Developing endpoints for the cardiac burden in myotonic dystrophy type 1: A workshop report

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.