Development of new anti-epilepsy treatments targeting cellular energetics through mitochondrial modulation with optimal pharmacokinetics and toxicity profiles

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Neuroene Therapeutics is a biotech company established to develop and commercialize safe effective therapies for epilepsy. 1 in 26 people develop epilepsy in their lifetime, however the currently available anti- epileptic drugs (AEDs) have several issues and liabilities that leave unmet market needs, such as (1) not controlling seizures for 40% of patients with epilepsy, (2) current AEDs only treat the symptoms of epilepsy and do not modify underlying disease, (3) adverse effects. We have discovered new anti-epilepsy compounds that protect mitochondrial and neuronal health and have successfully completed the Phase I STTR: we have optimized the lead compound through careful design and synthesis, which now has excellent serum half-life (5.6 hr, compared to previous t1/2 of 1 hr), rentention, and oral bioavailability (100%) in vivo in mice, as well as increased antiseizure activity compared to our prior lead. Our goal now is to complete IND-enabling studies for our lead compound. The ultimate goal of Neuroene Therapeutics is to develop a new generation of AED for patients with medication-resistant epilepsy and those with severe side-effects from their current medication. There are currently no AEDs that target mitochondrial dysfunction, despite being a major contributing factor for epilepsy. Targeting an alternative mechanism of action, and having a low therapeutic dose compared to current AEDs on the market means this novel therapy is likely to be more effective with fewer potential side effects. Establishing the optimal oral formulation and pharmacokinetic (PK) and pharmacodynamic (PD) relationship in rodents will reveal the best dosing strategies and the best epilepsy subset for the lead compound that will enable future studies of this potential oral-based AED in higher mammals and humans. Aim 1. Synthesis, ADMET, and formulation. Our ultimate goal is to produce a safe AED that can be orally delivered in humans. An optimized oral formulation with a minimum of 80% oral bioavailability will be delivered. Aim 2. Oral dosing and brain bioavailability. We will determine the oral maximum tolerated dose (MTD), optimum dose, and dosing regimen of the lead compound in rodents. The lead compound should have no observable geno- or chronic toxicity, and will maintain a significant CMAX in brain tissue with excellent target selectivity. Aim 3: Anti-seizure efficacy. The lead compound will be evaluated for anti-seizure efficacy in multiple rodent seizure models. The lead compound will be considered efficacious against rodent models of medication-resistant epilepsy, by reducing incidence of seizures at doses below MTD, and PD (duration of acute anti-epileptic effect) will be correlated with PK. At the end of this Phase II study, the lead compound will be deemed feasible as a new generation of AED based on achieving in vivo efficacy and PK/PD milestones, allowing for studies in higher mammals required for pre-IND filing for human studies. Partnerships with Pharma and Biotech will be sought to take the therapeutic agent into human clinical trials and to complete commercialization of the product.