Dyne Therapeutics, Inc. announced new clinical data from its ongoing Phase 1/2 ACHIEVE trial of DYNE-101 in patients with myotonic dystrophy type 1 (DM1). DYNE-101 continued to demonstrate a compelling impact on key disease biomarkers, including DMPK and splicing correction, reversal of disease progression across multiple functional endpoints, and a favorable safety profile. Dyne plans to initiate a global Registrational Expansion Cohort with the potential to support a submission for U.S. Accelerated Approval based on biomarker and functional data in first half 2026.

Phase 1/2 ACHIEVE Trial of DYNE-101 in DM1: ACHIEVE is a randomized, placebo-controlled, double-blind, Phase 1/2 clinical trial designed with a Multiple Ascending Dose (MAD) portion to evaluate the safety and efficacy of DYNE-101 in DM1. The study was designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of DYNE-101 administered intravenously. The study protocol also allows for the creation of a Registrational Expansion Cohort to support a submission for U.S. Accelerated Approval.

Activity of DYNE-101 was assessed using key biomarkers including DMPK and the Composite Alternative Splicing Index (CASI-22). Myotonia, muscle strength, timed function tests, and patient reported outcomes, including CNS-related disease manifestations, were also assessed in the trial. CASI-22 was used to assess the utility of splicing correction to serve as surrogate endpoint and to support selection of a dose for the Registrational Expansion Cohort.

Dyne measured splicing in all study participants using CASI-22 to quantify the splicing abnormalities that directly lead to the hallmark and multi-organ symptoms of DM1, including myotonia, loss of muscle strength and function, cardiac arrhythmias, gastrointestinal problems, and cognitive impairments. Dyne has completed the MAD portion of the study and selected the 6.8 mg/kg Q8W dose (approximate ASO dose) to be evaluated in the Registrational Expansion Cohort based on its potential to demonstrate broad functional benefit. DYNE-101 Efficacy Data: Dyne reported efficacy data from adult DM1 patients enrolled in the randomized, placebo-controlled MAD portion of the DYNE-101 ACHIEVE trial, including data from the 6.8 mg/kg Q8W cohort (n=8) at up to 6 months.

At the 6.8 mg/kg Q8W dose, DYNE-101 resulted in significant splicing correction at 3 months compared to baseline, which was associated with improvement in multiple functional endpoints, beginning at 3 months and continuing at 6 months. Key findings from ACHIEVE include: Biomarker Data and Functional Improvements: DMPK: Analysis of muscle biopsy data for the 6.8 mg/kg Q8W cohort demonstrated a substantial knockdown of DMPK (DYNE-101 molecular target) RNA levels. Composite Alternative Splicing Index (CASI-22): Splicing correction at 3 months for the 6.8 mg/kg Q8W cohort was robust and was associated with improvement in multiple functional endpoints, supporting CASI-22 at 3 months as a surrogate endpoint for potential U.S. Accelerated Approval.

Myotonia (vHOT): Early and sustained improvement in myotonia as measured by video hand opening time (vHOT) was seen in the 6.8 mg/kg Q8W cohort, as well as at low doses with modest splicing correction, deepening with more time on drug. Strength and Timed Assessments: Functional measures such as 5 Times Sit to Stand Test, reflective of muscle strength and dynamic balance, Quantitative Myometry Testing (QMT), a test of muscle strength and fatigue, and the 10-Meter Walk/Run Test (10MWR) showed early and sustained clinical benefit at the 6.8 mg/kg Q8W dose. Patient Reported Outcomes (PROs): Myotonic Dystrophy Health Index (MDHI): DYNE-101 at the 6.8 mg/kg Q8W doses showed encouraging trends on the MDHI patient reported outcome (PRO) measure, including those subscales that assess central nervous system disease manifestations.

These represent some of the most burdensome manifestations of DM1 and daily quality of life issues for patients and their families. DYNE-101 Safety and Tolerability Data: Dyne also reported safety and tolerability data from 56 patients enrolled through the 6.8 mg/kg Q8W cohort of the ACHIEVE trial. DYNE-101 demonstrated a favorable safety profile.

The majority of treatment emergent adverse events were mild or moderate, and no related serious treatment emergent adverse events have been identified. Approximately 855 doses have been administered, representing over 72-patient years of follow-up, with some patients being followed for up to 2.1 years. Clinical Plan to Support DYNE-101 Product Registration and Upcoming Milestones: Based on previous dialogue with the Center for Drug Evaluation and Research (CDER) division of the U.S. Food and Drug Administration (FDA), Dyne continues to pursue accelerated approval in the U.S. based on splicing as a surrogate endpoint.

Dyne plans to initiate a global placebo-controlled Registrational Expansion Cohort in ACHIEVE that includes approximately 32 patients at the 6.8 mg/kg Q8W dose. The primary endpoint for this cohort will be mean splicing correction at 3 months as measured by the composite alternative splicing index (CASI-22), supported by clinically meaningful measures of muscle strength and function. The Registrational Expansion Cohort will also assess various quality of life and CNS-related endpoints (e.g., fatigue, daytime sleepiness).

Dyne intends that the data from the approximately 32-patient Registrational Expansion Cohort and the 56 patients from the long-term extension portion of ACHIEVE will support a submission for U.S. Accelerated Approval. Dyne is also pursuing expedited approval pathways globally for DYNE-101. Dyne anticipates completion of enrollment of the Registrational Expansion Cohort in mid-2025 and submission for U.S. Accelerated Approval in first half 2026.