Duchenne Agent AOC 1044 Demonstrates Significant Delivery of PMO Concentrations

Author(s):

AOC 1044 was well-tolerated in healthy volunteers, delivering dose-dependent increases in PMO concentrations in skeletal muscle following administration.

Sarah Boyce

New topline data from the phase 1/2 EXPLORE44 trial (NCT05670730) showed that AOC 1044 (Avidity Biosciences) was safe among healthy volunteers and delivered 50-times greater concentrations of phosphorodiamidate morpholino oligomers (PMO) in skeletal muscle following administration. The company plans to announce additional data from the study in the second half of 2024, featuring patients with Duchenne muscular dystrophy amenable to exon 44 skipping (DMD44).¹

EXPLORE44, a randomized, placebo-controlled, double-blind study, evaluates the efficacy and safety of AOC 1044 in healthy volunteers and patients with DMD44. In a cohort of approximately 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 peptide 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. The investigational therapy, which has received orphan drug and fast track designations from the FDA, was well tolerated in healthy volunteers, with all treatment-emergent adverse events (TEAEs) considered mild to moderate. There were no reports of symptomatic hemoglobin changes, no hypomagnesemia, and no renal events.

"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," Sarah Boyce, president and chief executive officer, Avidity, said in a statement.¹ "We are rapidly advancing AOC 1044 and look forward to sharing data in people living with DMD44 in 2024. Data from our clinical programs continue to reinforce the broad and disruptive potential of our AOC platform for the treatment of high burden muscle diseases like DMD, DM1 and FSHD."

EXPLORE44, designed to assess exon skipping and dystrophin protein levels of patients treated with AOC 1044, includes approximately 24 participants with DMD44, ages 7-27 years old. Coming into the study, patients must be clinically diagnosed or have a clear onset of DMD symptoms before the age of 6 years old. Following the completion of the double-blind period, patients will have an option to enroll into an open-label extension study.

Avidity’s proprietary AOCs were developed in combination with the specificity of monoclonal antibodies and the precision of oligonucleotide therapies to directly address the causes of diseases that were previously untreatable using RNA therapeutics. In DMD, the condition is driven by a genetic mutation, preventing the body from the production of the dystrophin protein. Therefore, the lack of functional dystrophin can lead to stress and tears of muscle cell membranes, which then ultimately results in muscle cell death, inflammation, and progressive loss of muscle function. Hence, AOC 1044 aims to deliver PMOs to skeletal muscle and heart tissue, causing exon 44 of the dystrophin gene to be skipped and enabling the production of functional dystrophin protein.

In addition to AOC 1044, Avidity has advanced its other proprietary agent AOC 1001 in the MARINA open-label extension (OLE) study for patients with myotonic dystrophy type 1. MARINA was a double-blind, placebo-controlled study in which 38 patients with DM1 were assigned 3:1 to either 1 dose of 1 mg/kg of AOC 1001, 3 doses of either 2 mg/kg of AOC 1001 or 4 mg/kg of AOC 1001, or placebo. All 37 participants completed the double-blind portion entered the OLE, where they received either 2 or 4 mg/kg of AOC 1001.

At the recently concluded 28th Annual Congress of the World Muscle Society, new data from the OLE of MARINA highlighted the therapy’s safety profile. With over 200 infusions of AOC 1001 totaling 46.2 patient-years of exposure, the most common AEs were procedural pain (22%) and pain in extremity and headache (16%). Of note, there were no discontinuations during the OLE and no reports of anemia. In the MARINA clinical program, anemia has been asymptomatic except for 1 participant who did not require treatment. In addition, there was 1 resolved AE of mild increase in liver enzymes.²

REFERENCES
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 13, 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
2. Johnson N, Day J, Hamel J, et al. Topline safety and efficacy data analysis of phase 1/2 clinical trial evaluating AOC 1001 in adults with myotonic dystrophy type 1: MARINA. Presented at: World Muscle Society 2023; October 3-7; Charleston, SC.