Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is a rare, genetic condition that is characterized by progressive muscle damage and weakness. It is caused by a genetic mutation that prevents the body from producing a protein called dystrophin, which is an important protein that protects muscle cells from injury during contraction. The lack of functional dystrophin leads to stress and tears of muscle cell membranes, resulting in muscle cell death and progressive loss of muscle function. Those living with the condition often require special aid and assistance throughout their lives and have significantly shortened life expectancy. DMD is a monogenic, X-linked, recessive disease that primarily affects males, with 1 in 3,500 to 5,000 boys born worldwide having Duchenne.

We are developing AOCs to treat the underlying cause of DMD. The oligonucleotides in our AOCs for treatment of DMD are designed to promote the skipping of specific exons to allow the production of the dystrophin gene product in patients with DMD. In preclinical studies, we observed that treatment of an mdx mouse, a widely used animal model for DMD, with an AOC caused a greater than 50-fold increase in exon skipping compared to an equimolar dose of the unconjugated oligonucleotide.

DMD Exons Amenable to Skipping:

Several DMD exons are amenable to skipping. Avidity is pursing AOCs for Exons 51, 45 and 44, representing ~30% of mutations amenable to skipping.

AOC 1044

AOC 1044 is designed for people living with DMD amenable to exon 44 (DMD44) and is the first of multiple AOCs we are developing for DMD. Currently, there are no approved therapies to treat the underlying mechanism of disease for people living with DMD 44 skipping. AOC 1044 is designed to deliver phosphorodiamidate morpholino oligomers (PMO) to skeletal muscle and heart tissue to specifically skip exon 44 of dystrophin mRNA to enable dystrophin production. AOC 1044 is currently in Phase 1/2 development as part of the EXPLORE44™ trial in people with DMD44.

In December 2023, Avidity announced positive AOC 1044 data in healthy volunteers from the Phase 1/2 EXPLORE44 trial. AOC 1044 delivered unprecedented concentrations of phosphorodiamidate morpholino oligomers (PMO) in skeletal muscle with up to 50-times greater concentrations of PMO in skeletal muscle following a single dose compared to peptide conjugated PMOs in healthy volunteers. AOC 1044 was well tolerated, demonstrated statistically significant exon 44 skipping compared to placebo of up to 1.5% in healthy volunteers after a single dose of 10 mg/kg AOC 1044 and increased exon skipping in all participants. Avidity plans to provide a first look at AOC 1044 data in people living with DMD44 in second half of 2024. The U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) granted Orphan designation for AOC 1044. The U.S. Food and Drug Administration (FDA) has granted AOC 1044 Rare Pediatric Disease designation and Fast Track designation.

The EXPLORE44™ trial is a randomized, placebo-controlled, double-blind, Phase 1/2 clinical trial to evaluate AOC 1044 in healthy volunteers and participants with DMD mutations amenable to exon 44 skipping (DMD44). EXPLORE44 will evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of single and multiple ascending doses of AOC 1044 administered intravenously. EXPLORE44 is expected to enroll approximately 40 healthy volunteers and 24 participants with DMD44, ages seven to 27 years old. The EXPLORE44 trial will assess exon skipping and dystrophin protein levels in participants with DMD44. Participants with DMD44 will have the option to enroll into an extension study. For more information on this study click here or visit www.clinicaltrials.gov and search for NCT05670730.