WVE-003 for Huntington’s disease

Last updated Jan. 21, 2025, by Marisa Wexler, MS
Fact-checked by Inês Martins, PhD

What is WVE-003 for Huntington’s disease?

WVE-003 is an experimental injection therapy Wave Life Sciences is developing as a potential treatment to slow the progression of Huntington’s disease.

The medication, which has completed a Phase 1a/2b clinical trial, is being developed for people with early Huntington’s carrying the SNP3 mutation in the HTT gene. It is administered directly into the spinal canal via an intrathecal injection.

Therapy snapshot

How does WVE-003 work in Huntington’s disease?

Huntington’s disease is caused by mutations in the HTT gene, which provides instructions for making the huntingtin protein that’s important for nerve cell health.

Huntington’s-causing mutations lead to the production of an abnormal form of huntingtin, which is prone to form toxic clumps and impairs the function of the healthy huntingtin. This is believed to drive brain damage that leads to the disease’s symptoms.

When the HTT gene is read to make huntingtin protein, the genetic code is copied from the cell’s DNA into a temporary molecule called messenger RNA, or mRNA. The mRNA is then used as a template for making the protein.

WVE-003 is an antisense oligonucleotide, a small piece of genetic material that is able to bind to mutant HTT mRNA and target it for destruction. WVE-003  targets a particular mutation called SNP3. This mutation doesn’t directly cause Huntington’s, but it’s present in the mutant gene in roughly 40% of Huntington’s patients and not on the healthy version of the HTT gene.

By targeting this mutation, the therapy is designed to destroy the faulty HTT mRNA while leaving the normal mRNA intact. This is expected to prevent the production of the mutant huntingtin protein while allowing the normal version of the protein to be made.

How will WVE-003 be administered in Huntington’s disease?

In a completed Phase 1a/2b clinical trial, WVE-003 was administered via intrathecal injection, which delivers the therapy directly into the fluid that surrounds the brain and spinal cord.

WVE-003 has been tested at single doses ranging from 30-90 mg of the experimental therapy. After data showed that the 30 mg dose was the safest and most well tolerated, patients in the multi-dose part of the trial received injections at that dose every eight weeks.

WVE-003 is still in the early stages of development, so it’s not known if this dose and method of administration will be ultimately used if and when the therapy gains regulatory approval.

WVE-003 in Huntington’s disease clinical trials

A Phase 1b/2a clinical trial called SELECT-HD trial (NCT05032196) tested the safety, tolerability, and pharmacological properties of WVE-003 in people with early-stage Huntington’s disease carrying the SNP3 mutation.

In the first part, 47 participants were randomly assigned to receive one intrathecal injection of WVE-003 — at doses of 30, 60 or 90 mg — or a placebo, and were then monitored for long-term outcomes.

Results showed that all three doses were generally well tolerated, with no serious side effects reported. An interim analysis of the first two dose groups also showed that WVE-003 reduced levels of mutant huntingtin protein by 22% after 85 days, a 35% greater reduction than that seen in the placebo group.

Levels of the healthy huntingtin protein were not significantly changed, indicating the treatment was selectively targeting the mutant protein as intended.

In the second part of the study, 23 patients were given three intrathecal injections of either 30 mg WVE-003 or a placebo every eight weeks. Participants received the injections over the course of 3.5 months, and were followed for up to 28 weeks, or about 6.5 months.

Results showed no serious side effects were seen, and data again indicated the therapy reduced mutant huntingtin protein as designed. At 24 weeks, eight weeks after the last injection, mutant protein levels were reduced by 46% relative to the placebo and levels remained low at 28 weeks, with a 44% reduction relative to the placebo.

The reduction in mutant huntingtin levels was correlated with less atrophy (shrinkage) in the caudate nucleus, a brain region particularly affected in Huntington’s. Exploratory analyses of motor symptom severity also indicated that patients given WVE-003 tended to have less motor symptom worsening over 24 weeks compared with those given a placebo.

Common side effects of WVE-003

Clinical testing of WVE-003 in people with Huntington’s is still in the early stages, and detailed safety data has not yet been reported.

In the Phase 1a/2b clinical trial, some patients experienced side effects judged mild or moderate in severity, but details about specific side effects were not announced. No serious side effects related to WVE-003 were seen in the trial.

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