SBIR-STTR Award

Epilepsy is the 4th most common neurological disorder, with 1 in 26 people developing epilepsy (the occurrence of more than one unprovoked seizure) at some point in their lifetime. Unfortunately, 30-40% 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, (1) reduced seizures in zebrafish at concentrations 200-fold less than valproic acid (a common AED), (2) was effective in multiple mouse models of epilepsy, (3) was non-toxic when tested acutely or injected IP daily for three weeks at 100 mg/kg, (4) penetrates mouse brain rapidly within 15 min and (5) 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 (~1 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 1. Design and synthesize 30-50 Alkyne-VK analogs and confirm neuroprotection in vitro and efficacy in vivo in a zebrafish model of epilepsy. Aim 2: 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 (>6 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 30-40% of patients do not have good control of their seizures, this represents a population of 4 million in the US, not including patients with adverse effects related to their current medication. We expect the market value to be at least $700 million if the therapy is approved for clinical use, based on a conservative estimation of the AED market at $3.7 billion (20% 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 Statement:


Public Health Relevance:
Epilepsy is the 4th most common neurological disorder, with 1 in 26 people developing epilepsy at some point in their lifetime; however, 30-40% 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.

NIH Spending Category:
Biotechnology; Brain Disorders; Epilepsy; Neurodegenerative; Neurosciences; Nutrition

Project Terms:
Adverse effects; Alkynes; analog; Anticonvulsants; Antiepileptic Agents; base; Biological Availability; Biotechnology; Brain; Cell Death; Cells; Chemicals; Clinical; Clinical Trials; commercial application; cost; design; Development; Dose; drug market; Drug resistance; Drug Targeting; Epilepsy; Evaluation; Foundations; Future; gamma-Aminobutyric Acid; Generations; Goals; Half-Life; Head; Homeostasis; Human; In Vitro; in vivo; Ion Channel; Laboratories; Lead; Marketing; Medical; Medical Research; meetings; Modeling; Modification; mouse model; Mus; nervous system disorder; Neurons; neuroprotection; new therapeutic target; novel; novel therapeutics; Oral; Outcome; Patients; Penetration; Peripheral; Pharmaceutical Preparations; Pharmacotherapy; Phase; phase 1 study; phase 2 study; Population; pre-clinical; Process; Property; public health relevance; research and development; Resistance; Role; Seizures; Serum; Small Business Technology Transfer Research; South Carolina; Specificity; Testing; Therapeutic; Therapeutic Agents; Tissues; Toxic effect; Toxicology; Universities; Valproic Acid; Vertebrates; Vitamin K; Vitamin K 1; Zebrafish

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.

Public Health Relevance Statement:
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 have several issues and liabilities and are not effective for 40% of the population. Neuroene Therapeutics has discovered new anti-epilepsy compounds that target a new mechanism of action to protect mitochondrial and neuronal health. 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.

Project Terms:
absorption; Acute; Adverse effects; Antiepileptic Agents; base; Bioavailable; Biological Availability; Biotechnology; Blood - brain barrier anatomy; Brain; brain tissue; capsule; cellular targeting; Chronic; clinical candidate; Clinical Trials; commercial application; commercialization; Correlation Studies; design; Development; Disease; dosage; Dose; Drug Interactions; Drug Kinetics; Drug Targeting; effective therapy; Epilepsy; Excretory function; Formulation; Frequencies; Future; Generations; Goals; Half-Life; Health; Human; In Vitro; in vivo; Incidence; Lead; lead optimization; Mammals; Maximum Tolerated Dose; Metabolism; Mitochondria; mitochondrial dysfunction; Modeling; Mus; National Institute of Neurological Disorders and Stroke; Neurons; novel drug combination; novel therapeutics; Oral; Outcome; Oxides; Patients; Peripheral; Pharmaceutical Preparations; Pharmacodynamics; Phase; phase 2 study; Population; Production; Property; Rattus; Regimen; Resistance; Rodent; Rodent Model; Safety; Seizures; Serum; Small Business Technology Transfer Research; symptom treatment; Tablets; Therapeutic; Therapeutic Agents; Tissues; Toxic effect