Safety and Efficacy of DYNE-101 in Adults with DM1: Phase 1/2 ACHIEVE Trial Data
Daniel Wolf1, Guillaume Bassez2, Jordi Diaz-Manera3, Joost Kools4, James Lilleker5, Marika Pane6, Richard Roxburgh7, Benedikt Schoser8, Christopher Turner9, Chris Mix1, Soma Ray1, Baoguang Han1, Douglas Kerr1, Valeria Sansone10
1Dyne Therapeutics, Inc., 2Institut de Myologie, 3Newcastle University, 4Radboud University Medical Center, 5Muscle Disease Unit, Northern Care Alliance NHS Foundation Trust, Manchester Academic Health Science Centre, 6Fondazione Policlinico Universitario A. Gemelli, 7Neurogenetics Clinic Centre for Brain Research, University of Auckland, 8Friedrich-Baur-Institute, Dep. of Neurology LMU Clinics, Ludwig-Maximilians University, 9University College London Hospitals, 10Centro Clinico NEMO, University of Milan
Objective:

Determine the safety and efficacy of DYNE-101 in adults with myotonic dystrophy type 1 (DM1) in the Phase 1/2 ACHIEVE trial (NCT05481879).

Background:

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 for RHase H-mediated degradation to correct splicing.

Design/Methods:

As of the latest analysis, safety data were available for 56 participants in the ACHIEVE study enrolled through the 6.8 mg/kg (ASO equivalent dose) Q4W 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.

Results:

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 a 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.

Conclusions:

DYNE-101 has a favorable safety profile and results in early improvement in molecular biomarkers and clinical outcomes in DM1.

10.1212/WNL.0000000000210508
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