delpacibart zotadirsen (AOC-1044) / Eli Lilly, Avidity Biosci - LARVOL DELTA

EXPLORE44OLE: Ph2 Open-label Study of AOC 1044 in Duchenne Muscular Dystrophy Participants With Mutations Amenable to Exon44 Skipping (clinicaltrials.gov) - P2 | N=39 | Active, not recruiting | Sponsor: Avidity Biosciences, Inc. | Trial completion date: Dec 2026 ➔ Jul 2027 | Trial primary completion date: Dec 2025 ➔ Apr 2027

Trial completion date • Trial primary completion date • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

AOC 1044 induces exon 44 skipping and restores dystrophin protein in preclinical models of Duchenne muscular dystrophy. (PubMed, Nucleic Acids Res) - "We developed AOC 1044, an antibody-oligonucleotide conjugate (AOC) that combines a PMO-targeting exon 44 with an antibody against the transferrin receptor (TfR1), enhancing delivery to muscle tissues for patients with DMD amenable to exon 44 skipping (DMD44)...In nonhuman primates, single or repeated AOC 1044 doses resulted in dose-dependent increases in PMO concentration and exon 44 skipping across a range of muscle tissues, including the heart. Collectively, these findings highlight AOC 1044 as a promising therapeutic candidate for patients with DMD44, offering improved muscle targeting and meaningful dystrophin restoration, with potential clinical benefits in reducing muscle degeneration."

Journal • Preclinical • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy • TFRC

Avidity Biosciences Announces Positive Topline Del-zota Data Demonstrating Consistent, Statistically Significant Improvements in Dystrophin, Exon Skipping and Creatine Kinase in People Living with Duchenne Muscular Dystrophy Amenable to Exon 44 Skipping in Phase 1/2 EXPLORE44 Trial (PRNewswire) - P1/2 | N=70 | EXPLORE44 (NCT05670730) | P2 | N=35 | EXPLORE44OLE (NCT06244082) | Sponsor: Avidity Biosciences, Inc. | "'...we believe dystrophin data from EXPLORE44 combined with the safety data from our fully enrolled EXPLORE44-OLE trial will support our planned BLA submission at the end of this year.'...Safety and tolerability data were assessed from 26 participants in the completed Phase 1/2 EXPLORE44 trial and 38 participants in the ongoing EXPLORE44 Open-Label Extension (OLE) trial...Targeted delivery of PMOs resulting in tissue concentrations of approximately 200nM in skeletal muscle; Statistically significant increases of approximately 40% in exon 44 skipping; Statistically significant increase of approximately 25% of normal in dystrophin production and restored total dystrophin up to 58% of normal...Significant reductions in creatine kinase levels were sustained in the EXPLORE44-OLE trial with continued treatment up to one year."

P1/2 data • P2 data • Duchenne Muscular Dystrophy

Avidity Biosciences Announces Upcoming Presentations at the Muscular Dystrophy Association (MDA) Clinical & Scientific Conference (PRNewswire) - "Avidity Biosciences, Inc...today announced that the company will be presenting one oral and two poster presentations at the 2025 MDA Clinical & Scientific Conference (MDA) in Dallas, Texas, being held March 16-19, 2025 and will host an investor and analyst webcast event on March 17, 2025....Aravindhan Veerapandiyan, MD, Associate Professor of Pediatrics, University of Arkansas for Medical Sciences and Arkansas Children's Hospital and EXPLORE44 trial investigator, will present topline del-zota data from Phase 1/2 EXPLORE44 trial at 2025 MDA Clinical & Scientific Conference in Dallas, Texas."

Clinical protocol • P1/2 data • Duchenne Muscular Dystrophy • Myotonic Dystrophy

EXPLORE44: Study of AOC 1044 in Healthy Adult Volunteers and Participants with Duchenne Muscular Dystrophy (DMD) Mutations Amenable to Exon 44 Skipping (clinicaltrials.gov) - P1/2 | N=70 | Completed | Sponsor: Avidity Biosciences, Inc. | Active, not recruiting ➔ Completed

Trial completion • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Avidity Biosciences Reports Fourth Quarter 2024 Financial Results and Recent Highlights (PRNewswire) - "Delpacibart zotadirsen (del-zota) for the treatment of DMD44: Planned BLA submission year end 2025....Presentation of topline data from the EXPLORE44 trial (Q1). Presentation of topline data from the ongoing EXPLORE44-OLE trial (Q4). Delpacibart etedesiran (del-desiran) for the treatment of myotonic dystrophy type 1 (DM1)...Publication of data analyses from the completed Phase 1/2 MARINA trial (2025)....Research and Development (R&D) Expenses: These expenses were $95.6 million for the fourth quarter of 2024 compared with $52.8 million for the fourth quarter of 2023, and $303.6 million for the year ended 2024 compared with $191.0 million for the year ended 2023. The increases were primarily driven by the advancement of del-desiran, del-brax and del-zota, as well as internal and external costs related to the expansion of the company's overall research capabilities."

