Zeleciment basivarsen targets the underlying cause of DM1 to enable functional improvement in the Phase 1/2 ACHIEVE trial

Topic:

Clinical Trials

Poster Number: 135 M

Author(s):

Shauna Andersson, MD, PhD, Dyne Therapeutics, Guillaume Bassez, Institut de Myologie, Paris, France, Jordi Diaz-Manera, MD, PhD, John Walton Muscular Dystrophy Research Centre, Newcastle University, UK, James B. Lilleker, Dr, MBChB MRCP PhD, Muscle Disease Unit, Manchester Academic Health Science Center, Manchester, UK, Karlien Mul, MD, PhD, Radboud University Medical Center, Nijmegen, Netherlands, Marika Pane, MD, Fondazione Policlinico Universitario A. Gemelli, Richard H 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, Germany, Christopher Turner, MD, PhD, University College London Hospitals, London, UK, Soma Ray, PhD, Dyne Therapeutics, Huaihou Chen, Dyne Therapeutics, Douglas Kerr, MD/PhD/MBA, Dyne Therapeutics, Valeria Sansone, MD, The NeMO Clinical Center in Milan, Neurorehabilitation Unit, Milan, Italy

Background: Myotonic dystrophy type 1 (DM1) is a spliceopathy that results in multi-system clinical manifestations. Zeleciment basivarsen (z-basivarsen, also known as DYNE-101) consists of a TfR1-binding Fab conjugated to an ASO designed to target mutant nuclear DMPK RNA in both muscle and CNS to correct splicing with the goal of enabling functional improvement.

Objective: Assess the safety, tolerability, and efficacy of z-basivarsen in adults with DM1 in the Phase 1/2 ACHIEVE trial (NCT05481879).

Design/Methods: In the completed 24-week placebo-controlled Multiple Ascending Dose (MAD) portion of ACHIEVE, 56 participants received one of 5 IV dose regimens of z-basivarsen or placebo. Eligible participants subsequently entered the long-term extension portion at 6.8 mg/kg Q8W z-basivarsen.

Results: In six participants who received 6.8 mg/kg Q8W z-basivarsen in the MAD portion, substantial knockdown of DMPK RNA levels and improvement in splicing were noted as early as 3 months post-treatment. Improvement from baseline in myotonia, measured by video hand opening time (vHOT), was also noted at 3 months and sustained through 12 months of treatment. Improvement from baseline across multiple measures of muscle strength and function, including Quantitative Muscle Testing (QMT) total score, 10-meter walk/run test, 5 times sit-to-stand, and 9-hole peg test was sustained through 12 months. Clinical meaningfulness of improvements observed with z-basivarsen were supported and further contextualized by patient-reported outcomes measured by the myotonic dystrophy health index (MDHI) total score, as well as subscales that assess the impact of DM1 on CNS manifestations, mobility, ability to do activities, and upper extremity function. Improvement from baseline, as measured by clinician-reported global impression of change scales, was observed in 83% of patients at 12 months. As of April 23, 2025, z-basivarsen demonstrated a favorable safety profile, with no serious related TEAEs.

Conclusions: These data suggest that z-basivarsen has a favorable safety profile and showed functional improvement across several clinical measures, including myotonia, muscle strength and function, further contextualized by improvement in patient assessment of DM1 disease burden.