Safety and Efficacy of DYNE-101 in Adults with DM1: Phase 1/2 ACHIEVE Trial Data

Topic:

Clinical Trials

Poster Number: O44

Author(s):

James Lilleker, Dr, MBChB MRCP PhD, University of Manchester, Guillaume Bassez, Institut de Myologie, Jordi Diaz-Manera, MD, John Walton Muscular Dystrophy Research Centre, Joost Kools, MD, Radboud University Medical Center, Marika Pane, MD, Fondazione Policlinico Universitario A. Gemelli, Richard Roxburgh, PhD, FRACP, Neurogenetics Clinic Centre for Brain Research, University of Auckland, Benedikt Schoser, MD, PhD, Friedrich-Baur-Institute, Dep. of Neurology LMU Clinics, Ludwig-Maximilians University, Christopher Turner, University College London Hospitals, Chris Mix, MD, Dyne Therapeutics, Soma Ray, PhD, Dyne Therapeutics, Baoguang Han, Dyne Therapeutics, Daniel Wolf, PhD, Dyne Therapeutics, Douglas Kerr, MD/PhD/MBA, Dyne Therapeutics, Valeria Sansone, MD, Centro Clinico NEMO, University of Milan

In DM1, dysregulated alternative splicing leads to multisystem clinical manifestations. DYNE-101, an investigational therapeutic for the treatment of DM1, consists of a TfR1-binding Fab conjugated to an antisense oligonucleotide (ASO) designed to target mutant nuclear DMPK RNA to correct splicing. The safety and efficacy of DYNE-101 in adults with myotonic dystrophy type 1 (DM1) are being investigated in the Phase 1/2 ACHIEVE trial (NCT05481879).
As of the latest analysis, safety data were available for 56 participants in ACHIEVE enrolled through the 6.8 mg/kg (ASO equivalent dose) Q8W cohort. Efficacy data were available for participants enrolled in the 1.8 mg/kg Q4W (N=16), 3.4 mg/kg Q4W (N=16), and 5.4 mg/kg Q8W (N=8) cohorts.
DYNE-101 demonstrated dose-dependent delivery of ASO to muscle and consistent splicing correction at 3 months. All evaluable participants in the 3.4 mg/kg Q4W and 5.4 mg/kg Q8W cohorts demonstrated splicing correction, resulting in a mean improvement of 19% and 27%, respectively, in the composite alternative splicing index. Correction in splicing was associated with consistent functional benefit across multiple measures of muscle strength and function, including video hand opening time (vHOT), Quantitative Muscle Testing (QMT) total score, 10-meter walk/run test, and 5 times sit-to-stand. In the 1.8 mg/kg Q4W cohort, DYNE-101 resulted in continued improvement in vHOT, from 28% change from baseline at 3 months to 39% change at 12 months. The 5.4 mg/kg Q8W cohort, which had the greatest splicing correction, demonstrated an early and robust improvement in vHOT (38% change from baseline at 3 months), QMT, and timed function tests. DYNE-101 had a favorable safety profile as of the data cut date, with mostly mild/moderate TEAEs, and no related serious TEAEs.
DYNE-101 has a favorable safety profile and results in early improvement in molecular biomarkers and clinical outcomes in DM1. Additional data will be presented.