DMD treatment WVE-N531 boosts dystrophin: Interim trial data
Boys in Phase 1b/2a trial saw signs of improved muscle health, regeneration
Treatment with exon 53-skipping therapy WVE-N531 led to significant increases in muscle dystrophin levels along with signs of improved muscle health and regeneration in boys with Duchenne muscular dystrophy (DMD).
That’s according to new six-month interim data from the Phase 1b/2a FORWARD-53 trial (NCT04906460), which also found the treatment to be safe and well tolerated.
Developer Wave Life Sciences expects to complete the trial in early 2025, at which point it will get feedback from regulators on a potential pathway for accelerated approval.
“The high and consistent dystrophin levels at this interim timepoint are compelling and speak to the potential of WVE-N531 for boys amenable to exon 53 skipping, where better therapeutic options are urgently needed,” Anne-Marie Li-Kwai-Cheung, Wave’s chief development officer, said in a company press release.
Exon-skipping DMD treatment
DMD patients are lacking dystrophin, a protein important for protecting muscle cells from damage, due to mutations in the DMD gene.
Protein-coding portions of genetic material, called exons, are normally strung together and read sequentially by cells’ protein-making machinery to produce a functional protein. DMD-causing mutations often cause exons to be out of normal alignment, and the sequence can’t be properly read.
WVE-N531 belongs to a class of DMD treatments called exon-skipping therapies, which aim to skip over one or more exons, helping the remaining exons better fit together. This allows cells to produce a functional but shorter-than-usual version of dystrophin.
In particular, WVE-N531 is designed to skip exon 53 of DMD, an approach estimated to benefit about 8%-10% of patients.
The treatment was recently granted rare pediatric drug designation in the U.S., a status that aims to incentivize companies to develop treatments for serious or life-threatening rare diseases that mainly affect children.
FORWARD-53 enrolled 11 boys with DMD, ages 5 to 11, all but one of whom were ambulatory (able to walk). All enrolled participants have disease-causing mutations amenable to exon 53 skipping and are on stable regimens of corticosteroid therapy.
Data from the trial’s preliminary part A, involving three ambulatory boys, showed that the treatment was well tolerated and appeared to be working as expected.
In the main part of the trial, all 11 participants are being treated with WVE-N531 at a dose of 10 mg/kg once every two weeks, with muscle biopsies taken after 24 weeks (about six months) and 48 weeks (nearly a year).
The recent interim analysis, conducted at the 24-week point, indicated that WVE-251 was safe and well tolerated, with all adverse events being mild.
Among the ambulatory boys, mean muscle-adjusted dystrophin levels reached 9% of normal, with overall dystrophin levels reaching 5.5% of normal.
Nearly 90% of the boys achieved a muscle-adjusted dystrophin level of at least 5%, which Wave indicates is the goal for achieving meaningful gains in muscle function for boys with DMD.
‘Meaningful step forward’
“It has been challenging for the field to achieve dystrophin levels that can significantly improve clinical outcomes,” said Laurent Servais, MD, PhD, a professor at the University of Oxford and the trial’s principal investigator. “Achieving mean muscle content-adjusted dystrophin of 9% is a meaningful step forward,” Servais said.
Dystrophin can exist in multiple functional versions, or isoforms. Here, the researchers observed two isoforms that are consistent with ones seen in people with Becker muscular dystrophy, which is also caused by DMD gene mutations but is associated with higher dystrophin levels and milder disease.
The mean exon 53 skipping level achieved was 57%, and WVE-N531 was detected in muscle cells, or myocytes, for all participants. In most boys, it was also detected in myogenic stem cells, precursors that can generate new muscle cells, indicating the treatment could help to regenerate muscle fibers.
Participants showed improvements in multiple indicators of muscle health, with evidence of muscle fiber regeneration since the last analysis for participants who completed Part A, according to the company.
Blood biomarkers of muscle damage were significantly decreased from the study’s start, with reductions numerically larger than what’s usually seen with corticosteroid therapy.
Other experiments indicated that WVE-N531 reached a concentration of about 41,000 nanograms per gram in muscle tissue. Based on earlier preclinical data, Wave believes the treatment may have even higher activity in the heart and the diaphragm, a major muscle for breathing
Altogether, the data support a monthly dosing regimen of WVE-N531 moving forward, and trial participants are now being transitioned to that regimen.
As the company awaits final FORWARD-53 data, it is also working on advancing a larger pipeline of exon-skipping therapies, which it indicates could offer best-in-class treatment options for up to 40% of boys with DMD.
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