Initial Data from the ACHIEVE Trial of DYNE-101 in Adults with Myotonic Dystrophy Type 1 (DM1)

Topic:

Clinical Trials

Poster Number: T305

Author(s):

Valeria Sansone, Centro Clinico NEMO, University of Milan, Milan, Italy, Jordi Diaz-Manera, MD, PhD, John Walton Muscular Dystrophy Research Centre, Newcastle University, Newcastle-Upon-Tyne, UK, James Lilleker, Muscle Disease Unit, Northern Care Alliance NHS Foundation Trust, Manchester Academic Health Science, Marika Pane, POLICLINICO UNIV A. GEMELLI - DH NEUROPSICHIATRIA INFANTILE, Richard Roxburgh, PhD, FRACP, Neurogenetics Clinic Centre for Brain Research, University of Auckland, Auckland, NZ, Benedikt Schoser, MD, PhD, Friedrich-Baur-Institute, Dep. of Neurology LMU Clinics, Ludwig-Maximilians University, Munich, Christopher Turner, University College London Hospitals, London, UK, Chris Mix, MD, Dyne Therapeutics, Inc. Waltham, MA, USA, Soma Ray, Dyne Therapeutics, Inc. Waltham, MA, USA, Baoguang Han, Dyne Therapeutics, Inc. Waltham, MA, USA, Wildon Farwell, MD, Dyne Therapeutics, Inc. Waltham, MA, USA, Daniel Wolf, PhD, Dyne Therapeutics, Inc. Waltham, MA, USA, Baziel van Engelen, MD, PhD, Radboud Medical Center, Nijmegen, Netherlands, Guillaume Bassez, Institut de Myologie, Paris, France

Myotonic dystrophy type 1 (DM1) is a rare neuromuscular disorder with multisystemic presentation. It is caused by expansion of CUG repeats in the 3’-UTR of the dystrophia myotonica protein kinase (DMPK) RNA which form hairpin-loop structures that sequester splicing regulators into toxic nuclear foci. This leads to widespread dysregulation of RNA splicing (spliceopathy) that drives the multisystem clinical manifestations. No disease-modifying therapies are available limiting treatment to symptom management.

The FORCE™ platform is a novel technology that harnesses the natural expression of transferrin receptor (TfR)1 on muscle cells for targeted delivery of oligonucleotides. DYNE-101 is an investigational therapeutic for the treatment of DM1, designed based on the principles of the FORCE platform. It consists of a TfR1-binding fragment antibody conjugated to a gapmer antisense oligonucleotide (ASO) designed to target nuclear DMPK RNA for RNAse H-mediated degradation.

The safety and efficacy of intravenous administration of DYNE-101 are being investigated in the Phase 1/2 ACHIEVE trial in adults with DM1 who are 18 to 49 years old (NCT05481879). The primary endpoints are safety and tolerability, with secondary endpoints of pharmacokinetics and pharmacodynamics, including change from baseline in splicing, and measures of muscle strength and function.

As of October 30, 2023, 40 participants were enrolled in the initial two cohorts with over 150 doses of study drug administered. Enrollment was complete in cohorts evaluating 1.8 mg/kg ASO once every four weeks (n=16) and 3.4 mg/kg ASO once every four (n=16) and every eight weeks (n=8). All participants who completed the 24-week placebo-controlled period had entered the 24-week open-label extension. No participants demonstrated treatment-emergent anemia and there were no discontinuations. Safety and tolerability data from multiple cohorts and splicing data and analysis of the video hand opening time (vHOT) myotonia functional assessment from the 1.8 mg/kg cohort up to Week 25 will be presented.