The US Food and Drug Administration (FDA) has granted Breakthrough Therapy designation to delpacibart zotadirsen (del-zota), an investigational treatment for Duchenne muscular dystrophy (DMD) in patients with mutations amenable to exon 44 skipping (DMD44). Developed by Avidity Biosciences, del-zota represents a novel class of RNA therapeutics known as Antibody Oligonucleotide Conjugates (AOCs™), designed to transform treatment options for rare genetic diseases.
DMD is a severe, life-limiting genetic disorder that affects approximately 1 in 5,000 newborn boys. It’s caused by mutations in the dystrophin gene that result in little or no production of functional dystrophin protein, a structural component essential for maintaining muscle fiber integrity. The absence of dystrophin leads to progressive muscle degeneration, heart complications, loss of mobility, and early death.
Since many cases of DMD arise from mutations that disrupt the reading frame of the dystrophin gene, exon-skipping therapies that “skip” faulty sections of the gene during protein production have shown promise in enabling cells to produce a shortened but functional dystrophin protein. However, current therapies have limitations. Four FDA-approved antisense therapies using phosphorodiamidate morpholino oligomers (PMOs) target patients with DMD who are eligible for exon 45, 51, and 53 skipping. However, these therapies achieved only modest increases in dystrophin, with levels typically remaining below one percent of those found in healthy muscles.
A new class of precision RNA therapeutics
A key challenge for PMO therapies is effectively delivering them to muscle tissue, including the heart. AOCs are overcoming this by combining the gene regulatory potential of antisense oligonucleotides with the targeting capabilities of antibodies. This approach enables selective modulation of disease-causing proteins in affected tissues.
Del-zota combines a PMO-targeting exon 44 with an antibody linked to the transferrin receptor. TfR1 is a natural transporter that facilitates iron uptake into muscle cells. By leveraging this pathway, del-zota “piggybacks” into cells, where it releases the PMO. The PMO then traffics to the nucleus, binds pre-mRNA, and initiates exon 44 skipping, restoring dystrophin production.
Achieving effective delivery to both skeletal and cardiac muscle
Although six percent of DMD patients are eligible for exon 44 skipping, no disease-modifying therapy has been approved for this subgroup. Now, with the FDA’s Breakthrough Therapy designation granted to del‑zota, Avidity aims to change that. Del-zota was evaluated in the EXPLORE44® trial, a randomized, placebo-controlled, double-blind, Phase 1/2 clinical trial that enrolled 26 participants with DMD44. Topline results showed unprecedented delivery of PMOs to skeletal muscle, robust increases in dystrophin production, significant increases in exon 44 skipping, and significant and sustained decreases of creatine kinase levels to near normal ranges — an indicator of reduced muscle damage.
Importantly, del-zota demonstrated the ability to restore dystrophin in both skeletal and cardiac muscle. These results highlight the potential of AOC technology to fill a long-standing treatment gap for the DMD44 population, offering a novel therapeutic avenue to improve muscle function and overall quality of life.
Accelerated path forward
"Breakthrough Therapy designation 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.”
- Steve Hughes, Chief Medical Officer at Avidity Biosciences.
The FDA’s Breakthrough Therapy designation is intended to accelerate the development and review of drugs that target serious conditions and show preliminary clinical evidence of substantial improvement over existing therapies on clinically meaningful endpoints. With this designation, del-zota will now enter a more streamlined regulatory path, gaining access to more frequent FDA interactions and potential eligibility for accelerated approval.
"Breakthrough Therapy designation 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, Chief Medical Officer at Avidity Biosciences.
In addition to earning Breakthrough Therapy status, del-zota has previously received Orphan Drug designation from both the FDA and the European Medicines Agency (EMA), as well as Rare Pediatric Disease and Fast Track designations from the FDA, reinforcing its promise as a much-needed treatment for DMD44.
Del-zota is part of Avidity’s broader pipeline leveraging its proprietary AOC™ platform. The company is the first to demonstrate targeted RNA delivery to muscle in humans and is currently advancing clinical programs in three rare neuromuscular diseases: DMD, myotonic dystrophy type 1 (DM1), and facioscapulohumeral muscular dystrophy (FSHD).
