Development of WVE-004 to cease after Phase 1/2 trial failure

No functional status gains seen in FOCUS-C9 trial patients, despite toxicity reductions

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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WVE-004, Wave Life Sciences‘ investigational treatment for amyotrophic lateral sclerosis (ALS), significantly reduces toxic proteins associated with C9orf72 genetic mutations, but that doesn’t seem to translate into functional status gains in patients.

Based on findings from the Phase 1b/2a FOCUS-C9 trial (NCT04931862), the company has decided to discontinue developing WVE-004 for C9orf72-associated ALS.

“We are deeply disappointed that we were not able to see any evidence of potential benefits that would be expected to drive meaningful outcomes for these patients,” Paul Bolno, MD, president and CEO of Wave, said in a company press release.

C9orf72 mutations are the most common genetic cause of ALS and frontotemporal dementia (FTD), a related neurodegenerative condition. They are marked by the excessive repetition of six nucleotides, or DNA building blocks, in the gene’s code.

Normally, these six nucleotides — GGGGCC — are repeated up to a couple dozen times, but in ALS- or FTD-associated mutations, they are repeated hundreds or thousands of times. This results in abnormal proteins being produced, including poly(GP), that form toxic clumps inside cells.

WVE-004 is a type of therapy called an antisense oligonucleotide, which works to prevent the production of these toxic proteins by interfering with the gene’s messenger RNA (mRNA), an intermediate molecule produced from DNA that acts as a template for making protein.

The FOCUS-C9 study evaluated the safety and pharmacological properties of WVE-004 in people with ALS or FTD who carry C9orf72 mutations.

In its first part, participants were given a single dose of WVE-004 (10, 30, or 60 mg) or a placebo via an intrathecal injection (into the spinal canal) and were observed for three months.

Interim data indicated the therapy reduced poly(GP) levels in the cerebrospinal fluid, which surrounds the brain and spinal cord, at all tested doses, indicating it was engaging its intended biological target.

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Reductions in poly(GP), but no clinical gains

Wave extended the observation period to six months to see if poly(GP) would continue to decline and added a single 20 mg dosing group.

In another part of the trial, participants were assigned to receive multiple doses of 10 mg WVE-004 — either every four or 12 weeks — and were compared with a placebo group.

Top-line results concerning all dosing groups indicate single and multiple doses were generally well tolerated, with most side effects being mild and related to the disease progression or intrathecal injections. No new safety signals were identified since the interim analysis.

Strong reductions in poly(GP) were observed, with patients on a single 20 mg dose and those in the multiple dose groups all having a roughly 50% decrease in poly(GP) levels over the start of the study.

Still, no significant clinical benefits were observed after six months on any efficacy measure, including the ALS Functional Rating Scale-Revised (ALSFRS-R), a standard measure of functional status in ALS clinical trials.

Following our initial positive single dose data last year, we advanced WVE-004 with the hope that its potency and differentiated pharmacology may deliver a better result than C9orf72-targeting oligonucleotides discontinued by others in the field.

While those treated with WVE-004 every four weeks did see a significant reduction in ALSFRS-R declines relative to a placebo, the scores were not significantly different from the decline in a natural history control group from an ALS database and weren’t deemed clinically meaningful. Reductions in poly(GP) didn’t correlate with stabilizations or improvements in ALSFRS-R scores or other clinical measures.

Based on the data, Wave will discontinue developing the therapy, FOCUS-C9 and its open-label extension study will be stopped, and the latest results will be presented at a future medical congress.

“Following our initial positive single dose data last year, we advanced WVE-004 with the hope that its potency and differentiated pharmacology may deliver a better result than C9orf72-targeting oligonucleotides discontinued by others in the field,” Bolno said. “Our hope is that these data can help advance future research … On behalf of everyone at Wave, I wish to sincerely thank the participants, their families, the clinical sites, and our study advisory committees for their participation and support.”