Background: Duchenne muscular dystrophy (DMD) is characterized by progressive loss of muscle function leading to premature death. Approved therapies use exon skipping phosphorodiamidate morpholino oligomers (PMOs) that enable the translation of a shortened but functional dystrophin protein, but their success has been hampered by poor muscle delivery. We developed the FORCETM platform, which harnesses the natural expression of transferrin receptor (TfR)1 on muscle cells for targeted delivery of oligonucleotide payloads. DYNE-251 is an exon 51 skipping PMO conjugated to an antigen-binding fragment targeting TfR1. In non-human primates, DYNE-251 led to pronounced exon skipping in cardiac and skeletal muscle and demonstrated a favorable safety profile. Additionally, FORCE-M23D, a mouse-specific FORCE conjugate, achieved robust and durable exon skipping and dystrophin expression in muscle and functional improvement mdx mice.
Objectives: DELIVER is a randomized, double-blind, placebo-controlled, multiple ascending dose (MAD) study of DYNE-251 administered intravenously to ambulant and non-ambulant boys (4-16 years) with exon 51 skip-amenable mutations (NCT05524883). The study consists of a MAD/placebo-controlled period (24 weeks), open-label extension (OLE, 24 weeks), and long-term extension (LTE) period (96 weeks). 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.
Results: The purpose of the study is to evaluate the safety, tolerability, and dystrophin levels in muscle following multiple doses of DYNE-251. The study will enroll ~46 boys across 7 cohorts – 0.7, 1.4, 2.8, 5, 10, 20, and 40 mg/kg approximate PMO equivalent doses of DYNE-251. Participants will be randomized in a 2:1 or in a 3:1 ratio of DYNE-251 to placebo administered every 4 weeks during the MAD/placebo-controlled period. All participants will receive the highest safe and tolerable dose during the OLE and LTE periods.
Conclusions: This study will inform further development of DYNE-251 for the treatment of DMD.