Avidity Biosciences announced that the U.S. Food and Drug Administration has granted Breakthrough Therapy designation to delpacibart zotadirsen (del-zota) for treating Duchenne muscular dystrophy (DMD) in patients with mutations amenable to exon 44 skipping (DMD44). The designation underscores the FDA's recognition of del-zota's potential to address the underlying cause of this rare genetic condition affecting approximately one in 3,500 to 5,000 boys born worldwide.
Novel Therapeutic Approach Shows Promise
Del-zota represents the first of multiple Antibody Oligonucleotide Conjugates (AOCs) that Avidity is developing for DMD. The therapy is designed to deliver phosphorodiamidate morpholino oligomers (PMOs) to skeletal muscle and heart tissue, specifically targeting exon 44 of the dystrophin gene to enable production of near-full length dystrophin protein.
"Breakthrough Therapy designation further underscores the FDA's appreciation for the significant potential of del-zota to address the underlying cause of DMD44 and the urgent need to bring innovative treatment options to the DMD community," said Steve Hughes, M.D., chief medical officer at Avidity.
Strong Clinical Trial Results Drive Regulatory Recognition
The FDA's decision was based on compelling data from the completed Phase 1/2 EXPLORE44 trial, which enrolled 26 participants with DMD44. Del-zota demonstrated statistically significant increases in exon skipping, a substantial increase in dystrophin production, and a significant and sustained reduction in creatine kinase levels to near normal. The therapy also showed consistent favorable safety and tolerability profiles.
The EXPLORE44 trial was a randomized, placebo-controlled, double-blind study designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of single and multiple ascending doses of del-zota administered intravenously.
Ongoing Phase 2 Extension Study
Del-zota is currently being assessed in the Phase 2 EXPLORE44 Open-Label Extension (EXPLORE44-OLE) trial, which has completed enrollment with 39 participants total—23 from the original Phase 1/2 trial and 16 new enrollees. Participants receive 5 mg/kg of del-zota every six weeks for approximately 24 months, with a three-month safety follow-up period.
Avidity plans to present topline and functional data from the ongoing EXPLORE44-OLE trial in the fourth quarter of 2025, with the company remaining on track for a planned Biologics License Application submission at year-end 2025.
Addressing Critical Unmet Medical Need
Duchenne muscular dystrophy causes progressive muscle damage and weakness due to the loss of dystrophin protein, typically starting at a very young age. The dystrophin protein maintains muscle fiber integrity and acts as a shock absorber, connecting inner and outer elements of muscle cells. Patients with DMD suffer from progressive muscle weakness, eventually developing problems with walking and breathing as heart and respiratory muscles deteriorate.
Del-zota consists of a proprietary monoclonal antibody that binds to the transferrin receptor 1 (TfR1) conjugated with a PMO targeting exon 44. This approach combines the specificity of monoclonal antibodies with the precision of oligonucleotide therapies to address targets previously unreachable with existing RNA therapies.
Comprehensive Regulatory Support
In addition to the Breakthrough Therapy designation, del-zota has received multiple regulatory designations recognizing its potential impact. The FDA has previously granted Orphan designation, Rare Pediatric Disease designation, and Fast Track designation for DMD44 treatment. The European Medicines Agency has also granted Orphan designation.
Breakthrough Therapy designation is designed to expedite development and review of drugs intended to treat serious conditions where preliminary clinical evidence indicates the drug may demonstrate substantial improvement over available therapy on clinically significant endpoints.
Commercial Preparations Underway
Avidity's commercial preparations for a potential U.S. launch of del-zota in DMD44 following FDA approval are already underway. The anticipated launch would establish the foundation for potential sequential launches of Avidity's additional neuromuscular programs, including del-desiran for myotonic dystrophy type 1 (DM1) and del-brax for facioscapulohumeral muscular dystrophy (FSHD).
The company's proprietary AOC platform has demonstrated the first-ever successful targeted delivery of RNA into muscle tissue, positioning Avidity as a leader in developing treatments for rare neuromuscular diseases that have historically been difficult to address with conventional therapies.
