Robust preclinical data support development of DYNE-251 as a potential treatment for individuals with DMD mutations amenable to exon 51 skipping

Duchenne muscular dystrophy (DMD) is characterized by progressive loss of muscle function leading to premature death. Current therapeutic approaches use exon skipping phosphorodiamidate morpholino oligomers (PMOs) that enable the translation of a shortened, functional dystrophin protein, but their success has been hampered by poor muscle delivery. We developed the FORCE^TM platform, which harnesses the natural expression of transferrin receptor (TfR)1 on muscle cells for targeted delivery of oligonucleotides. DYNE-251, an investigational therapeutic for the treatment of DMD, consists of an exon 51 skipping PMO conjugated to an antigen-binding fragment (Fab) targeting TfR1. In non-human primates, DYNE-251 led to pronounced exon skipping in cardiac and skeletal muscle and demonstrated a favorable safety profile. We also demonstrated that a single dose of FORCE-M23D, a mouse-specific Fab-PMO conjugate designed to skip exon 23 of the murine Dmd pre-mRNA, led to robust and durable exon skipping and dystrophin restoration, and improved functional outcomes in mdx mice, compared to unconjugated PMO. These preclinical data supported the initiation of DELIVER, a randomized, double-blind, placebo-controlled, multiple ascending dose (MAD) study of DYNE-251 administered intravenously to ~46 ambulant and non-ambulant males (4-16 years) with exon 51 skip-amenable mutations (NCT05524883). The purpose of the study is to evaluate the safety, tolerability, and dystrophin levels in muscle following multiple doses of DYNE-251. Primary outcomes are the number of participants with treatment-emergent adverse events and the change from baseline in dystrophin levels in muscle at Week 25. The DELIVER study will inform the potential of DYNE-251 as a treatment for DMD.