First clinical evidence for satellite cell targeting in DMD: Results from Part A of a Phase 1b/2 study of WVE-N531


Clinical Trials

Poster Number: M168


Kuldeep Singh, DVM, MS, PhD, DACVP, Wave Life Sciences, Michael Tillinger, MD, Wave Life Sciences, Laurent Servais, MD, PhD, University of Oxford, Craig Campbell, University of Western Ontario, Department of Paediatrics, Children’s Hospital London Health Sciences, Xiao Hu, PhD, Wave Life Sciences, Andrew Hart, MS, Wave Life Sciences, Joseph Haegele, PhD, Wave Life Sciences, Jeanette Rheinhardt, BS, HTL, QIHC, Wave Life Sciences, Anamitra Ghosh, MS, PhD, Wave Life Sciences, Fangjun Liu, PhD, Wave Life Sciences, Chandra Vargeese, MS, PhD, Wave Life Sciences, Anne-Marie Li-Kwai-Cheung, MChem, MTOPRA, RAPS, Wave Life Sciences, Padma Narayanan, DVM, MS, PhD, Wave Life Sciences

Duchenne muscular dystrophy (DMD) is a severe neuromuscular disorder caused by mutations in the gene encoding dystrophin. Despite FDA accelerated approvals, accessing elusive myogenic stem cells or satellite cells, which may augment muscle regenerative capacity, remains a significant challenge. WVE-N531 is an investigational antisense oligonucleotide that contains PN (phosphoryl guanidine) chemistry that is designed to induce exon skipping and dystrophin restoration in patients who are amenable to exon 53 skipping.

Part A of a Phase 1b/2 open-label study (NCT04906460) demonstrated that WVE-N531 was generally safe and well-tolerated, with a promising pharmacokinetic and pharmacodynamic profile in three ambulatory boys. After three biweekly (every other week) doses, WVE-N531 yielded 53% mean exon skipping (RT-PCR) and reached a mean concentration of 42 µg/g in muscle tissue, with RNAscope (in situ hybridization) demonstrating that WVE-N531 reached the myocyte nucleus. Upon further analysis of the muscle biopsies from the three patients, WVE-N531 demonstrated clear uptake in satellite cells in all three patients as evaluated by a dual PAX7 (stem cell marker) immunohistochemistry and WVE-N531 RNAscope chromogenic assay.

This finding represents the first clinical evidence of a potential therapeutic for DMD having the ability to access satellite cells. Further studies are necessary to assess the therapeutic potential of WVE-N531 and the impact of exon-skipping in satellite cells in patients with DMD.