WVE-003 Safely Lowers Mutant Huntingtin Protein in Phase 1/2 Trial

Single injection works in Huntington's patients, leaves healthy protein unaffected

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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A single injection of Wave Life Science‘s experimental therapy WVE-003 was found, at either of the two lowest tested doses, to lead to reductions in the mutant huntingtin (mHTT) protein in people with Huntington’s disease — while leaving the healthy version of the protein unaffected.

That’s according to initial results from the SELECT-HD Phase 1b/2a clinical trial (NCT05032196), which also showed the treatment was safe and well-tolerated at all three evaluated doses.

Wave is now adapting the trial to expand these dosing groups, while continuing to monitor those at the highest-dose level. That group will be tested for mHTT levels when they reach 85 days after treatment. Additional trial data are expected in the first half of 2023.

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SELECT-HD is still recruiting up to 36 adults with early Huntington’s, ages 25 to 60, who have a specific disease-associated mutation. Enrollment is ongoing at 25 study sites across the U.K., Europe, Canada, and Australia.

“Based on these initial data, it appears that our preclinical data for WVE-003 are translating in the clinic,” Michael Panzara, MD, chief medical officer and head of therapeutics discovery and development at Wave, said in a company press release.

“We are grateful to the [Huntington’s] community, including the SELECT-HD participants, study sites and advisors, for their continued partnership and support of this program. We look forward to continuing to expand this study and sharing additional data next year,” Panzara added.

WVE-003’s effect on huntingtin protein

Huntington’s disease is caused by a mutation in the HTT gene, which leads to defects in the huntingtin protein that’s important for nerve cell function. It is estimated that about 40% of patients with the neurodegenerative disorder have a specific mutation called SNP3 in their HTT gene.

WVE-003 is an oligonucleotide — a short strand of DNA or RNA — designed to target the HTT mRNA that carries SNP3. mRNA is an intermediate molecule the body uses as a template for protein production.

By binding to the mutated mRNA, WVE-003 prevents it from being translated into mHTT. That, in turn, lowers the levels of the faulty protein in the body.

The therapy candidate is designed to spare any mRNA with instructions to produce a healthy protein — called wild-type — in what is known as an allele-specific approach.

The participants in SELECT-HD are adults at the earliest stages of Huntington’s who have the SNP3 mutation. Each is given a single injection of WVE-003 at one of four doses, or a placebo, administered directly into the spinal canal.

The study’s main goal is to monitor safety for up to 36 weeks, or about nine months. Also being assessed is the treatment’s movement through the body, called its pharmacokinetics, and the medication’s effects on the body, or pharmacodynamics. Measuring levels of a disease biomarker, like mHTT, is a type of pharmacodynamic assessment.

To date, 18 participants have been dosed: four patients each received a dose of 30 mg, 60 mg, or 90 mg, and six people were given a placebo.

For participants in the 30 mg, 60 mg, and placebo groups, enough follow-up data were available to assess mHTT levels in the cerebrospinal fluid, which surrounds the brain and spinal cord.

Treatment with WVE-033, with both dose groups combined, led to a 22% mean reduction in mHTT from the study’s start to 85 days later. That’s a 35% greater reduction than what seen in the placebo group.

Notably, the healthy HTT protein appeared to be preserved after treatment, supporting the proposed allele-selectivity of WVE-003.

“These preliminary data suggest WVE-003 is working as intended: to selectively reduce the toxic mHTT protein while avoiding targeting the healthy, wild-type huntingtin protein, thereby preserving its beneficial effects in the central nervous system,” said Ralf Reilmann, MD, founder of the George-Huntington Institute, in Germany, and a member of the SELECT-HD clinical advisory and dose escalation committees.

All three doses were generally safe and well-tolerated. Side effects, which were balanced across groups, were mostly mild or moderate in intensity; none were serious.

Some participants showed an increase in neurofilament light chain (NfL), a marker of nerve damage, after the treatment. Wave will continue to monitor NfL levels as the trial advances. No indicators of inflammation were observed.

No meaningful changes in clinical outcome measures were observed. However, neither the number of patients nor the length of time were sufficient for assessing the treatment’s effectiveness.

“Taken together, WVE-003 appears to have a unique profile with the potential to overcome prior therapeutic challenges in this field,” Reilmann said. “It is my hope that innovative adaptive trial designs like SELECT-HD become more commonplace to optimize dosing in early proof-of-concept studies.”

The treatment was designed using Wave’s PN backbone chemistry modifications, which enable the development of more stable mRNA-targeting molecules. This is the same technology used to develop the company’s investigational therapy for Duchenne muscular dystrophy, which is in clinical testing.