003 for a boost. Data from a phase 1b/2a trial of the candidate are due in the second half of the year. Wave is also pushing its Duchenne muscular dystrophy prospect into a potentially registrational phase 2 clinical trial.

Wave ended March with $207.6 million, giving it a runway that extends into 2025.