WVE-N531 Shows Potential as Exon 53 Skipping Therapy in Trial | First data on the first group of boys with Duchenne MD

wave life sciencesThe experimental WVE-N531 exon skipping therapy appears to be working as expected, based on early data from a small clinical trial of the therapy in a first group of three children with Duchenne muscular dystrophy (DMD).

“These data provide preliminary evidence that WVE-N531 is…causing substantial exon skipping after only three consecutive doses. This is the earliest time point that exon skipping has been reported in a clinical trial of children with DMD,” Anne-Marie Li-Kwai-Cheung, Wave’s director of development, said in a statement. company press release announcing the results.

“We are encouraged by these early results and are evaluating the next steps for the program, including continuing this initial cohort. We would like to express our sincere thanks to the children, their families and the researchers who participated in the study,” said Li-Kwai-Cheung.

Decisions on the “next steps” for WVE-N531 are expected in 2023, added Paul Bolno, MD, Wave’s president and CEO.

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More target dystrophin protein of exon skipping for Duchenne muscular dystrophy

DMD is caused by mutations in the DMD gene that provides instructions for making dystrophin, a protein that helps maintain muscle health. Like other protein-coding genes, DMD it is made up of individual sections called exons, which come together to form the mature protein-coding sequence, much like individual words come together to make a sentence.

Exon skipping is a therapeutic strategy that aims to have the molecular machinery of a cell leave out (skip) one or more exons when the DMD the gene is “read” to make the protein dystrophin. Ultimately, the goal is to make a shorter, but functional, version of the protein.

WVE-N531 is designed to treat patients susceptible to skipping exon 53 in the DMD gene. According to Wave, this represents approximately 8-10% of DMD patients.

Wave is sponsoring an open label Phase 1b/2a study (NCT04906460) to test the safety, pharmacological properties and clinical effects of WVE-N531. Open to patients 5 to 18 years of age on a stable corticosteroid regimen and with a disease-causing mutation capable of skipping exon 53, the trial is recruiting participants on sites in the UK and Canada.

These preliminary results are from three children with DMD, all able to walk, initially treated with a single dose of 1 mg/kg, then single doses of 3, 6, and 10 mg/kg. They were then given three doses of 10 mg/kg every two weeks. The experimental therapy was administered by infusion into the bloodstream.

Two weeks after the third and final dose (six weeks after the initial dose), muscle biopsies were taken for analysis. The findings showed that WVE-N531 resulted in an average exon skipping of 53% at the RNA level. (A copy of the gene is made in RNA as an intermediate step when “reading” a gene to make protein.)

“It is exciting to see this level of exon skipping in such a short period of time, especially since skipping would be expected to increase over a longer dosing interval,” said Laurent Servais, MD, PhD, principal investigator of the study at Oxford Children’s. Hospital.

The mean level of dystrophin protein was 0.27% of normal levels, which is below the lower limit of reliable detection.

“While dystrophin was below the lower limit of detection, dystrophin protein production is expected to delay splicing of RNA transcription,” Li-Kwai-Cheung said.

“Dystrophin expression after longer exposure will of course be key to confirming the promise of these early data,” Servais said. “I look forward to the continued progression of clinical research for WVE-N531.”

Pharmacological data from these first three patients suggest that WVE-N531 might be suitable for monthly dosing, according to Wave. All reported safety-related events were mild, except for one moderate case of COVID-19 infection.

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