FDA Grants Rare Pediatric Disease Designation to Duchenne Agent AOC 1044 for Mutations Amenable to Exon 44 Skipping

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Avidity Biosciences anticipates to provide new cohort data from the phase 1/2 EXPLORE44 trial assessing AOC 1044 in Duchenne muscular dystrophy mutations amenable to exon 44 skipping in the second half of 2024.

Steve Hughes, MD

(Credit: Avidity)

Steve Hughes, MD

(Credit: Avidity)

According to a recent announcement, the FDA has granted rare pediatric disease designation to AOC 1044, Avidity Biosciences’ investigational therapy for the treatment of Duchenne muscular dystrophy (DMD) in patients living with mutations amenable to exon 44 skipping (DMD44).1 The company noted that it is expected to share 5 mg/kg cohort data from the phase 1/2 EXPLORE44 trial (NCT05670730) assessing the therapy in patients with DMD44 in the second half of 2024.2

EXPLORE44 is a randomized, placebo-controlled, double-blind trial comprised of healthy volunteers and patients with DMD44. In December 2023, the company announced topline data from the trial that showed AOC 1044 was safe among healthy volunteers and delivered 50-times greater concentrations of phosphorodiamidate morpholino oligomers (PMO) in skeletal muscle following administration. AOC 1044, a proprietary monoclonal antibody, binds the transferrin receptor 1 conjugated with a PMO targeting exon 44.

"We are pleased that the FDA has granted rare pediatric disease designation to AOC 1044, adding to the orphan drug and fast track designations already granted. The effects of DMD44 are devastating, with symptoms often starting in childhood. These designations by the FDA underscore the urgent need for innovative treatments and validate the potential of AOC 1044 to address the unmet need of patients living with Duchenne muscular dystrophy," Steve Hughes, MD, chief medical officer at Avidity, said in a statement.1

Top Clinical Takeaways

  • AOC 1044 has received rare pediatric disease, orphan drug, and fast track designations from the FDA for treating Duchenne muscular dystrophy (DMD).
  • Early trial results indicate AOC 1044 significantly increased PMO concentrations in skeletal muscle and is well tolerated with mild to moderate adverse events.
  • The promising results and FDA designations underscore the potential of AOC 1044 to meet the urgent need for new treatments for patients with DMD.

READ MORE: FDA Grants Rare Pediatric Disease Designation to DMD Gene Therapy Candidate SGT-003

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 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 recently shared healthy volunteer data of AOC 1044 from our phase 1/2 EXPLORE44 trial demonstrating unprecedented delivery of therapeutic oligonucleotide in skeletal muscle and consistent exon skipping in healthy volunteers, and we look forward to sharing data from that study in patients living with DMD44 later this year. We remain steadfast in our commitment to advancing science and improving the lives of people and their families affected by this devastating condition,” Hughes said in a statement.1

In August 2023, the FDA granted orphan drug designation to AOC 1044 for patients with DMD44.3 Following this news, Hughes sat down with NeurologyLive® to discuss how the EXPLORE44 trial addresses the challenges associated with rare disease treatments, specifically with DMD. He also talked about the significance of FDA orphan drug designation and fast track status for the development of treatments for rare diseases, in particular with AOC 1044. In addition, Hughes elaborated on the 2 phases of EXPLORE44 and how they both will contribute to its potential success.

DMD is a 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 another recent announcement, the FDA has granted breakthrough therapy designation to the company's AOC 1001 for the treatment of myotonic dystrophy type 1 (DM1).4 The therapy, also known as del-desiran, consists of a monoclonal antibody that binds to the transferrin receptor 1 conjugated with a small interfering RNA targeting DMPK mRNA, the underlying cause of DM1.

Sarah Boyce  (Credit: Avidity)

Sarah Boyce

(Credit: Avidity)

"We are pleased that the FDA has granted breakthrough therapy designation to del-desiran for DM1, underscoring the potential of del-desiran to be an effective treatment and the urgency of bringing this treatment to patients living with DM1," Sarah Boyce, president and chief executive officer at Avidity, said in a statement.4 "Initiation is underway for our global phase 3 HARBOR study as we focus on rapidly advancing del-desiran for patients living with DM1, who currently have no treatment options to address the underlying cause of this devastating rare muscle disease."

In March 2024, the company announced additional data from the long-term, open-label extension (OLE) of the phase 2 MARINA trial (NCT05479981) which further highlighted AOC 1001’s potential as a treatment for patients with DM1.5 These results were recently presented at the 2024 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference, held March 3-6, in Orlando, Florida, by lead author John W. Day, MD, PhD, medical advisor and care center director at the MDA.6 The phase 3 HARBOR study, a subsequent trial to MARINA, is expected to initiate in the second quarter of 2024.

HARBOR is expected to include the same key end points as MARINA, with change in video hand opening time as the primary end point, along with secondary outcomes of muscle strength and activities of daily living. The trial, spanning more than 40 global sites, will randomly assign 150 patients to either AOC 1001 4 mg/kg or placebo every 8 weeks for a 54-week treatment period, followed by an OLE. Of note, the primary analysis is expected to cover the first 30 weeks of the study.

REFERENCES
1. Avidity Biosciences Receives FDA Rare Pediatric Disease Designation for AOC 1044 for Treatment of Duchenne Muscular Dystrophy in People with Mutations Amenable to Exon 44 Skipping. News Release. Avidity Biosciences. Published February 20, 2024. Accessed May 16, 2024. https://www.prnewswire.com/news-releases/avidity-biosciences-receives-fda-rare-pediatric-disease-designation-for-aoc-1044-for-treatment-of-duchenne-muscular-dystrophy-in-people-with-mutations-amenable-to-exon-44-skipping-302065520.html
2. Avidity Biosciences Reports First Quarter 2024 Financial Results and Recent Highlights. News Release. Avidity Biosciences. Published May 9, 2024. Accessed May 16, 2024. https://www.prnewswire.com/news-releases/avidity-biosciences-reports-first-quarter-2024-financial-results-and-recent-highlights-302141622.html
3. 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. May 16, 2024. https://aviditybiosciences.investorroom.com/2023-08-15-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
4. Avidity Biosciences Receives FDA Breakthrough Therapy Designation for Delpacibart Etedesiran (AOC 1001) for Treatment of Myotonic Dystrophy Type 1. News Release. Avidity Biosciences. Published May 8, 2024. Accessed May 16, 2024. https://aviditybiosciences.investorroom.com/2024-05-08-Avidity-Biosciences-Receives-FDA-Breakthrough-Therapy-Designation-for-Delpacibart-Etedesiran-AOC-1001-for-Treatment-of-Myotonic-Dystrophy-Type-1
5. Avidity Biosciences announces positive AOC 1001 long-term data showing reversal of disease progression in people living with myotonic dystrophy type 1 across multiple end points; same key endpoints agreed for phase 3 HARBOR study. News release. Avidity Biosciences. March 4, 2024. Accessed May 16, 2024. https://www.prnewswire.com/news-releases/avidity-biosciences-announces-positive-aoc-1001-long-term-data-showing-reversal-of-disease-progression-in-people-living-with-myotonic-dystrophy-type-1-across-multiple-endpoints-same-key-endpoints-agreed-for-phase-3-harbor-trial-302078020.html
6. Johnson N, Day J, Hamel J, et al. Initial results of the phase 2 open-label extension study of AOC 1001 in adults with myotonic dystrophy type 1: MARINA-OLE. Presented at: MDA Clinical and Scientific Conference; March 3-6, 2024; Orlando, FL. POSTER POSTER T307
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