221P Initial data from the achieve trial of DYNE-101 in adults with myotonic dystrophy type 1 (DM1)

DM1 is a spliceopathy caused by expansion of CUG repeats in the DMPK RNA that leads to multisystem clinical manifestations. DYNE-101, an investigational therapeutic for treatment of DM1, consists of a TfR1-binding Fab conjugated to an ASO designed against mutant nuclear DMPK RNA to correct splicing. The safety and efficacy of DYNE-101 in adults (18-49 years old) are being investigated in the Phase1/2 ACHIEVE trial (NCT05481879). For this analysis, 16 participants had efficacy data through 6 months (6M) of follow-up in the 1.8 mg/kg (approximate ASO) dose cohort and 16 participants had biopsy data through 3M of follow-up in the 3.4 mg/kg dose cohort of the MAD portion of ACHIEVE. Participants were randomized to receive DYNE-101 (n=6) or placebo (n=4) Q4W, or two doses of DYNE-101 followed by placebo for the remainder of the MAD period (n=6). Safety and tolerability are based on 45 participants enrolled in ACHIEVE as of the data cut-off date. At 3M, 1.8 and 3.4 mg/kg DYNE-101 showed mean 10.0 ng/g and 21.5 ng/g ASO concentration, mean 25% and 40% DMPK knockdown, and mean 13% and 19% splicing correction from baseline, respectively. At 6M, 1.8 mg/kg DYNE-101 showed mean 16% DMPK knockdown, +7% CASI change from baseline, 3.8-second improvement in myotonia, and improvement in MDHI, a patient-reported outcome. 3/5 evaluable participants had splicing correction at 3M, persisting through 6M. In the 3.4 mg/kg cohort, 5/5 evaluable participants had splicing correction at 3M. DYNE-101 had a favorable safety profile as of the data cut-off date, with mostly mild or moderate TEAEs and no clinically meaningful changes in kidney and liver parameters or treatment-emergent anemia. The initial data with DYNE-101 demonstrated dose-dependent ASO delivery, DMPK knockdown, and splicing correction with durable effect. Improvement in myotonia was also observed at the lowest dose tested. The data support the continued development of DYNE-101 for the treatment of DM1.