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 neuromuscular, 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)
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.
The Phase 1/2 EXPLORE44™ trial is now complete. The study 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 evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of single and multiple ascending doses of del-zota administered intravenously, and assessed exon skipping and dystrophin protein levels in participants with DMD44. Participants in the EXPLORE44 trial had the option to enroll into the 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.
EXPLORE44-OLE™
The Phase 2 EXPLORE44-OLE™ trial is an open-label, multi-center trial designed to evaluate the long-term safety and tolerability of del-zota in participants living with DMD44. EXPLORE44-OLE completed enrollment in February 20245 with 23 participants who were previously enrolled in the Phase 1/2 EXPLORE44 study and 15 additional new participants who enrolled directly into the EXPLOREO44-OLE study. This trial will continue to evaluate the safety, tolerability, PK, PD, and efficacy of del-zota in participants enrolled in the randomized, placebo-controlled, double-blind Phase 1/2 EXPLORE44 clinical trial. Participants enrolled in the EXPLORE44-OLE study will receive 5 mg/kg of del-zota every six weeks. The total duration of active treatment with del-zota in the EXPLORE44-OLE study is approximately 24 months. Once patients have completed active treatment, there will be a three-month safety follow-up period. Avidity may extend active treatment beyond 24 months at a future timepoint. For more information on this study click here or visit http://www.clinicaltrials.gov and search for NCT06244082.
