Avidity Biosciences' antibody oligonucleotide conjugate (AOC) therapy, delpacibart etedesiran (del-desiran; AOC 1001), has been granted Breakthrough Therapy Designation by the FDA for the treatment of myotonic dystrophy type 1 (DM1). This decision underscores the potential of del-desiran to address the underlying cause of this rare and debilitating muscle disease, for which there are currently no approved treatments.
Mechanism of Action and Clinical Development
Del-desiran consists of a proprietary monoclonal antibody that binds to the transferrin receptor 1 (TfR1), conjugated with a siRNA targeting DMPK mRNA. This mechanism is designed to reduce DMPK mRNA, addressing the root cause of DM1. The FDA had previously granted Orphan Drug and Fast Track designations to del-desiran, while the European Medicines Agency granted it Orphan designation.
Avidity is preparing to initiate the global pivotal Phase 3 HARBOR study of del-desiran in the second quarter of 2024. The primary endpoint of the study will be video hand opening time (vHOT), with key secondary endpoints including muscle strength as measured by hand grip strength, quantitative muscle testing (QMT) total score, and activities of daily living as measured by DM1-Activ.
Positive Long-Term Data from MARINA-OLE Trial
The Breakthrough Therapy Designation was supported by positive long-term data from the Phase 2 MARINA-OLE trial (NCT05479981). As of January 2024, the study included over 265 infusions of AOC 1001, totaling 61.1 patient-years of experience. All 37 participants entered the OLE, receiving either 2 mg/kg doses of AOC 1001 escalating to 4 mg/kg, or continuing to be dosed at 4 mg/kg throughout the study.
In the OLE, 35 patients (95%) experienced adverse events (AEs), most of which were mild or moderate. The most common related AEs reported in two or more participants included nausea and headache. Notably, there were no discontinuations from the OLE, and all patients remain in the ongoing study. Several serious AEs, such as nausea/vomiting, worsening of atrial fibrillation, and chest pain, were deemed unrelated to AOC 1001 and consistent with DM1. One participant experienced acute cholelithiasis and biliary pancreatitis.
Efficacy data from the 4 mg/kg group of AOC 1001 showed consistent and durable improvements in measures of strength, including hand grip and Quantitative Muscle Testing total score. Treated patients also demonstrated improvements in myotonia and DM1-Activ, a patient-reported outcome measuring activities of daily living.
Expert Commentary
"The long-term data from the MARINA-OLE study demonstrating that del-desiran improved measures of disease progression in DM1 patients compared to natural history data is remarkable," said John W. Day, MD, PhD, professor of neurology and pediatrics, and director, Division of Neuromuscular Medicine, Stanford University School of Medicine. "The favorable long-term safety data and consistent, durable improvement in myotonia, muscle strength and patient-reported outcomes measures show the potential of del-desiran to make a meaningful difference in the lives of DM1 patients. I am very encouraged by the prospect of del-desiran as a potential treatment for DM1."
