The U.S. Food and Drug Administration (FDA) has removed the partial clinical hold on Avidity Biosciences' investigational drug, delpacibart etedesiran (del-desiran/AOC 1001), designed to address the root cause of myotonic dystrophy type 1 (DM1). This decision allows Avidity to continue its clinical development program for del-desiran, including the ongoing Phase 3 HARBOR trial. The resolution of the clinical hold marks a significant step forward in the development of a much-needed therapy for DM1, a progressive and often fatal neuromuscular disease with no approved treatments.
Background on the Clinical Hold
The FDA initially placed a partial clinical hold in September 2022 after a serious adverse event was reported in a patient enrolled in the 40-mg arm of the Phase I/II MARINA trial (NCT05027269). The MARINA trial was evaluating del-desiran in patients with DM1. Although the specific details of the adverse event were not disclosed, the FDA lifted the partial clinical hold the following year, allowing Avidity to resume enrollment of new patients.
Del-desiran: A Targeted Approach to DM1
Del-desiran is an antibody oligonucleotide conjugate (AOC) comprised of a proprietary monoclonal antibody that binds to the transferrin receptor 1 (TfR1), conjugated with a small interfering RNA (siRNA) targeting myotonic dystrophy protein kinase (DMPK) mRNA. DM1 is caused by a triplet-repeat expansion in the DMPK gene, resulting in a toxic gain-of-function mRNA that disrupts normal cellular processes. Del-desiran is designed to reduce the levels of this disease-related DMPK mRNA, addressing the underlying cause of DM1.
Phase 3 HARBOR Trial
Avidity has initiated the pivotal Phase 3 HARBOR trial (NCT06411288) to evaluate the safety and efficacy of del-desiran in patients with DM1. This randomized, placebo-controlled study is expected to enroll 150 participants who will be assessed over 54 weeks. The primary endpoint of the HARBOR trial is the improvement of myotonia over 30 weeks, measured using video Hand Opening Time (vHOT), which assesses the average time to extend the right third and first digits. Secondary endpoints include functional assessments of myotonia, such as hand grip strength, quantitative muscle testing composite score, and the Myotonic Dystrophy Type 1 Activity and Participation Scale.
Prioritizing DM1 Treatment
Del-desiran has been granted Breakthrough Therapy, Orphan Drug, and Fast Track designations by the FDA, as well as Orphan designation by the European Medicines Agency (EMA). These designations underscore the urgent need for effective treatments for DM1 and highlight the potential of del-desiran to address this unmet medical need.
Myotonic Dystrophy Type 1: An Unmet Need
DM1 is an inherited, progressive disease affecting skeletal and cardiac muscle, leading to muscle weakness, myotonia, respiratory problems, cardiac abnormalities, and other complications. There are currently no approved therapies for DM1, and management primarily focuses on symptomatic treatment. The disease is caused by a triplet-repeat expansion in the DMPK gene, resulting in a toxic gain of function mRNA. Avidity’s del-desiran represents a promising approach by targeting the root cause of DM1.
Competitive Landscape
Other therapies are in development for treating DM1, including AMO Pharma’s AMO-02 (tideglusib), an irreversible inhibitor of glycogen synthase kinase 3 (GSK-3) that aims to disrupt the RNA repeats causing congenital DM1. AMO Pharma announced plans to initiate a Phase III trial for AMO-02 in DM1 patients. If approved, GlobalData expects del-desiran to generate over $1.2 billion in sales by 2030.
