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  • Review Article
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New epilepsy therapies in development

Nature Reviews Drug Discovery volume 23, pages 682–708 (2024)Cite this article

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Abstract

Epilepsy is a common brain disorder, characterized by spontaneous recurrent seizures, with associated neuropsychiatric and cognitive comorbidities and increased mortality. Although people at risk can often be identified, interventions to prevent the development of the disorder are not available. Moreover, in at least 30% of patients, epilepsy cannot be controlled by current antiseizure medications (ASMs). As a result of considerable progress in epilepsy genetics and the development of novel disease models, drug screening technologies and innovative therapeutic modalities over the past 10 years, more than 200 novel epilepsy therapies are currently in the preclinical or clinical pipeline, including many treatments that act by new mechanisms. Assisted by diagnostic and predictive biomarkers, the treatment of epilepsy is undergoing paradigm shifts from symptom-only ASMs to disease prevention, and from broad trial-and-error treatments for seizures in general to mechanism-based treatments for specific epilepsy syndromes. In this Review, we assess recent progress in ASM development and outline future directions for the development of new therapies for the treatment and prevention of epilepsy.

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Fig. 1: Molecular targets of clinically approved antiseizure medications.
Fig. 2: Paths to the development of targeted therapeutic strategies in genetic epilepsy.
Fig. 3: Evolving views on epilepsy pathophysiology drive therapy development.
Fig. 4: The long and winding road of development of GABAA receptor PAMs.
Fig. 5: The GABAA receptor as a target of antiseizure medications.
Fig. 6: Paradigm shift in the treatment of epilepsy from symptomatic-only to syndrome modulation and disease prevention.

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Acknowledgements

We are very grateful to J. O. McNamara and K. D. Fink for their comments and constructive criticisms on an earlier draft of the manuscript. H. Rezavandi, F. Fauteux and R. Buonfiglio are gratefully acknowledged for their help with listing epilepsy drug discovery pipeline projects.

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Author notes

  1. These authors contributed equally: Pavel Klein, Wolfgang Löscher.

Authors and Affiliations

  1. Mid-Atlantic Epilepsy and Sleep Center, Bethesda, MD, USA

    Pavel Klein

  2. Angelini Pharma, Rome, Italy

    Rafal M. Kaminski

  3. Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, University College London, London, UK

    Matthias Koepp

  4. Translational Neuropharmacology Lab., NIFE, Department of Experimental Otology of the ENT Clinics, Hannover Medical School, Hannover, Germany

    Wolfgang Löscher

  5. Center for Systems Neuroscience, Hannover, Germany

    Wolfgang Löscher

Authors
  1. Pavel Klein
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  2. Rafal M. Kaminski
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  3. Matthias Koepp
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  4. Wolfgang Löscher
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Contributions

All authors researched data for the article. All authors contributed substantially to discussion of the content. P.K., M.K. and W.L. wrote the article. All authors reviewed and/or edited the manuscript before submission.

Corresponding authors

Correspondence to Pavel Klein or Wolfgang Löscher.

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Competing interests

P.K. has served as a consultant, advisory board member or speaker for Abbott, Angelini, Aquestive, Arvelle Therapeutics, Aucta Pharmaceuticals, Dr Reddy’s, Eisai, Jazz Pharmaceuticals, Neurelis, Neurona, Paladin, SK Life Science, Sunovion, UCB Pharma, UNEEG, UniQure, is a member of the Medical Advisory Board of Stratus and of the Scientific Advisory Board of OB Pharma, is on DSMB of Neurona Therapeutics for the NRTX-1001 trial, is co-founder and the CEO of PrevEp, and has received research support from CURE/Department of Defense and from the NIH/SBIR. M.K. has served as a consultant, advisory board member or speaker for Angelini, Arvelle Therapeutics, Bial, Eisai, GE, Novartis, Jazz Pharmaceuticals, UCB Pharma, is co-founder of PrevEp, has received research support from Epilepsy Research UK, the Epilepsy Society, MRC and Wellcome Trust. R.M.K. is employed by Angelini Pharma. W.L. has served as a consultant or advisory board member for AC Immune, Addex, Atlas Venture, Angelini, Axonis, Boehringer Ingelheim, Celltech, Clexio, Cogent, Idorsia, Lundbeck, ND Capital, Novartis, Ovid, Pragma, and Selene, is co-founder and the CSO of PrevEp, and has received research support from the German Research Foundation, the European Union and the NINDS/NIH.

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Supplementary information

Glossary

Anti-epileptogenic therapies 

Treatments that, when administered immediately after a brain insult, prevent or reduce the long-term consequences of the insult after drug washout, including the development of epilepsy, neurodegeneration and cognitive or behavioural alterations.

Antiseizure medications

(ASMs). Also termed anticonvulsant or anti-epileptic drugs, compounds that inhibit or control seizures that are associated with epilepsy or other conditions.

Blood–brain barrier

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.

Breakthrough seizures

Epileptic seizures that occur despite the ongoing use of antiseizure medication or other seizure management strategies.

Disease-modifying therapies 

Treatments that alter the development or progression of epilepsy by affecting the underlying pathophysiology and natural history of the disease.

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 by which normal brain tissue becomes epileptic, encompassing the events in the latent period between an initial brain injury and the onset of recurrent seizures.

Ictogenic mechanism

The processes or factors that trigger or contribute to the generation of seizures in epilepsy; derived from the Greek word iktos, meaning seizure.

Intrathecal delivery

Drug delivery directly into the cerebrospinal fluid in the space surrounding the spinal cord, bypassing the bloodstream.

Temporal lobe epilepsy

A common, difficult-to-treat epilepsy characterized by focal seizures that originate from medial (hippocampus or amygdala) or lateral temporal lobe regions.

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Klein, P., Kaminski, R.M., Koepp, M. et al. New epilepsy therapies in development. Nat Rev Drug Discov 23, 682–708 (2024). https://doi.org/10.1038/s41573-024-00981-w

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