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Published on: May 16, 2019
Antiepileptic Drugs in Clinical Development: Differentiate or Die?
1Unit of Neurology, San Giovanni di Dio Hospital, Via Di Torregalli n 3, 50143, Firenze, Italy.
Background:
Animal models when carefully selected, designed and conducted, are important parts of any translational drug development strategy. However, research of new compounds for patients with drugresistant epilepsies is still based on animal experiments, mostly in rodents, which are far from being a model of chronic human epilepsy and have failed to differentiate the efficacy of new compounds versus standard drug treatment.
Objective:
The objective was identification and description of compounds in clinical development in 2016.
Method:
Search was conducted from the website of the U.S. National Institutes of Health and from literature.
Results:
Identified compounds have been divided in two groups: 1) compounds initially developed for the treatment of diseases other than epilepsy: biperiden, bumetanide, everolimus, fenfluramine, melatonin, minocycline, verapamil. 2) Compounds specifically developed for the treatment of epilepsy: allopregnanolone, cannabidiol, cannabidivarin, ganaxolone, nalutozan, PF-06372865, UCB0942, and cenobamate. Everolimus, and perhaps, fenfluramine are effective in specific epileptic diseases and may be considered as true disease modifying antiepileptic drugs. These are tuberous sclerosis complex for everolimus and Dravet syndrome for fenfluramine. With the exception of a few other compounds such as cannabinidiol, cannabidivarin and minocycline, the vast majority of other compounds had mechanisms of action which are similar to the mechanism of action of the anti-seizure drugs already in the market.
Conclusion:
Substantial improvements in the efficacy, specifically as pharmacological treatment of drug-resistant epilepsy is regarded, are not expected. New drugs should be developed to specifically target the biochemical alteration which characterizes the underlying disease and also include targets that contribute to epileptogenesis in relevant epilepsy models.
Insights
New epilepsy drugs in clinical development often mimic existing treatments, showing limited innovation for drug-resistant cases. Future therapies require novel targets addressing underlying disease mechanisms for better efficacy.
Area of Science:
- Neuroscience
- Pharmacology
- Drug Development
Background:
- Animal models are crucial for translational drug development but often fail to accurately represent chronic human epilepsy.
- Rodent models have limitations in differentiating novel compound efficacy compared to standard treatments for drug-resistant epilepsies.
Purpose of the Study:
- To identify and describe antiepileptic compounds in clinical development as of 2016.
- To categorize these compounds based on their development pathway (epilepsy-specific vs. repurposed).
Main Methods:
- Searches were conducted on the U.S. National Institutes of Health website and relevant scientific literature.
- Compounds were classified into two groups: those initially developed for other conditions and those specifically for epilepsy.
Main Results:
- Compounds identified included repurposed drugs (e.g., everolimus, fenfluramine) and epilepsy-specific agents (e.g., cannabidiol, cenobamate).
- Everolimus and fenfluramine show disease-modifying potential in specific conditions like tuberous sclerosis complex and Dravet syndrome, respectively.
- Most compounds, apart from a few like cannabidiol, share mechanisms with existing anti-seizure medications.
Conclusions:
- Significant advancements in treating drug-resistant epilepsy pharmacologically are not anticipated with current approaches.
- Future drug development must target underlying biochemical alterations and epileptogenesis mechanisms in relevant models for improved therapeutic outcomes.
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