Introduction

Field: Medicine (Health Sciences)

Based on a 2010 systematic review and meta-analysis, Beyenburg et al. 1 recently concluded that modern antiepileptic drugs (AEDs) have little impact on patients with refractory epilepsy, lamenting the lack of progress in the development of novel AEDs. Such articles have highlighted the importance of the continued quest for effective, novel therapies to help patients with this condition. This supplement provides an overview of the development of perampanel, the first non-competitive AMPA-type glutamate receptor antagonist to be developed as an adjunctive treatment for refractory partial-onset seizures. After years of development, this AED has now been approved by the European Medicines Agency (EMA) and the Food and Drug Administration (FDA). Perampanel has completed clinical evaluation in three pivotal, randomized, double-blind, placebo-controlled Phase III registration studies in patients experiencing partial-onset seizures despite treatment with up to three AEDs 2-4. In these studies, adjunctive perampanel provided significant improvements in seizure reduction. In addition, perampanel was associated with a favorable adverse event profile, with few cognitive or psychiatric side effects: a vital attribute in this vulnerable population. Previously, most AEDs have been discovered through serendipity, screening large numbers of compounds, or the further development of existing AEDs. Perampanel, however, is one of the few to be developed based upon a specific hypothesis of seizure inhibition. This development program will be reviewed by Andrew Satlin and colleagues in the first article in this supplement 5. In the second article, Michael Rogawski 6 provides an in-depth account of the role of AMPA receptors in seizures and epileptogenesis, while in the third article, Michael Rogawski and Takahisa Hanada 7 will go on to review the exciting possibilities of AMPA receptor antagonism and how perampanel utilizes this mechanism to inhibit seizure occurrence. As perampanel is now approved for use in Europe and the USA, it is important that clinicians have an understanding of how this drug can be used to treat patients in a real-life clinical setting. With this in mind, the fourth article in this supplement, by Frank Kerling and Burkhard Kasper 8, will provide an overview of efficacy data from the published Phase II and Phase III clinical trials. Alongside this, Jose Serratosa, Vicente Villanueva, Frank Kerling and Burkhard Kasper 9 will provide an overview of Phase II and Phase III safety data in the fifth article. Severe seizures are particularly difficult to control, and the more AEDs a patient has tried previously, the less likely they are to respond to the next AED 10. Therefore, in the sixth and final article in this supplement, David Ko and Eugene Ramsay 11 will discuss the efficacy of perampanel for the treatment of severe seizures in refractory patients already receiving one or more concomitant AEDs. As perampanel is now approved for use in Europe and the USA, we hope that the information covered in this supplement will support the reader in treating eligible and appropriate patients with this third-generation AED. However, it is important to recognize that the full potential of perampanel is not yet known and many challenges still remain. For example, 'How effective will perampanel be in monotherapy?' and 'Will patients with generalized seizure types also benefit from treatment (as indicated in animal models) 12?' Only further rigorous studies will be able to answer the question of whether perampanel is a broad spectrum AED for patients with varied seizure types and syndromes or not. The future is indeed exciting. David Squillacote, MD, of Eisai Inc. assisted in the preparation of the article by providing up-to-date data access and editorial support. Editorial support was provided by Hannah FitzGibbon, PhD, of Complete Medical Communications and was funded by Eisai Inc. E. Ben-Menachem is currently an investigator for Eisai and UCB Pharma and is a consultant for Biocontrol, Eisai, Janssen-Cilag, Lundbeck, and UCB Pharma. She has received a research grant from Västra Götelands Region and is chief editor of Acta Neurologica Scandinavica.