Michael Flanagan, PhD, on Del-Zota for Duchenne Muscular Dystrophy
The chief scientific officer at Avidity Biosciences discussed the function and mechanism of the investigational antisense treatment, which is in development for DMD amenable to exon 44 skipping.
"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."
In humans, the DMD gene codes for dystrophin, a protein critical for muscle fiber stability. Duchenne muscular dystrophy (DMD), a severe X-linked disorder, results from genetic mutations in DMD. Among the many therapeutics currently in development with the intent of treating DMD is Avidity Biosciences' antibody-oligonucleotide conjugate (AOC) delpacibart zotadirsen (also known as del-zota), which consists of an anti-transferrin receptor 1 (TfR1) antibody conjugated to an exon 44-skipping phosphorodiamidate morpholino conjugate (PMO). Del-zota is currently being evaluated in the phase 1/2 EXPLORE44 trial (NCT05670730), which is assessing multiple ascending doses of del-zota.
Notably, results from part B of the randomized, double-blind, placebo-controlled study were recently presented at the 2025 Muscular Dystrophy Association (MDA) Clinical & Scientific conference, held March 16 to 19, in Dallas, Texas. The trial randomly assigned 24 patients with DMD in a 3:1 ratio to receive either the AOC or a placebo. The treatment period spanned about 12 or 16 weeks, depending on a 6 or 8 week infusion schedule. Treatment with the agent was found to be safe, and effected statistically significant increases in exon skipping and dystrophin production in skeletal muscle, along with significant decreases in creatine kinase levels in the blood.
At the conference, NeurologyLive® sat down with Michael Flanagan, PhD, the chief scientific officer at Avidity, to learn more about the mechanism behind del-zota. 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 nonambulatory 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
Roadblocks Faced by Gene Therapies for Muscular Dystrophies
March 14th 2025John Brandsema, MD, a pediatric neurologist in the Division of Neurology at Children’s Hospital of Philadelphia, offered insights into the obstacles the clinical community is facing around integrating gene therapies into clinical practice.
