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.

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

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.

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.

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