For information on the EXPLORE44™️ study for DMD with mutations amenable to exon 44 skipping (DMD44) and to check your eligibility to participate in this study Visit EXPLORE44™️ study website
We are advancing and expanding our innovative AOC pipeline to offer treatment options for patients and their families across a wide range of therapeutic areas. We have three AOC programs for three distinct rare diseases in clinical development from our muscle disease franchise: myotonic dystrophy type 1 (DM1), facioscapulohumeral muscular dystrophy (FSHD), and Duchenne Muscular Dystrophy (DMD). Our pipeline also includes advancing AOCs to address additional DMD, rare skeletal muscle, and rare precision cardiology programs. We continue to broaden our reach of AOCs in other indications including cardiology and immunology through partnerships.
Duchenne Muscular Dystrophy
Duchenne muscular dystrophy (DMD) is a rare, genetic condition that is characterized by progressive muscle damage and weakness. It is caused by a genetic mutation that prevents the body from producing a protein called dystrophin, which is an important protein that protects muscle cells from injury during contraction. The lack of functional dystrophin leads to stress and tears of muscle cell membranes, resulting in muscle cell death and progressive loss of muscle function. Those living with the condition often require special aid and assistance throughout their lives and have significantly shortened life expectancy. DMD is a monogenic, X-linked, recessive disease that primarily affects males, with 1 in 3,500 to 5,000 boys born worldwide having Duchenne.
We are developing AOCs to treat the underlying cause of DMD. The oligonucleotides in our AOCs for treatment of DMD are designed to promote the skipping of specific exons to allow the production of the dystrophin gene product in patients with DMD.
In preclinical studies, we observed that treatment of an mdx mouse, a widely used animal model for DMD, with an AOC caused a greater than 50-fold increase in exon skipping compared to an equimolar dose of the unconjugated oligonucleotide.
DMD Exons Amenable to Skipping:
Delpacibart zotadirsen or del-zota (AOC 1044)
Delpacibart zotadirsen or del-zota is designed to treat people living with Duchenne muscular dystrophy amenable to exon 44 (DMD44) and is the first of multiple AOCs we are developing for DMD. Del-zota is designed to deliver phosphorodiamidate morpholino oligomers (PMO) to skeletal muscle and heart tissue to specifically skip exon 44 of dystrophin mRNA to enable dystrophin production. Del-zota is currently in Phase 1/2 development as part of the EXPLORE44™ trial in people with DMD44. The U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) granted Orphan designation for del-zota. The U.S. Food and Drug Administration (FDA) has granted del-zota Rare Pediatric Disease designation and Fast Track designation.
Initial 5 mg/kg Del-zota data for People Living with DMD44 Presented in August 2024
In August 2024, Avidity announced positive del-zota 5 mg/kg data demonstrating unsurpassed delivery of phosphorodiamidate morpholino oligomers (PMO) concentrations to skeletal muscle, statistically significant increase of 25% of normal in dystrophin production and statistically significant increase of 37% in exon 44 skipping in the Phase 1/2 EXPLORE44™ clinical trial. Del-zota 5 mg/kg reduced creatine kinase levels to near normal with greater than 80% reduction compared to baseline.
This initial assessment from the randomized, double-blind, placebo-controlled Phase 1/2 EXPLORE44 trial of del-zota provided a look at the safety and tolerability for 25 participants across two dose levels (5 mg/kg and 10 mg/kg). For the four-month assessment in the 5 mg/kg cohort, participants received three doses of 5 mg/kg del-zota (PMO dose), or placebo every six weeks. Data on muscle delivery, exon skipping, dystrophin production and creatine kinase were assessed from 10 participants in the 5 mg/kg cohort.
Del-zota Healthy Volunteer Data Announced in December 2023
In December 2023, Avidity announced positive del-zota data in healthy volunteers from the Phase 1/2 EXPLORE44™ trial. Del-zota delivered unprecedented concentrations of phosphorodiamidate morpholino oligomers (PMO) in skeletal muscle with up to 50-times greater concentrations of PMO in skeletal muscle following a single dose compared to peptide conjugated PMOs in healthy volunteers. Del-zota was well tolerated, demonstrated statistically significant exon 44 skipping compared to placebo of up to 1.5% in healthy volunteers after a single dose of 10 mg/kg AOC 1044 and increased exon skipping in all participants.
The EXPLORE44™ trial is a randomized, placebo-controlled, double-blind, Phase 1/2 clinical trial to evaluate del-zota in healthy volunteers and participants living with DMD44. EXPLORE44 has completed enrollment and is evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of single and multiple ascending doses of del-zota administered intravenously. The EXPLORE44 trial is assessing exon skipping and dystrophin protein levels in participants with DMD44. Participants with DMD44 have the option to enroll into an open-label extension study, EXPLORE44-OLE. For more information about the EXPLORE44 trial, visit the EXPLORE44 study website or visit https://www.clinicaltrials.gov and search for NCT05670730.
