Myotonic dystrophy type 1 (DM1) is a spliceopathy that results in multi-systemic clinical manifestations, significant morbidity, and early mortality. High unmet need exists for a treatment that addresses the underlying cause of DM1 in systems where patients report the most impact, including muscle and CNS. Zeleciment basivarsen (z-basivarsen, also known as DYNE-101) is an investigational therapeutic that consists of a TfR1-binding Fab conjugated to an ASO designed to target mutant nuclear DMPK RNA in both muscle and CNS with the goal of correcting the underlying spliceopathy.
The z-basivarsen clinical development plan includes ACHIEVE (NCT05481879), a global, Phase 1/2, randomized, placebo-controlled study consisting of a multiple ascending dose (MAD) period to identify the optimal dose regimen and a registrational expansion cohort (REC) to evaluate the selected dose. Based on a favorable benefit-risk profile observed in the MAD portion of ACHIEVE, the selected dose regimen of 6.8mg/kg Q8W is currently being evaluated in the REC, with the primary endpoint being change from baseline in middle finger myotonia as measured by video hand opening time (vHOT) at 6 months compared with placebo. Myotonia is a hallmark feature of DM1 and was previously demonstrated to be rapidly responsive to splicing correction in animal models of disease (Wheeler et al., 2012; Tanner et al., 2021). Therefore, improvement in myotonia as demonstrated by vHOT supports its utility as an important clinical tool that is predicted to serve as an early indicator of functional improvement. Data from ACHIEVE, including vHOT and additional functional measures, will potentially serve to deliver a therapeutic option for individuals living with DM1. To further assess the multi-system impact of z-basivarsen, a global, randomized, double-blind, placebo-controlled Phase 3 study will be conducted. It will be powered to evaluate broader functional performance, including a clinically meaningful primary endpoint that captures abilities of high relevance to individuals living with DM1. The Phase 3 study will also include a broad set of secondary and exploratory assessments to measure impact across multiple systems. Details of the Phase 3 study design will be shared.