Clinical Potential of AOC 1044 in Treating Duchenne Muscular Dystrophy Amenable to Exon 44 Skipping

Steve Hughes, MD

Duchenne muscular dystrophy (DMD), a neuromuscular disorder, causes a lack of functional dystrophin that leads to stress and tears of muscle cell membranes, resulting in muscle cell death and the progressive loss of muscle function. It is the most common hereditary neuromuscular disease and does not exhibit a predilection for any race or ethnic group. This genetic disease is inherited as an X-linked recessive trait; however, approximately 30% of cases are because of new mutations.

Avidity Biosciences has been developing a new class of RNA therapeutics–Antibody Oligonucleotide Conjugates (AOCs), that combine the specificity of monoclonal antibodies with the precision of oligonucleotide therapies to treat diseases that were previously unreachable with existing RNA therapies. One of its agents, AOC 1044, is designed to deliver phosphorodiamidate morpholino oligomers (PMOs) to skeletal muscle and heart tissue to specifically skip exon 44 of the dystrophin gene to enable dystrophin production in patients with DMD with mutations amenable to exon 44 skipping.

AOC 1044 is currently being assessed in EXPLORE44, a randomized, placebo-controlled, double-blind phase 1 trial comprised of healthy volunteers and patients with DMD44. In recently announced topline data of 40 healthy volunteers, AOC 1044 delivered unprecedented, dose-dependent increases in PMO concentrations in skeletal muscle following a single dose of 5 mg/kg or 10 mg/kg, which were significantly greater when compared with a single dose of conjugated PMOs. At day 29, patients treated with a single dose of 10 mg AOC 1044 demonstrated statistically significant exon 44 skipping of up to 1.5% in comparison with placebo.

To gain greater insights on the trial and the topline data, NeurologyLive® reached out to Steve Hughes, MD, chief medical officer at Avidity. Hughes provided answers on his reaction to the data, the significance of delivering PMO, and whether a specific dosage of AOC 1044 will prove to be more effective in treating DMD.

NeurologyLive^®: What was your reaction to this initial data? What should neurologists take from this readout?

Steve Hughes, MD: We are excited with the early data set of AOC 1044 demonstrating unprecedented delivery of therapeutic oligonucleotide in skeletal muscle and consistent exon skipping in healthy volunteers from the Phase 1/2 EXPLORE44™ clinical trial for the treatment of Duchenne muscular dystrophy mutations amenable to exon 44 skipping (DMD44). 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.

Data also showed that 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. These data reinforce the broad and disruptive potential of our proprietary AOC platform to treat high burden diseases such as DMD44.

Describe the significance of delivering PMO? What exactly does this do for patients?

AOC 1044 is designed to deliver PMO to skeletal muscle and heart tissue to specifically skip exon 44 of the dystrophin gene to enable dystrophin production in those living with Duchenne muscular dystrophy with mutations amenable to exon 44 skipping (DMD44). With unprecedented increases in PMO concentrations in skeletal muscle following a single dose of 5 mg/kg or 10 mg/kg of AOC 1044, we have shown that AOC 1044 can effectively deliver PMO to muscle. It is the effective delivery to muscle that enables increased exon skipping, which was demonstrated in all healthy volunteers given AOC 1044.

How does AOC 1044 work? What makes its mechanism of action attractive for patients with DMD amenable to exon 44 skipping?

AOC 1044 was developed using our proprietary Antibody Oligonucleotide Conjugates (AOCs™) platform and is designed to deliver PMO to skeletal muscle and heart tissue to specifically skip exon 44 of the dystrophin gene to enable dystrophin production for people living with DMD amenable to exon 44 skipping.

DMD causes a lack of functional dystrophin that leads to stress and tears of muscle cell membranes, resulting in muscle cell death and the progressive loss of muscle function. The dystrophin protein maintains the integrity of muscle fibers and acts as a shock absorber through its role as the foundation of a group of proteins that connects the inner and outer elements of muscle cells. People living with DMD suffer from progressive muscle weakness that typically starts at a very young age. While there are treatments approved to treat people with DMD, there remains a very high unmet need.

In the first part of the EXPLORE44 study which was conducted in healthy volunteers, AOC 1044 was well tolerated, demonstrated statistically significant exon 44 skipping compared to placebo of up to 1.5% after a single dose of 10 mg/kg AOC 1044 and increased exon skipping in all participants. It is our hope that AOC 1044 will enable dystrophin production for people living with DMD amenable to exon 44 skipping. AOC 1044 is the first of multiple AOCs that Avidity is developing for DMD.

Do we believe that one dose will be more preferred/effective than the other?

The Phase 1/2 EXPLORE44 clinical trial is a dose-escalation study, which means that we will look at the data from multiple different dose levels and determine the dose that we would like to move forward with. The data reported from both the 5 mg/kg and 10 mg/kg doses of AOC 1044 are very encouraging.

What are the future plans for this drug?

We continue to advance AOC 1044 in the Phase 1/2 EXPLORE44 trial and look forward to sharing data in people living with DMD amenable to 44 skipping in the second half of 2024. AOC 1044 is the first of multiple AOCs that Avidity is developing for DMD.

REFERENCE
1. Avidity Biosciences reports positive data demonstrating AOC 1044 delivers unprecedented concentrations of PMO in muscle following a single dose in healthy volunteers from phase 1/2 EXPLORE44 trial for Duchenne muscular dystrophy. News release. Avidity Biosciences. December 13, 2023. Accessed December 21, 2023. https://www.prnewswire.com/news-releases/avidity-biosciences-reports-positive-data-demonstrating-aoc-1044-delivers-unprecedented-concentrations-of-pmo-in-muscle-following-a-single-dose-in-healthy-volunteers-from-phase-12-explore44-trial-for-duchenne-muscular-dystrophy-302013456.html