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 myotonic dystrophy type 1 (DM1).
DM1 is a rare, dominantly inherited, progressive neuromuscular disease caused by a toxic gain-of-function mutation in the DM1 protein kinase (DMPK) gene. Removing DMPK transcripts is a rational approach to address the molecular pathology of DM1. Currently, no disease-modifying therapies exist.
AOC 1001 is an antibody oligonucleotide conjugate (AOC) comprised of a DMPK siRNA conjugated to a humanized antibody targeting human transferrin receptor 1 (TfR1), designed for functional delivery to muscle cells, where it can reduce the toxic DMPK-specific mRNA that is responsible for DM1 pathogenesis.
This phase 1/2 study (NCT05027269) is a randomized, placebo-controlled, double-blind trial conducted in two parts. Part A was a single dose design. Part B is a multiple-ascending dose design with 3 cohorts (dose levels), with quarterly doses and 1 booster after the first 6 weeks. The cohorts were initiated in a staggered fashion based on a safety data review of the preceding cohort(s). After completing MARINA, all patients may enroll in an open-label extension study and receive AOC 1001 for a 24-month treatment period.
The primary objective is safety and tolerability. Secondary objectives include spliceopathy, pharmacokinetics, and pharmacodynamics (DMPK mRNA knockdown). Exploratory objectives include efficacy measures (myotonia, mobility, muscle strength, and muscle function), and patient-reported outcomes.
Results (Trial Update)
The MARINA study is currently ongoing and has enrolled 38 adults aged 18 to 65 years with a genetic diagnosis of DM1: eight in Part A and 30 in Part B. MARINA-OLE has commenced enrolling patients.
AOC 1001 represents a novel potential therapy addressing the underlying cause of DM1.