Wave plans next steps to develop WVE-003 after positive trial data

Treatment reduced mutant huntingtin, Phase 1b/2a data showed

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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More than three months of treatment with WVE-003 safely leads to significant reductions in mutant huntingtin — the protein that toxically accumulates in Huntington’s disease — for people with early Huntington’s, while preserving levels of the healthy version of huntingtin and trends of slower brain tissue loss and clinical decline.

That’s according to data from the Phase 1b/2a SELECT-HD trial (NCT05032196).

The data prompted developer Wave Life Sciences to consider a clinical development path for the treatment that could support accelerated approval.

“These results represent a significant achievement for Wave … and most importantly, for the HD community,” Anne-Marie Li-Kwai-Cheung, chief development officer at Wave, said in a company press release. “We believe these strong data compel a case for accelerated approval for WVE-003, which we plan to discuss with regulators.”

The company aims to engage regulators by the end of the year.

Accelerated, or conditional, approval allows promising therapies to be marketed based on early trial evidence that they’re probably effective. To gain full approval, further testing needs to prove the therapy provides clinical benefits as expected.

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Targeting mutant huntingtin

Huntingtin is a protein that’s important for nerve cell health. But in Huntington’s, mutations in the HTT gene lead to the production of an abnormal huntingtin version that forms toxic clumps inside cells.

Inheriting one mutated HTT gene copy is enough for a person to develop the neurodegenerative disease, even if the remaining healthy copy is still able to produce healthy protein.

The mutant huntingtin (mHTT) protein impairs the function of the healthy, or wild-type, huntingtin (wtHTT), meaning that symptoms of Huntington’s likely arise not only from nerve damage due to toxic mHTT clumps, but also from wtHTT’s loss of function.

WVE-003 aims to specifically reduce production of mHTT while preserving wtHTT for the approximately 40% of Huntington’s patients who have the SNP3 mutation in the HTT gene. This mutation is not the cause of disease, but it resides near the standard Huntington’s-causing mutation on mutated HTT gene copies.

The investigational treatment is an oligonucleotide, or a short strand of genetic material, designed to bind to the section on HTT’s messenger RNA (mRNA) — the intermediate molecule derived from DNA that guides protein production — where SNP3 resides.

In doing so, it stops the mutated mRNA template from being translated into mHTT. The SNP3 mutation is only found on mutated HTT copies, so any mRNA templates encoding wtHTT production will be spared.

The two-part SELECT-HD trial was mainly designed to test the treatment’s safety and pharmacological properties in early Huntington’s patients, ages 25-60, who carry the SNP3 mutation.

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Testing doses

In its single-dose part, 47 participants received one intrathecal (administered directly into the spinal canal) injection of one of three doses of WVE-003 (30, 60, or 90 mg) or a placebo.

Data showed that single WVE-003 doses led to reductions of mHTT levels in the cerebrospinal fluid (CSF), or the fluid surrounding the brain and spinal cord, relative to the placebo, with preservation of wtHTT levels.

This was seen for all three doses, and effects persisted for about three months after dosing. A 30 mg dose appeared to be the safest and most well tolerated.

In the study’s subsequent multiple-dose part, 23 new participants were randomly assigned to receive three intrathecal injections of either 30 mg of WVE-003 or a placebo, separated by eight weeks, totaling about 3.5 months of treatment. Patients were then followed up to 28 weeks, or a little over six months.

Wave has now reported findings from this part of the trial showing that mHTT levels were significantly reduced with WVE-003 treatment.

With WVE-003 treatment, CSF mHTT levels were reduced by a mean of 46% at two months after the last dose and 44% after three months relative to the placebo. Wave said that finding supports dosing once every three months, or less frequently, in future studies.

WVE-003 was associated not only with a preservation of CSF wtHTT levels, but also with statistically significant increases relative to the placebo.

About two months after the last dose, mHTT reductions were significantly associated with a slowing of tissue loss (atrophy) in the caudate nucleus, a brain region particularly affected in Huntington’s. According to Wave, caudate atrophy is a biomarker that predicts clinical deterioration in Huntington’s.

The trial was not specifically designed to look at clinical outcomes, but changes in the Total Motor Score, which measures the severity of motor symptoms, favored WVE-003 over the placebo.

Multidose treatment was generally well tolerated, without reports of serious adverse events.

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Plan to study caudate atrophy

“These data provide hope and a compelling path forward as the community continues to drive toward a long-awaited therapy to treat this devastating disease,” said Ralf Reilmann, MD, the trial’s primary investigator and founder of the George-Huntington Institute in Germany.

SELECT-HD findings were shared on a company webcast in which the company released a draft study design for a potential future trial to test the therapy against a placebo in about 150 adults with early Huntington’s and the SNP3 mutation.

The study, which would last about a year to a year and a half, would be designed to specifically look at caudate atrophy as an indicator of clinical efficacy.

“Alongside the [Huntington’s disease] community, we have been working diligently to establish caudate volume as a biomarker for clinical development due to its association with clinical outcomes,” Li-Kwai-Cheung said.