Commercial • FDA filing • P1/2 data • P2 data • Duchenne Muscular Dystrophy • Muscular Dystrophy • Myotonic Dystrophy

EXPLORE44OLE: Ph2 Open-label Study of AOC 1044 in Duchenne Muscular Dystrophy Participants with Mutations Amenable to Exon44 Skipping (clinicaltrials.gov) - P2 | N=35 | Active, not recruiting | Sponsor: Avidity Biosciences, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

EXPLORE44OLE: Ph2 Open-label Study of AOC 1044 in Duchenne Muscular Dystrophy Participants with Mutations Amenable to Exon44 Skipping (clinicaltrials.gov) - P2 | N=35 | Recruiting | Sponsor: Avidity Biosciences, Inc. | Enrolling by invitation ➔ Recruiting | N=24 ➔ 35

Enrollment change • Enrollment status • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

EXPLORE44: Study of AOC 1044 in Healthy Adult Volunteers and Participants with Duchenne Muscular Dystrophy (DMD) Mutations Amenable to Exon 44 Skipping (clinicaltrials.gov) - P1/2 | N=64 | Active, not recruiting | Sponsor: Avidity Biosciences, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Phase 1/2 Trial Evaluating AOC 1044 in Healthy Volunteers and Participants with DMD Mutations Amenable to Exon 44 Skipping (DMD44): EXPLORE44 Trial Design (AAN 2024) - P1/2 | "AOC 1044 is an antibody-oligonucleotide conjugate (AOCTM) comprised of a humanized anti-transferrin receptor 1 (TfR1) antibody conjugated to multiple copies of a phosphorodiamidate morpholino oligomer (PMO) targeting DMD44 mRNA to produce truncated but functional dystrophin protein.Design/EXPLORE44TM (NCT05670730) is a randomized, placebo-controlled, double-blind phase 1/2 trial conducted in two parts...N/A"

Clinical • P1/2 data • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy • TFRC

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 (PRNewswire) - "Avidity Biosciences, Inc...announced that the U.S. Food and Drug Administration (FDA) has granted Rare Pediatric Disease designation to AOC 1044, the company's investigational therapy for the treatment of Duchenne muscular dystrophy (DMD) in people living with mutations amenable to exon 44 skipping (DMD44). AOC 1044 is being assessed in the Phase 1/2 EXPLORE44 trial for people living with DMD44 and is the first of multiple AOCs the company is developing for DMD."

FDA event • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

AOC 1044 as a Novel Therapeutic Approach for DMD Patients Amenable to Exon 44 Skipping: EXPLORE44 Phase 1/2 Healthy Volunteer Data (MDA 2024) - P1/2 | "These data represent the first-in-human experience using an AOC to deliver PMOs to muscle. Persistently high levels of PMO and exon skipping on Day 29 support the potential for AOC 1044 to result in accumulation of exon 44-skipped transcripts and dystrophin protein in DMD patients over an extended dosing interval. These results are supported by nonclinical data in humanized exon 44 skip-amenable DMD/mdx mice demonstrating dose-dependent exon skipping and dystrophin restoration in skeletal and cardiac muscle as well as efficient PMO delivery and exon 44 skipping in non-human primates."

Clinical • P1/2 data • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy • TFRC

EXPLORE44OLE: Ph2 Open-label Study of AOC 1044 in Duchenne Muscular Dystrophy Participants With Mutations Amenable to Exon44 Skipping (clinicaltrials.gov) - P2 | N=24 | Enrolling by invitation | Sponsor: Avidity Biosciences, Inc.

New P2 trial • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

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 (PRNewswire) - "Avidity Biosciences, Inc...today announced that the U.S. Food and Drug Administration (FDA) has granted Orphan Drug designation to AOC 1044, the company's investigational therapy in development for the treatment of Duchenne muscular dystrophy (DMD) in people with mutations amenable to exon 44 skipping (DMD44)."

Orphan drug • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Phase 1/2 trial evaluating AOC 1044 in healthy volunteers and participants with DMD mutations amenable to exon 44 Skipping: EXPLORE44 Trial Design (WMS 2023) - No abstract available

Clinical • P1/2 data

EXPLORE44: Study of AOC 1044 in Healthy Adult Volunteers and Participants With Duchenne Muscular Dystrophy (DMD) Mutations Amenable to Exon 44 Skipping (clinicaltrials.gov) - P1/2 | N=64 | Recruiting | Sponsor: Avidity Biosciences, Inc.

New P1/2 trial • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Durable AOC mediated exon 44 skipping in non-human primate muscle tissue and dystrophin protein restoration in DMD patient derived skeletal muscle cells (WMS 2022) - "In patient-derived DMD skeletal muscle cells, PMO44 (the PMO component of AOC 1044), produced concentration-dependent exon 44 skipping and robust restoration of dystrophin protein as well as restoration of the machinery responsible for muscle contraction/relaxation, indicating that the resulting dystrophin was functionally active in human disease cells. These data support the development of AOC 1044 for the treatment of DMD."

Clinical • CNS Disorders • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Avidity Biosciences Announces 2021 Pipeline Updates and Research Collaboration with MyoKardia (PRNewswire) - "In 2H 2021, Avidity plans to initiate a Phase 1/2 clinical study of AOC 1001 in adults with myotonic dystrophy type 1 (DM1)....AOC DMD is a therapeutic program in development for the treatment of Duchenne muscular dystrophy (DMD). Avidity has expanded its efforts for this indication and is now advancing three programs for DMD which target different mutations that are amenable to skipping, including Exon 44, Exon 51 and Exon 45....In 2022, Avidity plans to submit a regulatory filing to support a clinical trial."

New P1/2 trial • New trial • Duchenne Muscular Dystrophy • Myotonic Dystrophy