AED Drug Development: The Challenging but Worthwhile Study of Rare Epilepsy Syndromes

Rare Epilepsy, Antiepileptic Drug Studies


For many rare conditions, effective treatments can be frustratingly elusive—and epilepsy is no exception. Despite the development and availability of more than 20 antiepileptic drugs (AEDs), current medications still fail to control seizures in 20-30% of patients.

That’s why there are incentives in place to encourage the clinical development of new therapies for rare diseases, including rare epilepsy syndromes, particularly for those that do not respond well to existing marketed antiepileptic drugs. For example, the Orphan Drug Act guarantees market exclusivity to the drug’s developer for seven years, as well as financial and regulatory benefits during development, from tax credits to the elimination of fees for users. The American National Institutes for Neurological Disorders and Stroke Anticonvulsant Screening Program offers another incentive: free screening of antiepileptic compounds and sophisticated pre-clinical characterization of promising molecules.

Rare Epilepsy, Antiepileptic Drug Studies

Innovative Clinical Study Designs for Rare Epilepsy Syndromes

Epilepsy, by its nature, poses challenges to clinical development, and with the presence of over 20 AEDs on the market and a low success rate for Phase III epilepsy trials, we’ve seen enthusiasm for traditional antiepileptic drug development decrease. However, the need for development of new therapies is as urgent as ever, with ~30% of the epileptic patients continuing to have poorly controlled seizures despite therapy.

Given the presence of numerous approved AEDs for seizure control, conducting pure placebo-controlled designs is considered unethical in the epilepsy population, exposing the patients to unnecessary risk. A newer approach is to take patients who continue to have seizures despite a regimen of background antiepileptic drugs and give them the placebo or the study drug on top of their existing AEDs. Once a maintenance period has been achieved, the background AEDs are withdrawn. Another study design is a pseudo-placebo study, with low and high doses of the study drug. In both of these cases, the study duration does not need to be fixed—rather, these trials can have a time-to-event design, where patients receive rescue therapy following a certain number of seizures.

Another new approach is to narrow the patient population for antiepileptic drug studies, which have typically included patients with complex partial seizures, with or without secondary generalized seizures. A study drug may be effective against one seizure type, but ineffective against others, leading to many false negatives. A more homogenous patient population, identified through a specific etiology or biomarker, can make for a more effective study.

Another promising technique may be to repurpose drugs from other therapeutic areas that can either treat elements of epilepsy or that work hand-in-hand with existing AED drugs to work effectively against refractory epilepsy. This technique could reduce the level of time and investment necessary for drug discovery and development. 

As our understanding of the mechanisms mediating the development of epilepsy and the causes of drug resistance has grown substantially over the past decade, so have the opportunities for the discovery and development of more effective antiepileptic and antiepileptogenic drugs. New strategies for the discovery and clinical development of AEDs that also offer a compelling case for industry investment must be pursued in order to provide new and improved treatment options for patients with epilepsy and, importantly, rare epilepsy syndromes.

To learn more, read this article, titled “Improving Development of Antiepileptic Drugs for Rare Forms of Epilepsy,” which appeared in the Journal for Clinical Studies

Jayne Abraham, Ph.D., is a Director of Medical and Scientific Affairs for Neuroscience at Worldwide Clinical Trials, and Idil Çavuş, M.D., Ph.D., is a Senior Medical Director of Medical and Scientific Affairs for Neuroscience at Worldwide Clinical Trials.

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