Finding a better drug for epilepsy: preclinical screening strategies and experimental trial design.
The antiepileptic drugs (AEDs) introduced during the past two decades have provided several benefits: they offered new treatment options for symptomatic treatment of seizures, improved ease of use and tolerability, and lowered risk for hypersensitivity reactions and detrimental drug-drug interactions. These drugs, however, neither attenuated the problem of drug-refractory epilepsy nor proved capable of preventing or curing the disease. Therefore, new preclinical screening strategies are needed to identify AEDs that target these unmet medical needs. New therapies may derive from novel targets identified on the basis of existing hypotheses for drug-refractory epilepsy and the biology of epileptogenesis; from research on genetics, transcriptomics, and epigenetics; and from mechanisms relevant for other therapy areas. Novel targets should be explored using new preclinical screening strategies, and new technologies should be used to develop medium- to high-throughput screening models. In vivo testing of novel drugs should be performed in models mimicking relevant aspects of drug refractory epilepsy and/or epileptogenesis. To minimize the high attrition rate associated with drug development, which arises mainly from a failure to demonstrate sufficient clinical efficacy of new treatments, it is important to define integrated strategies for preclinical screening and experimental trial design. An important tool will be the discovery and implementation of relevant biomarkers that will facilitate a continuum of proof-of-concept approaches during early clinical testing to rapidly confirm or reject preclinical findings, and thereby lower the risk of the overall development effort. In this review, we overview some of the issues related to these topics and provide examples of new approaches that we hope will be more successful than those used in the past.
Section of Pharmacology, Department of Clinical and Experimental Medicine, University of Ferrara, and National Institute of Neuroscience, via Fossato di Mortara 17-19, Ferrara, Italy. michele.simonato@unife.it
Michele
M
Simonato
Wolfgang
W
Löscher
Andrew J
AJ
Cole
F Edward
FE
Dudek
Jerome
J
Engel
Rafal M
RM
Kaminski
Jeffrey A
JA
Loeb
Helen
H
Scharfman
Kevin J
KJ
Staley
Libor
L
Velíšek
Henrik
H
Klitgaard
D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D002986:Clinical Trials as Topic / Q000379:methods*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004827:Epilepsy / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D012107:Research Design
D000927:Anticonvulsants; D015415:Biomarkers