Zeleciment Basivarsen Targets the Underlying Cause of DM1 to Enable Functional Improvement in the Phase I/II ACHIEVE Trial
Shauna Andersson1, Guillaume Bassez2, Jordi Diaz-Manera3, James Lilleker4, Karlien Mul5, marika pane6, Richard Roxburgh7, Benedikt Schoser8, Chris Turner9, Soma Ray1, Huaihou Chen1, Douglas Kerr1, Valeria Sansone10
1Dyne Therapeutics, 2Faculte De Medecine De Creteil, 3Newcastle University, 4University of Manchester, 5Radboud University Medical Center, 6Fondazione Policlinico Universitario A. Gemelli, 7Auckland Hospital, 8Friedrich-Baur-Institute, Dep. of Neurology LMU Clinics, Ludwig-Maximilians University, 9University College London Hospitals, 10The NeMO Clinical Center - Neurorehabilitation Unit, University of Milan
Objective:
Determine the safety and efficacy of zeleciment basivarsen (z-basivarsen, also known as DYNE-101) in adults with myotonic dystrophy type 1 (DM1) in the Phase 1/2 ACHIEVE trial (NCT05481879).
Background:
DM1 is a spliceopathy that results in multi-system clinical manifestations. z-basivarsen consists of a TfR1-binding Fab conjugated to an ASO designed to target mutant nuclear DMPK RNA to correct splicing with the goal of enabling functional improvement.
Design/Methods:
In the completed 24-week placebo-controlled MAD portion of ACHIEVE, 56 participants received one of 5 dose/dose regimens of z-basivarsen or placebo. Eligible participants continued into the open-label/long-term extension portions 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 in myotonia, measured by video hand opening time, was also noted at 3 months and sustained through 12 months of treatment. Sustained improvement was observed across multiple measures of muscle strength and function at 12 months, including Quantitative Muscle Testing (QMT) total score, 10-meter walk/run test, 5 times sit-to-stand, and 9-hole peg test. Improvements were noted in QMT scores across both the upper and lower extremities. Clinical meaningfulness of improvements observed with z-basivarsen was supported by patient-reported outcomes measured by the myotonic dystrophy health index total score, as well as subdomains that assess CNS manifestations, mobility, ability to do activities, and upper extremity function. Improvements from baseline were also noted in both patient and clinician impressions of global function. As of April 23, 2025, z-basivarsen has 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 which was supported by patient-reported outcomes.
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