AAV-delivery of enhanced potassium channel in refractory epilepsy: CTA-enabling preclinical development programme

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Epilepsy affects 1% of the general population; 3.3 million patients in the US, 4.5 million in the EU, 670,000 in the UK and about 50 million globally**.** Around 80% of people with epilepsy live in low or middle income countries. People with epilepsy tend to have more physical problems, and higher rates of psychological conditions, including anxiety and depression. Risk of premature death in people with epilepsy is up to three times higher than in the general population.Approximately 70% of people with epilepsy will have focal epilepsy, defined as a diverse group of epilepsies where seizures start in a specific brain area. Around 35% of patients continue to experience seizures despite optimal anti-seizure medication. This group of patients with focal, refractory epilepsy represents a common and severe neurological disorder. Drug treatment of epilepsy frequently fails because it affects the whole brain, inducing dose-limiting neurological side-effects, and occasionally results in a paradoxical worsening of seizures. Individuals with refractory epilepsy have high rates of comorbidity and a 0.5% to 1% annual risk of sudden unexpected death in epilepsy (SUDEP).The current gold standard treatment for refractory focal epilepsy is resective surgery, which is an option for a limited subset of patients only. It involves the destruction of brain tissue from which seizures arise and carries a risk of permanent neurological damage. Only 20% of patients with focal, refractory epilepsy are deemed suitable for assessment for surgery; of these, only 25% eventually undergo resective surgery. Thus, overall, only an estimated 5% of the overall population with focal, refractory epilepsy undergoes surgical resection. Many patients are unwilling to undergo surgery even when the risk/benefit ratio is deemed clinically acceptable because of its irreversible destructive nature. Alternatives such as vagal nerve and deep brain stimulation are largely palliative and the chance of seizure freedom with further trials of new antiseizure medications is less than 5%.There is thus an urgent need for novel, effective treatments that spares vital brain tissue. EpilepsyGTx is developing EPY201as a novel gene therapy that has a more specific mechanism of action by reducing the excitability of seizure-causing circuits without silencing neurons, leading to decreased severity, duration, and frequency of seizures.As a result, EPY201 addresses a substantial unmet need. This project seeks to establish preclinical proof of concept through mouse efficacy, tolerability and toxicology studies, and to generate a CTA-enabling preclinical data package.