226P Phase 3, randomized, global study assessing efficacy and safety of del-desiran for the treatment of myotonic dystrophy type 1: HARBOR trial design

Myotonic dystrophy type 1 (DM1) is a rare, dominantly inherited, progressive neuromuscular disease caused by a toxic gain-of-function mutation in the DM1 protein kinase (DMPK) gene. DM1 is primarily characterized by myotonia along with progressive muscular weakness and wasting, leading to deficits in hand function, immobility, respiratory insufficiency, dysarthria, and dysphagia. Hand function impairment is caused by both myotonia and hand weakness leading to negative impact on quality of life. Delpacibart etedesiran (del-desiran, formerly AOC 1001) is an antibody-oligonucleotide conjugate (AOC™) comprised of a DMPK siRNA conjugated to a humanized antibody targeting transferrin receptor 1 (TfR1) for delivery of siRNA to muscle cells to mediate DMPK mRNA degradation addressing the underlying cause of DM1. Long-term safety and tolerability data from the Phase 1/2 MARINA® and MARINA-OLE™ clinical trials demonstrated that del-desiran is well tolerated in patients with DM1 and demonstrated efficacy compared to placebo and natural history for multiple functional endpoints. This phase 3, randomized, double-blind, placebo-controlled, 54-week study will be conducted across ∼40 global sites. This study will enroll participants aged 16+ years with a clinical and genetic diagnosis of DM1 (DMPK CTG repeat ≥100). Participants will be randomized 1:1 to receive either 4 mg/kg del-desiran or placebo administered intravenously every 8 weeks. The first dose of del-desiran will be 2 mg/kg. Primary analysis will take place at Week 30, with the duration of the placebo-controlled study being 54 weeks. Eligible participants will have the option to enroll in an open-label extension trial. The primary objective is to evaluate the efficacy of del-desiran on hand opening time to observe changes in myotonia and hand function. Key secondary objectives are to evaluate the efficacy of del-desiran on muscle strength and activities of daily living.