Replacing valproate with a safer, broad-spectrum drug for epilepsy treatment
Lead Research Organisation:
University College London
Department Name: Institute of Neurology
Abstract
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.
Technical Summary
Goal: To provide ADME/Toxicity analysis of a potential replacement for sodium valproate, trans-4-butylcyclohexane carboxylic acid (4BCCA), to enable industry uptake and clinical trials in the
treatment of generalized epilepsy.
Need: Sodium valproate is the most effective drug for the treatment of generalized epilepsies; however, it is contraindicated in women of childbearing age due to teratogenicity. Thus, in the UK, >200K women are unable to receive optimal treatment for their epilepsy.
Rationale: From initial studies in preclinical seizure models, we identified 4BCCA, as a potent compound with valproate-like antiseizure effects. Further studies identified additional 4BCCA- mediated antiseizure mechanisms including AMPA receptor and sodium channel inhibition. The benefit of multiple targets is reflected in enhanced potency and activity of 4BCCA in drug-resistant models. In vivo, 4BCCA demonstrated a broad spectrum of activity including pharmacoresistant generalized, tonic clonic, absence, and focal seizure models. Crucially, 4BCCA does not inhibit histone deacetylation which has been proposed to be a major mechanism underlying valproate's teratogenicity.
Proposed experiments: The project will build the comprehensive preclinical data package required for regulatory approval of first-in-human clinical trials. To de-risk this programme, oral dosing efficacy and ex vivo teratogenicity studies will be undertaken ahead of GLP toxicity studies. The aim is to build on the in vitro mechanistic data and initial intra-peritoneal in vivo efficacy data. If preliminary studies are successful, a rat GLP embryo-fetal (pEFD) toxicity study will be undertaken, and these data compared to historic Valproate controls. A direct comparison to Valproate cannot be undertaken as it is unethical to administer a known teratogen in this model. The final elements will be GLP regulatory; ADME, genotoxicity and 14 day two species (rat and mini-pig) in vivo safety toxicity studies.
treatment of generalized epilepsy.
Need: Sodium valproate is the most effective drug for the treatment of generalized epilepsies; however, it is contraindicated in women of childbearing age due to teratogenicity. Thus, in the UK, >200K women are unable to receive optimal treatment for their epilepsy.
Rationale: From initial studies in preclinical seizure models, we identified 4BCCA, as a potent compound with valproate-like antiseizure effects. Further studies identified additional 4BCCA- mediated antiseizure mechanisms including AMPA receptor and sodium channel inhibition. The benefit of multiple targets is reflected in enhanced potency and activity of 4BCCA in drug-resistant models. In vivo, 4BCCA demonstrated a broad spectrum of activity including pharmacoresistant generalized, tonic clonic, absence, and focal seizure models. Crucially, 4BCCA does not inhibit histone deacetylation which has been proposed to be a major mechanism underlying valproate's teratogenicity.
Proposed experiments: The project will build the comprehensive preclinical data package required for regulatory approval of first-in-human clinical trials. To de-risk this programme, oral dosing efficacy and ex vivo teratogenicity studies will be undertaken ahead of GLP toxicity studies. The aim is to build on the in vitro mechanistic data and initial intra-peritoneal in vivo efficacy data. If preliminary studies are successful, a rat GLP embryo-fetal (pEFD) toxicity study will be undertaken, and these data compared to historic Valproate controls. A direct comparison to Valproate cannot be undertaken as it is unethical to administer a known teratogen in this model. The final elements will be GLP regulatory; ADME, genotoxicity and 14 day two species (rat and mini-pig) in vivo safety toxicity studies.
