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New avenues for anti-epileptic drug discovery and development

Nature Reviews Drug Discovery volume 12, pages 757–776 (2013)Cite this article

Subjects

Key Points

  • Despite the introduction of over 15 third-generation anti-epileptic drugs (AEDs) during the past three decades, current medications cannot control seizures in 20–30% of patients and there remains an absence of epilepsy therapies that prevent or cure the disease.

  • The consequences of the standstill in the development of more efficacious drugs for the treatment of epilepsy are several-fold, including the loss of interest of pharmaceutical companies in developing novel AEDs.

  • However, our understanding of the mechanisms mediating epilepsy development as well as the causes of drug resistance have recently grown substantially, providing opportunities for the discovery and development of more efficacious anti-epileptic and anti-epileptogenic drugs.

  • In this article, we discuss how previous preclinical models and clinic trial designs may have hampered the discovery of improved treatments and suggest a promising potential of new target-driven approaches, comparative preclinical proof-of-concept studies and innovative clinical trials designs for the identification of future treatments that target remaining unmet medical need in epilepsy.

  • The successful identification and implementation of the tools for future AED discovery and development will critically depend on new concepts for a joint endeavour between academia and industry.

  • New AEDs with superior efficacy against the relevant standard of care for drug-resistant epilepsy or with the ability to markedly alter the course or the prognosis of epilepsy address major unmet medical needs and offer a promising business opportunity that could revitalize joint AED discovery and development efforts between academia and the pharmaceutical industry.

Abstract

Despite the introduction of over 15 third-generation anti-epileptic drugs, current medications fail to control seizures in 20–30% of patients. However, our understanding of the mechanisms mediating the development of epilepsy and the causes of drug resistance has grown substantially over the past decade, providing opportunities for the discovery and development of more efficacious anti-epileptic and anti-epileptogenic drugs. In this Review we discuss how previous preclinical models and clinical trial designs may have hampered the discovery of better treatments. We propose that future anti-epileptic drug development may be improved through a new joint endeavour between academia and the industry, through the identification and application of tools for new target-driven approaches, and through comparative preclinical proof-of-concept studies and innovative clinical trials designs.

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Figure 1
Figure 2: Novel anti-epileptic or anti-epileptogenic drug targets.
Figure 3: Possible determinants of AED resistance in human and experimental epilepsies.
Figure 4: Roadmap for the discovery and development of medications for drug-resistant epilepsy and for epilepsy prevention or disease modification.

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Acknowledgements

The authors are very grateful to A. Vezzani, L. Kramer, E. Perucca and M. Rogawski for their comments and constructive criticisms on an earlier draft of the manuscript.

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Authors and Affiliations

  1. Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine, Hannover, 30559, Germany

    Wolfgang Löscher

  2. Center for Systems Neuroscience, Hannover, 30559, Germany

    Wolfgang Löscher

  3. UCB Pharma, Neurosciences Therapeutic Area, 1420, Braine-l'Alleud, Belgium

    Henrik Klitgaard

  4. Janssen Research & Development, Raritan, 08869, New Jersey, USA

    Roy E. Twyman

  5. Epilepsy Research Group, Berlin, 14163, Germany

    Dieter Schmidt

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  1. Wolfgang Löscher
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  4. Dieter Schmidt
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Corresponding author

Correspondence to Wolfgang Löscher.

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Competing interests

H.K. is an employee of UCB Pharma.

R.E.T. is an employee of Janssen Pharmaceuticals R&D.

W.L. and D.S. declare no competing financial interests.

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PowerPoint slides

Glossary

Epilepsy

A chronic brain disorder that is characterized by partial or generalized spontaneous (unprovoked) recurrent epileptic seizures and, often, comorbidities such as anxiety and depression.

Epileptogenesis

The gradual process (also termed latent period) by which epilepsy develops in the normal brain following brain insults or gene mutations.

Anti-epileptic drugs

(AEDs). Also termed anticonvulsant or anti-seizure drugs. Compounds that, when administered systemically in animal models or to patients, inhibit or control seizures that are associated with epilepsy or other conditions.

