Replacing valproate with a safer, broad-spectrum drug for epilepsy treatment

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Epilepsy is a major health concern, affecting around 1 in 30 people in their lifetime. About one third of people with epilepsy have seizures that are not well controlled with current therapies. Approximately 40% of people with epilepsy are diagnosed with 'generalised' epilepsies (often epilepsies that are genetically driven) in which the most effective drug is sodium valproate. Sodium valproate has been a successful antiseizure treatment for over 50 years, but, more recently, it has been recognised to cause birth defects, learning disability and autism in children exposed to it in the womb. This has led to severe restrictions of valproate's use in women of child bearing age. Thus, a key unmet need in medicine is the development of a well-tolerated treatment for generalised epilepsies that can replace valproate, with equal or enhanced antiseizure activity, but without valproate's devastating effect on children exposed to it in early pregnancy. This project seeks to address this need. Our proposed solution has been to develop a valproate-like compound, 4BCCA, which is a highly promising compound, with shared antiseizure mechanisms with valproate but also with additional mechanisms of action, which may mean that it could even be more effective than valproate. Indeed, 4BCCA is effective in multiple different preclinical animal seizure models with increased potency and therapeutic index compared to valproate. Importantly, it has been particularly selected because it lacks one of the main molecular mechanisms proposed to underlie valproate's damaging effect on the unborn child. The aim of this project is to progress 4BBCA to the point of regulatory submission for first-in-human trials. To that end, we propose to confirm its promising effectiveness in seizures and its lack of side-effects, including a more detailed assessment in models which predict the adverse effects of valproate in causing birth defects. If these studies succeed, then we will be in a position to undertake clinical trials with, hopefully, the development of an antiseizure medication to replace valproate.