Clinical Trial Design for Disease-Modifying Therapies for Genetic Epilepsies

Although trials with anti-seizure medications (ASMs) have not shown clear anti-epileptogenic or disease-modifying activity in humans to date, rapid advancements in genomic technology and emerging gene-mediated and gene replacement options offer hope for the successful development of disease-modifying therapies (DMTs) for genetic epilepsies. In fact, more than 26 potential DMTs are in various stages of preclinical and/or clinical development for genetic syndromes associated with epilepsy. The scope of disease-modification includes but is not limited to effects on the underlying pathophysiology, the condition's natural history, epilepsy severity, developmental achievement, function, behavior, sleep, and quality of life. While conventional regulatory clinical trials for epilepsy therapeutics have historically focused on seizure reduction, similarly designed trials may prove ill-equipped to identify these broader disease-modifying benefits. As we look forward to this pipeline of DMTs, focused consideration should be given to the challenges they pose to conventional clinical trial designs for epilepsy therapeutics. Just as DMTs promise to fundamentally alter how we approach the care of patients with genetic epilepsy syndromes, DMTs likewise challenge how we traditionally construct and measure the success of clinical trials. In the following, we briefly review the historical and preclinical frameworks for DMT development for genetic epilepsies and explore the many novel challenges posed for such trials, including the choice of suitable outcome measures, trial structure, timing and duration of treatment, feasible follow-up period, varying safety profile, and ethical concerns.