MES seizure test

(Maximal electroshock seizure test). A model in which a short (0.2-second) transcorneal or transauricular application of a 50 or 60 Hz electrical stimulus in rodents induces generalized tonic–clonic seizures that are mediated by brainstem structures.

Pentylenetetrazole

(PTZ). A chemical convulsant that, when administered systemically to rodents, induces characteristic myoclonic and clonic convulsions that are mediated by forebrain structures.

Amygdala kindling

Repeated administration of an initially subconvulsive electrical stimuli via a depth electrode in the amygdala, which induces seizures that progressively increase in severity and duration; once established, the increased susceptibility to the induction of kindled seizures is a permanent phenomenon.

GAERS rat

(Genetic absence epileptic rat from Strasbourg). A genetic rat model that displays characteristic 6–7 Hz spike-wave electrographic seizures and a pharmacological profile that is consistent with generalized absence epilepsy.

6-Hz psychomotor seizure model

A seizure model in which a prolonged (4-second) transcorneal application of a 6-Hz electrical stimulus in mice induces limbic seizures that are characterized by a stun, vibrissae chomping, forelimb clonus and a Straub tail; these seizures are resistant to phenytoin and some other anti-epileptic drugs.

Non-inferiority trial design

A clinical trial design that determines whether a test compound is inferior to another compound; the lower limit (95% confidence interval) of a test compound's treatment efficacy or effectiveness is to be compared to a preset lower boundary of efficacy or effectiveness relative to the adequate comparator's point estimate of efficacy or effectiveness.

Anti-epileptogenic drugs

Compounds that, when administered systemically in animal models or to patients immediately following a brain insult, prevent or reduce the long-term consequences of the insult after washout, including the development of epilepsy, neurodegeneration and cognitive or behavioural alterations.

Ictogenesis

The complex mechanisms that initiate and maintain a seizure, involving the transition from the interictal (or pre-ictal) to ictal state with abnormal, excessive, hypersynchronous discharges from an aggregate of central nervous system neurons.

Disease-modifying drugs

Compounds that alter the development or progression of epilepsy by affecting the underlying pathophysiology and natural history of the disease, thus altering the severity of epilepsy or the development of pharmacoresistance, neurodegeneration and cognitive or behavioural alterations.

Temporal lobe epilepsy

A common, difficult-to-treat type of epilepsy that is characterized by simple partial or complex partial seizures originating from medial or lateral temporal lobe regions such as the hippocampus or amygdala.

Blood–brain barrier

(BBB). A dynamic interface that separates the brain from the circulatory system and protects the brain from potentially harmful chemicals, while regulating the transport of essential molecules and maintaining a stable environment. It is formed by highly specialized endothelial cells that line brain capillaries and are connected by extensive tight junctions that restrict paracellular penetration of compounds.

Comparator drug

A current standard-of-care drug given at a recommended daily dose for the same setting as the intended use of the test drug with an absolute minimum point estimate for an efficacy or effectiveness of 50%; this prevents the use of well tolerated but inefficacious drugs as comparators.

P-glycoprotein

A well-characterized efflux transporter that transports a variety of substrates across extra- and intracellular membranes, including endothelial cells of the blood–brain barrier, and protects cells from intoxication by potentially harmful lipophilic compounds, thereby restricting the distribution of many therapeutically used drugs.

Active-control trial

A clinical trial design comparing the outcome of an experimental compound to a drug whose efficacy has been established.

Superiority trials

Studies that are designed to detect a difference in the primary outcome (that is, efficacy and/or effectiveness) between the study treatment and the comparator using an intent-to-treat analysis; the limit of a >20% absolute (rather than relative) difference is arbitrary, context-specific, and subject to change with time.

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Löscher, W., Klitgaard, H., Twyman, R. et al. New avenues for anti-epileptic drug discovery and development. Nat Rev Drug Discov 12, 757–776 (2013). https://doi.org/10.1038/nrd4126

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