Preliminary Assessment of the Phase 1/2 Clinical Trial Evaluating the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AOC 1001 Administered Intravenously to Adult Patients with Myotonic Dystrophy Type 1 (DM1) (MARINA)
Nicholas Johnson1, John Day2, Johanna Hamel3, Charles Thornton3, S Subramony4, Payam Soltanzadeh5, Jeffrey Statland6, William Arnold7, Matthew Wicklund8, Kelly Ditrapani9, Carrie Heusner9, Chao-Yin Chen9, Bradley McEvoy9, Yiming Zhu9, Li-Jung Tai9, Elizabeth Ackermann9
1Virginia Commonwealth University, 2Stanford University School of Medicine, 3University of Rochester, 4University of Florida, 5UCLA Reed Neurological Research Center, 6University of Kansas Medical Center, 7University of Missouri, 8University of Colorado, 9Avidity Biosciences
Objective:
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.
Background:
DM1 is a rare, dominantly inherited, progressive neuromuscular disease caused by a toxic gain-of-function mutation in the DM1 protein kinase (DMPK) gene. 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.
Design/Methods:
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). 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.
The study has enrolled 38 adults aged 18 to 65 years with a genetic diagnosis of DM1: eight in Part A and 30 in Part B. After completing MARINA, all patients may enroll in an open-label extension study and receive AOC 1001 for a 24-month treatment period. MARINA-OLE has commenced enrolling patients.
Results:
The MARINA study is currently ongoing. The preliminary analysis will include safety and tolerability, pharmacokinetics, pharmacodynamics, and the changes in RNA splicing from the initial cohorts. These results will be presented.
Conclusions:
AOC 1001 represents a novel potential therapy addressing the underlying cause of DM1.