Exon 44 Skipping Agent AOC 1044 Granted FDA Orphan Drug Designation for Duchenne Muscular Dystrophy

Steve Hughes, MD

Recently, the FDA granted orphan drug designation to Avidity Biosciences’ AOC 1044, an investigational therapy in development for the treatment of Duchenne muscular dystrophy (DMD) in patients with mutations amenable to exon 44 skipping (DMD44).¹ The therapy is being assessed in the phase 1/2 EXPLORE44 trial (NCT05670730) with results from the healthy volunteer portion of the trial expected to come in the fourth quarter of 2023.

AOC 1044, a proprietary monoclonal antibody, binds the transferrin receptor 1 conjugated with a phosphorodiamidate morpholino oligomers (PMOs) targeting exon 44. In a preclinical model using the therapy, a murine active AOC created durable exon skipping and functional dystrophin protein in skeletal muscle and heart tissue after a single intravenous dose. Earlier this year, the agent received FDA fast track designation for the treatment of DMD44, further validating its the potential in this patient population.²

“It is very encouraging to receive FDA fast track designation as it further validates the potential of AOC 1044 to target the underlying cause of DMD44 and the importance of bringing people living with this devastating disease an effective treatment option. This recognition also means that now all three of our clinical-stage programs have Fast Track status, further reinforcing our efforts to make a profound difference in people's lives," Steve Hughes, MD, chief medical officer at Avidity said in a statement at the time.² "We will continue to work closely with the FDA as we advance AOC 1044 and look forward to the anticipated data readout from the healthy volunteer portion of our phase 1/2 EXPLORE44 clinical trial later this year."

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EXPLORE44 is a randomized, placebo-controlled, double-blind, phase 1/2 trial evaluating AOC 1044 among healthy volunteers and patients with DMD44. The trial plans to assess the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of single and multiple ascending doses of the therapy, administered intravenously. EXPLORE44, anticipated to have approximately 40 healthy volunteers and 24 patients with DMD44 enrolled between the ages of 7 and 27 years old, will primarily focus on exon skipping and dystrophin protein levels in treated patients, who will have the option to enroll into an extension study upon completion of the double-blind period.

The company’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.

"We are pleased that the FDA has granted both Orphan Drug and Fast Track designation to AOC 1044, highlighting the importance of advancing new treatments for patients living with DMD," Hughes said based on the recent news in a statement.¹ "There are currently no treatment options that target the underlying cause of DMD44. AOC 1044 is designed to specifically skip exon 44 of the dystrophin gene to enable the production of functional dystrophin protein. We look forward to advancing AOC 1044 in clinical development and bringing this very important treatment to patients as quickly and safely as possible."

REFERENCES
1. Avidity Biosciences Receives FDA Orphan Drug Designation for AOC 1044 for Treatment of Duchenne Muscular Dystrophy in People with Mutations Amenable to Exon 44 Skipping. News Release. Avidity Biosciences. Published August 15, 2023. Accessed August 15, 2023. https://www.prnewswire.com/news-releases/avidity-biosciences-receives-fda-orphan-drug-designation-for-aoc-1044-for-treatment-of-duchenne-muscular-dystrophy-in-people-with-mutations-amenable-to-exon-44-skipping-301900264.html#:~:text=(Nasdaq%3A%20RNA)%2C%20a,company's%20investigational%20therapy%20in%20development
2. Avidity Biosciences Granted FDA Fast Track Designation for AOC 1044 for Treatment of Duchenne Muscular Dystrophy Mutations Amenable to Exon 44 Skipping. News Release. Avidity Biosciences. Published April 24, 2023. Accessed August 15, 2023. https://www.prnewswire.com/news-releases/avidity-biosciences-granted-fda-fast-track-designation-for-aoc-1044-for-treatment-of-duchenne-muscular-dystrophy-mutations-amenable-to-exon-44-skipping-301804651.html