Issues related to development of antiepileptogenic therapies

Abstract

Several preclinical proof-of-concept studies have provided evidence for positive treatment effects on epileptogenesis. However, none of these hypothetical treatments has advanced to the clinic. The experience in other fields of neurology such as stroke, Alzheimer's disease, or amyotrophic lateral sclerosis has indicated several problems in the design of preclinical studies, which likely contribute to failures in translating the positive preclinical data to the clinic. The Working Group on "Issues related to development of antiepileptogenic therapies" of the International League Against Epilepsy (ILAE) and the American Epilepsy Society (AES) has considered the possible problems that arise when moving from proof-of-concept antiepileptogenesis (AEG) studies to preclinical AEG trials, and eventually to clinical AEG trials. This article summarizes the discussions and provides recommendations on how to design a preclinical AEG monotherapy trial in adult animals. We specifically address study design, animal and model selection, number of studies needed, issues related to administration of the treatment, outcome measures, statistics, and reporting. In addition, we give recommendations for future actions to advance the preclinical AEG testing.

Keywords: Disease modification; Epilepsy; Epileptogenesis; Preclinical; Protocol; Therapy.

Figure 1

Different phases of pre-clinical drug discovery. “Compound repurposing” refers to studying small molecules approved to treat other diseases or conditions whether they would be safe and effective antiepileptogenic drugs. Abbreviations: PK, pharmacokinetic studies; PoC, proof-of-concept study; Tox, toxicological studies.

Figure 2

Schematic graph demonstrating the epileptogenic process and points for antiepileptogenic interventions. Different targets can be expressed, depending on the stage of the epileptogenic process. Target expression can vary in magnitude and duration, and there can be temporal overlap in their expression. Note that as epileptogenesis continues even after epilepsy diagnosis, antiepileptogenic treatments can be started even after the appearance of spontaneous seizures.