Abstract Details

Duchenne muscular dystrophy (DMD) is caused by absence of functional dystrophin protein. Approved PMO therapies induce exon skipping to restore the DMD mRNA reading frame leading to the production of truncated, functional dystrophin, but their potential is limited by poor muscle delivery. DYNE-251, an investigational therapeutic for DMD, consists of an exon 51-skipping PMO conjugated to a TfR1-targeting Fab to deliver increased levels of PMO to muscles.

Determine the safety and efficacy of DYNE-251 in ambulant and non-ambulant males aged 4-16 with DMD mutations amenable to exon 51 skipping (Phase 1/2 DELIVER trial, NCT05524883).

In the MAD portion of DELIVER, participants are randomized to receive DYNE-251 or placebo Q4W for 6 months across 7 PMO dose levels up to 40 mg/kg. For analysis of exon skipping and dystrophin data from the 5 mg/kg cohort, 4 participants received DYNE-251 and 2 received placebo. Safety and tolerability are based on 37 participants enrolled in DELIVER as of the data cutoff date.

At 6 months, 5 mg/kg DYNE-251 showed a mean 657 ng/g PMO concentration in muscle and mean absolute exon skipping level of 0.90% (0.80% difference from baseline). Mean absolute dystrophin level, measured by Western blot, increased from 0.60% at baseline to 0.88% of normal at 6 months, and the mean level of dystrophin positive fibers (PDPF) increased from 2.4% at baseline to 22.2% at 6 months. As of the data cut-off date, DYNE-251 demonstrated a favorable safety profile with mostly mild or moderate TEAEs. There was no treatment-emergent anemia or clinically meaningful changes in kidney parameters or electrolytes.

Based on these initial data, DYNE-251 had a favorable safety profile and reached levels of dystrophin expression, exon skipping, and PDPF at 6 months that exceeded levels reported at the same time point in prior clinical trials evaluating the standard of care PMO.