The mainstay of therapy for epilepsy is anti-seizure drugs (ASDs, also referred to as anticonvulsants and anti-epileptic medications). Through much of the past century, only a handful for ASDs were available for clinical use. However, with the creation of the U.S. National Institutes of Health/National Institute of Neurological Disorders and Stroke (NINDS)-sponsored Anticonvulsant Screening Program (ASP), coupled with the emergence of high-throughput screening platforms and methodologies, and advances in our understanding of the fundamental neurobiology of epilepsy, ASD development has greatly accelerated over the past 25 years. More than 18 new ASDs have been approved for clinical use since the inception of the ASP. Despite this remarkable success and the emergence of drugs possessing more favorable pharmacokinetic profiles that act on novel molecular targets, there has been increasing recognition that the paradigms for drug discovery have not yielded significant improvements in therapeutic efficacy, and that disease modification (i.e., anti-epileptogenesis), among other challenges, must be addressed. Thus, with the renewed framework and mission of improving the lives of people with epilepsy, the name of the ASP was changed to the Epilepsy Therapy Screening Program (ETSP). This review briefly summarizes the history of ASD development and outlines some of the challenges and opportunities for the next generation of drug therapies for the epilepsy field.

This report represents a summary of the discussions led by the antiseizure treatment working group of the International League Against Epilepsy (ILAE)/American Epilepsy Society (AES) Working Groups joint meeting in London (London Meeting). We review here what is currently known about the pharmacologic characteristics of current models of refractory seizures, both for adult and pediatric epilepsy. In addition, we address how the National Institute of Neurological Disorders and Stroke (NINDS)-funded Anticonvulsant Screening Program (ASP) is evolving to incorporate appropriate animal models in the search for molecules that might be sufficiently novel to warrant further pharmacologic development. We also briefly address what we believe is necessary, going forward, to achieve the goal of stopping seizures in all patients, with a call to arms for funding agencies, the pharmaceutical industry, and basic researchers.

Infantile spasms (IS) is a devastating epilepsy syndrome that typically begins in the first year of life. Symptoms consist of stereotypical spasms, developmental delay, and electroencephalogram (EEG) that may demonstrate Hypsarhythmia. Current therapeutic approaches are not always effective, and there is no reliable way to predict which patient will respond to therapy. Given this disorder's complexity and the potential impact of a disease-modifying approach, Citizens United for Research in Epilepsy (CURE) employed a "team science" approach to advance the understanding of IS pathology and explore therapeutic modalities that might lead to the development of new ways to potentially prevent spasms and Hypsarhythmia. This approach was a first-of-its-kind collaborative initiative in epilepsy. The IS initiative funded 8 investigative teams over the course of 1-3 years. Projects included the following: discovery on the basic biology of IS, discovery of novel therapeutic targets, cross-validation of targets, discovery of biomarkers, and prognosis and treatment of IS. The combined efforts of a strong investigative team led to numerous advances in understanding the neural pathways underlying IS, testing of small molecules in preclinical models of IS and generated preliminary data on potential biomarkers. Thus far, the initiative has resulted in over 19 publications and subsequent funding for several investigators. Investigators reported that the IS initiative generally affected their research positively due to its collaborative and iterative nature. It also provided a unique opportunity to mentor junior investigators with an interest in translational research. Learnings included the need for a dedicated project manager and more transparent and real-time communication with investigators. The CURE IS initiative represents a unique approach to fund scientific discoveries on epilepsy. It brought together an interdisciplinary group of investigators-who otherwise would not have collaborated-to find transformative therapies for IS. Learnings from this initiative are being utilized for subsequent initiatives at CURE.