Wave to Discontinue Lead Huntington’s Programs After Disappointing Clinical Data


Disappointing data from two Phase Ib/IIa trials for both lead Huntington’s disease (HD) antisense candidates have pushed Wave Life Sciences to shelve the assets and focus on its next generation of therapies. The announcement comes just a week after Roche pulled the plug on a Phase III trial in HD patients for its antisense drug, tominersen.

HD is a progressive neurodegenerative genetic disease with no approved therapies. Antisense oligonucleotide therapies (ASOs) like Wave’s two drug candidates, WVE-120101 and WVE-120102, function by interfering with cellular machinery to prevent coding of specific proteins. RNA interference (RNAi) has seen some regulatory approvals for genetic diseases, like Duchenne muscular dystrophy (DMD).

In February, the U.S. Food and Drug Administration approved Sarepta Therapeutics’ Amondys 45 (casimersen) in DMD patients with a mutation amenable to exon 45 skipping, its third DMD approval.

Unlike Roche’s tominersen, which targets all HTT alleles to reduce both mutant and health proteins, Wave’s candidates each target a different single nucleotide polymorphism (SNPs) on the mutant HTT gene to block mHTT protein production only, preserving normal HTT production. Roche stopped dosing in its Phase III GENERATION HD1 and paused dosing in an open-label extension study following the recommendation of an independent data monitoring committee’s pre-planned review.

WVE-120101 and WVE-120102 were tested in the PRECISION-HD1 and PRECISION-HD2 trials, respectively. Patients in the PRECISION-HD2 cohort receiving monthly doses of up to 32 mg of WVE-120102 showed modest but inconsistent reductions in mHTT protein. WVE-120102 levels in cerebrospinal fluid correlated with mHTT reduction, but pharmacokinetic modeling discouraged Wave from testing higher doses.

Full data from PRECISION-HD1 is not yet available, but Wave said the results for a cohort receiving up to 16 mg of WVE-120101 mirrored the results seen in patients receiving the same dose of WVE-120102 in PRECISION-HD2.

“We are disappointed not to have better news to share with the HD community,” said Michael Panzara, Chief Medical Officer and Head of Therapeutics Discovery and Development at Wave. He added that despite the clinical failure, data from the trials and elsewhere support the company’s approach to targeting only mHTT protein, and said Wave remains committed to developing its next-generation HD therapy, WVE-003. That therapy, which targets a different SNP than WVE-120101 or WVE-120102, is on track to begin a Phase Ib/II trial this year.

Wave also has ASO therapies in preclinical development for DMD, amyotrophic lateral sclerosis (ALS), frontotemporal degeneration, spinocerebellar ataxia 3, and other neurological diseases.

Wave’s stock dropped almost 30% following yesterday’s announcement, and is down over 50% since Roche’s announcement.

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