Wave planning potentially pivotal trial of WVE-003 in patients
Developer to seek FDA clearance to launch US study of Huntington's therapy
Wave Life Sciences is making plans to launch a potentially pivotal Phase 2/3 clinical trial in the U.S. to test its therapy candidate WVE-003 in people with Huntington’s disease.
Pivotal trials are those whose data, if positive, are meant to be used to support applications seeking a treatment’s approval.
According to a company press release announcing financial and business updates, Wave expects to file an application with the U.S. Food and Drug Administration (FDA) in the second half of the year that’s meant to seek regulatory clearance to start such a trial in this country.
The company’s plans are based on positive initial feedback received from the FDA given at the end of 2024. The agency indicated it is receptive to a potential pathway toward WVE-003’s accelerated approval as a treatment for Huntington’s. The FDA also was receptive to Wave using shrinkage of the caudate nucleus, a brain region particularly affected in Huntington’s, as a primary measure to assess disease progression in the planned trial.
The accelerated approval pathway is a mechanism the FDA can use to give conditional authorization to treatments based on early clinical trial evidence supporting their efficacy. As a condition of accelerated approval, drug developers have to conduct further testing to confirm the therapy’s safety and effectiveness.
Plans for pivotal trial supported by positive data from SELECT-HD study
Huntington’s is caused by a mutation in at least one of the two copies of the HTT gene, which results in the production of abnormal huntingtin protein that forms toxic clumps inside nerve cells, driving their death.
WVE-003, administered intrathecally, or directly into the spinal canal, is designed to bind to a mutated version of HTT’s messenger RNA (mRNA) — an intermediate molecule used as a template to produce the protein, targeting it for destruction.
The therapy binds specifically to a particular HTT mutation called SNP3, which does not cause the disease but is present near the standard Huntington’s-causing mutation in about 40% of Huntington’s patients.
Given that the SNP3 mutation is only found on HTT copies carrying the standard Huntington’s-causing mutation, the therapy is expected to prevent the production of abnormal huntingtin, while allowing the production of the healthy protein version, which is needed for nerve cell health.
By sparing healthy huntingtin protein, WVE-003 may be beneficial to both carriers of the disease-causing mutation who are not yet showing symptoms and those who are already experiencing signs of the disease, according to the company.
The completed Phase 1b/2a SELECT-HD trial (NCT05032196) tested the therapy in people with early Huntington’s and SNP3 mutations, ages 25 to 60. In the first part of the trial, 47 patients were randomly assigned to receive either one of three doses of WVE-003 — 30, 60, or 90 mg — or a placebo.
The results, which were also presented at the CHDI’s 20th Annual Huntington’s Disease Therapeutics Conference last month, demonstrated the treatment was well tolerated.
In the study’s first part, single WVE-003 doses were shown to significantly reduce mutant HTT protein levels in the fluid surrounding the brain and spinal cord, while preserving healthy HTT levels.
In the trial’s second part, 23 new patients received three injections of either 30 mg WVE-003, the most well-tolerated dose, or a placebo, separated by eight weeks. Two months after the last injection, mutant protein levels were reduced by 46% relative to the placebo, and these reductions were linked to a slower caudate nucleus shrinkage.
At the CDHI conference, the company also presented Huntington’s natural history data demonstrating that slowing the rate of caudate nucleus shrinkage by 1% is associated with a delayed disability onset of at least 7.5 years.
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