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Developing endpoints for the cardiac burden in myotonic dystrophy type 1: A workshop report
Julia M Hartman1, Samuel Carrell1, William J Groh2
1Virginia Commonwealth University, Richmond, VA, USA.
Insights
Identifying effective cardiac endpoints for myotonic dystrophy type 1 (DM1) trials is crucial. Current endpoints like major cardiac events are too rare, necessitating further research into cardiac structure and function changes for better therapeutic assessment.
Area of Science:
- Cardiology
- Neurology
- Genetics
Background:
- Cardiac disease, including conduction slowing and arrhythmias, is a significant manifestation of myotonic dystrophy type 1 (DM1).
- Disease-modifying therapies for DM1 are under development, highlighting the need for reliable cardiac endpoints to assess treatment efficacy.
- Existing cardiac endpoints may not be sufficiently sensitive or frequent to evaluate therapeutic effects in clinical trials.
Purpose of the Study:
- To evaluate potential cardiac endpoints for clinical trials in myotonic dystrophy type 1 (DM1).
- To assess the clinical impact and trial feasibility of various cardiac outcome measures.
- To inform future research directions for DM1 cardiac endpoint development.
Main Methods:
- Convened a workshop with the Myotonic Dystrophy Clinical Research Network (DMCRN) and Myotonic Dystrophy Foundation (MDF) to discuss cardiac endpoints.
- Performed a secondary analysis of cardiac outcomes from published literature.
- Evaluated endpoint feasibility based on incidence rates and potential for detecting therapeutic change.
Main Results:
- Major cardiac events in DM1 are infrequent, with an annual incidence below 1%, making them statistically challenging endpoints.
- Composite endpoints or progression of cardiac conduction prolongation may also be underpowered for conventional clinical trials.
- The study identified limitations in current cardiac endpoints for assessing novel DM1 therapies.
Conclusions:
- Further natural history studies are needed to better understand longitudinal cardiac structural and functional changes in DM1.
- Identifying alternative measures sensitive to therapeutic impact is essential for future DM1 clinical trials.
- Specialized patient selection may be required to enhance the feasibility of cardiac endpoint assessment in DM1 trials.
Abstract:
Cardiac disease is a well-established manifestation of myotonic dystrophy type 1 (DM1), characterized by progressive cardiac conduction slowing with increased risk of atrial and ventricular arrhythmias, heart block, and sudden cardiac death. Multiple disease modifying therapies are in clinical trials for DM1 and show promise in improving skeletal muscle weakness and myotonia. Testing the effects of these medicines, or others, in the heart is of critical importance, but requires identification of endpoints of cardiac function that accurately reflect the state of DM1 cardiac disease. To better define cardiac endpoints, the Myotonic Dystrophy Clinical Research Network (DMCRN) and the Myotonic Dystrophy Foundation (MDF) convened a workshop entitled ''Cardiac Endpoint Workshop'' in May 2025 at the Myotonic Dystrophy Foundation International Conference. Here, we summarize the discussion at the workshop and perform secondary analysis of cardiac outcomes in the published literature to evaluate cardiac endpoints for clinical impact and trial feasibility. This analysis demonstrates that major cardiac events are too infrequent (<1% annual incidence), and alternatives such as composite endpoints or progression of cardiac conduction prolongation would likely be underpowered in a conventional clinical trial. Given these limitations, we identify areas for further natural history study to better describe longitudinal cardiac structural and functional changes to inform specialized patient selection or identify alternative measures with sensitivity to detect therapeutic impact in a trial.
