Background: Duchenne muscular dystrophy (DMD) is an X-linked muscular disease caused by mutations in the DMD gene that prevent expression of a functional dystrophin protein.
Avidity’s antibody-oligonucleotide conjugate (AOC) technology is designed to optimize the delivery of oligonucleotides to muscle tissue. AOC 1044 is comprised of a humanized anti-transferrin receptor 1 (TfR1) antibody conjugated to multiple copies of exon 44-skipping phosphorodiamidate morpholino oligomers (PMOs) to restore the reading frame and result in the production of dystrophin protein.
Design/Objectives: Part A of the Phase 1/2 EXPLORE44 (NCT05670730) trial is a randomized, placebo-controlled, double-blind study assessing the safety, tolerability, pharmacokinetics, and exon skipping of single-ascending doses of AOC 1044 in healthy male volunteers (HVs).
Results: 44 HVs (18-55 years) will be randomized 3:1 in 5 ascending-dose cohorts to receive a single dose of AOC 1044 or placebo. Safety and tolerability were monitored for three months. Initial HV data indicates that AOC 1044 has an acceptable safety and tolerability profile.
Conclusion: These data represent the first-in-human experience using an AOC to deliver PMOs to muscle. Persistently high levels of PMO and exon skipping on Day 29 support the potential for AOC 1044 to result in accumulation of exon 44-skipped transcripts and dystrophin protein in DMD patients over an extended dosing interval. These results are supported by nonclinical data in humanized exon 44 skip-amenable DMD/mdx mice demonstrating dose-dependent exon skipping and dystrophin restoration in skeletal and cardiac muscle as well as efficient PMO delivery and exon 44 skipping in non-human primates. Collectively, these data support the continued evaluation of AOC 1044 in Part B of the Phase 1/2 EXPLORE44 trial in DMD patients amenable to exon 44 skipping.