The primary objective of the MARINA study is to evaluate the safety and tolerability of single and multiple ascending doses of AOC 1001 in adults with DM1.
DM1 is a dominantly inherited, progressive neuromuscular disease. Currently, no disease-modifying therapies exist. DM1 is caused by a toxic CTG repeat expansion in the 3’ untranslated region of the DM1 protein kinase (DMPK) gene, which leads to mRNA aggregation, dysregulation of RNA regulating proteins, and downstream mis-splicing of multiple genes, resulting in multiorgan manifestations of DM1. Removing DMPK transcripts is a rational approach to address the molecular pathology of DM1.
AOC 1001, an RNA therapeutic designed to target the pathogenic driver of DM1, is a DMPK siRNA conjugated to a humanized antibody targeting human transferrin receptor 1 (TfR1). The antibody targets muscles for delivery of siRNA into the cytoplasm and nucleus where it mediates DMPK mRNA degradation.
This phase 1/2 study (AOC 1001-CS1; NCT05027269) is a two-part, randomized, placebo-controlled, double-blind trial in adults with DM1. In part A, after a single intravenous dose of AOC 1001, subjects are followed for 6 months to evaluate safety and tolerability. Part B includes 3 cohorts at ascending dose levels. Each subject receives 3 doses of AOC 1001 in the first 3 months, followed by 3 months of post-treatment monitoring. The cohorts will be initiated in a staggered fashion based on safety data reviews of preceding cohorts. The primary endpoint is treatment-emergent adverse events. Secondary endpoints include pharmacokinetic measurements of AOC 1001 and pharmacodynamic measurements, including DMPK mRNA knockdown and spliceopathy in muscle biopsies.
The study will enroll 44 symptomatic adults aged 18 to 65 years with genetically confirmed DM1 (CTG repeat length ? 100). Eligible participants from parts A and B will have the option to participate in an open-label extension study.