Mechanism and Promise Behind Del-Zota for Duchenne Muscular Dystrophy: Michael Flanagan, PhD

WATCH TIME: 3 minutes

"Our AOC technology combines an antibody with a PMO (phosphorodiamidate morpholino oligo), leveraging the transferrin receptor to piggyback on the body's natural transport mechanisms. This allows us to deliver the PMO into muscle cells, including skeletal, smooth, and cardiac muscle, where it skips defective exons and restores near-full-length dystrophin protein."

Duchenne muscular dystrophy (DMD) is a severe X-linked genetic disorder caused by mutations in the DMD gene, which encodes dystrophin–a critical protein for muscle fiber stability. Delpacibart zotadirsen, or del-zota (Avidity Biosciences), is an antibody-oligonucleotide conjugate (AOC) comprised of an anti-transferrin receptor 1 (TfR1) antibody conjugated to an exon 44-skipping phosphorodiamidate morpholino conjugate (PMO).

At the 2025 Muscular Dystrophy Association (MDA) Clinical & Scientific conference, held March 16-19, in Dallas, Texas, investigators presented data from part B of the phase 1/2 EXPLORE44 trial (NCT05670730), a randomized, double-blind, placebo-controlled study testing multiple ascending doses of del-zota. A total of 24 patients with DMD were randomly assigned 3:1 to either del-zota or placebo for a treatment period lasting approximately 12 or 16 weeks (dependent upon a 6 or 8 week infusion schedule). All told, results showed that treatment with the agent was safe, and resulted in statistically significant increases in exon skipping and dystrophin production in skeletal muscle, as well as significant reductions in blood creatine kinase levels.

To learn more about the mechanism behind del-zota, NeurologyLive® sat down with Michael Flanagan, PhD, chief scientific officer at Avidity. Flanagan, who has experience in developing therapeutic modalities, also gave commentary on the conduct of the phase 1/2 trial, which included a rigorous design and enrolled both ambulatory and non-ambulatory patients aged 7-27. Furthermore, he spoke on the key end points of the trial, the flexibility of the study, and its open-label extension that will be used for ongoing evaluation.

Click here for more MDA 2025 coverage.

REFERENCE
1. Veerapandiyan A, Eskuri J, Flanigan K, et al. Del-zota produced statistically significant increases in exon skipping and dystrophin levels in EXPLORE44, a Phase 1/2 study in patients with DMD44. Presented at: 2025 MDA Clinical & Scientific conference; March 16-19; ABSTRACT 072