Duchenne muscular dystrophy (DMD) is a X-linked muscular disease caused by mutations in the DMD gene that prevent the expression of a functional dystrophin protein. Dystrophin protein expression can often be restored through oligonucleotide-mediated skipping of individual DMD exons to restore the reading frame. Although several oligonucleotides targeting different exons have been approved, their clinical efficacy is limited due to poor muscle delivery. Avidity has developed a transferrin receptor 1 (TfR1) antibody-based technology that can overcome this delivery issue. We have previously demonstrated that antibody-oligonucleotide conjugates (AOCs) can achieve substantial exon 23 skipping, dystrophin protein restoration, and muscle function improvement in mdx mice, a model of DMD.
AOC 1044 is Avidity’s clinical candidate for DMD patients amenable to exon 44 skipping. In non-human primates, treatment with AOC 1044 was well tolerated and resulted in up to 11% exon 44 skipping in skeletal muscle at the highest dose tested. To evaluate the in vivo efficacy of the PMO component, an AOC 1044 surrogate molecule with a mouse TfR1 antibody was used in a humanized DMD/mdx mouse, containing the human DMD gene with exon 45 deletion that is amenable to exon 44 skipping. Dose-dependent exon skipping activity and dystrophin restoration in skeletal muscle and heart were observed for at least 4 weeks after a single intravenous dose of the surrogate molecule. Dystrophin protein levels in gastrocnemius and heart increased by up to 10% and 5% of the wild-type animals’ dystrophin, respectively. Importantly, AOC treatment also improved serum biomarkers of muscle damage (CK, ALT, AST) to control levels, suggesting a functional improvement in muscle physiology.
These data supported the evaluation of AOC 1044 in the Phase 1/2 EXPLORE44 trial in DMD patients amenable to exon 44 skipping.