Novel mechanism for the treatment of epilepsy: New Vitamin K analogs target energetics and have low toxicity due to excellent specificity and low dose requirements compared to current therapies

DESCRIPTION provided by applicant Epilepsy is the th most common neurological disorder with in people developing epilepsy the occurrence of more than one unprovoked seizure at some point in their lifetime Unfortunately of all patients have intractable medication resistant epilepsy Thus new anti epileptic drugs AEDs that target alternative mechanisms of action are needed The long term goal of Neuroene Therapeutics is to develop a new non toxic therapeutic agent for patients with intractable seizures and for patients who currently have unacceptable adverse effects from their current AED medication The goal of this STTR is to examine the feasibility of a new class of AEDs by optimizing its serum half life bioavailability and anticonvulsant activity A small targeted screen using a zebrafish model of epilepsy identified one hit with a central moiety based on Vitamin K VK a natural compound Additional VK analogs were synthesized The lead candidate Alkyne VK reduced seizures in zebrafish at concentrations fold less than valproic acid a common AED was effective in multiple mouse models of epilepsy was non toxic when tested acutely or injected IP daily for three weeks at mg kg penetrates mouse brain rapidly within min and has inherent highly potent neuroprotective properties due to its role in maintaining energy homeostasis There are currently no AEDs that target energetics despite this being a major contributing factor for epilepsy Having a low therapeutic dose compared to current AEDs on the market means this novel therapy is likely to have fewer side effects The greatest barrier for this to be a feasible treatment in humans is its short serum half life hr The hypothesis of this Phase I study is that a lead Alkyne VK analog will be achieved through synergistic chemical modification and rapid in vitro and in vivo characterization which will be defined as a new feasible AED Aim Design and synthesize Alkyne VK analogs and confirm neuroprotection in vitro and efficacy in vivo in a zebrafish model of epilepsy Aim Define the active VK candidate that has excellent brain penetration and retention in mice At the end of this study an Alkyne VK analog candidate with acceptable serum half life andgt hr retaining its anti epileptic activity will be deemed feasible as a new generation AED In Phase II studies the lead candidate will be evaluated for its anti seizure efficacy in multiple mouse models of epilepsy and undergo full pre clinical PK PD ADME and full toxicology evaluation leading to a pre IND filing and meeting with the FDA As of patients do not have good control of their seizures this represents a population of million in the US not including patients with adverse effects related to their current medication We expect the market value to be at least $ million if the therapy is approved for clinical use based on a conservative estimation of the AED market at $ billion of the market share After Phase II a pre IND candidate will be identified and partnerships with Pharma Biotech will be sought in collabration with the Foundation of Research Development at the Medical University of South Carolina to take the therapeutic agent into human clinical trials PUBLIC HEALTH RELEVANCE Epilepsy is the th most common neurological disorder with in people developing epilepsy at some point in their lifetime however of all patients have intractable medication resistant epilepsy The long term goal of Neuroene Therapeutics is to develop a new non toxic therapeutic agent for patients with intractable seizures and for patients who currently have unacceptable adverse effects from their current medication The goal of this Phase I STTR is to examine the feasibility of a new class of anti epileptic drugs by optimizing its serum half life bioavailability and anticonvulsant activity