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

通过线粒体调节开发针对细胞能量学的新型抗癫痫疗法，具有最佳的药代动力学和毒性特征

• 批准号: 9760014
• 负责人: SHERINE S CHAN
• 金额: $ 75万
• 依托单位: NEUROENE THERAPEUTICS INC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9760014
• 关键词: Acute; Adverse effects; Antiepileptic Agents; Bioavailable; Biological Availability; Biotechnology; Blood - brain barrier anatomy; Brain; Chronic; Clinical Trials; Correlation Studies; Development; Disease; Dose; Drug Interactions; Drug Kinetics; Drug Targeting; Epilepsy; Excretory function; Formulation; Frequencies; Future; Generations; Goals; Half-Life; Health; Human; In Vitro; Incidence; Lead; Mammals; Maximum Tolerated Dose; Metabolism; Mitochondria; Modeling; Mus; National Institute of Neurological Disorders and Stroke; Neurons; Oral; Outcome; Oxides; Patients; Peripheral; Pharmaceutical Preparations; Pharmacodynamics; Phase; Population; Production; Property; Rattus; Regimen; Resistance; Rodent; Rodent Model; Safety; Seizures; Serum; Small Business Technology Transfer Research; Tablets; Therapeutic; Therapeutic Agents; Tissues; Toxic effect; absorption; base; brain tissue; capsule; cellular targeting; clinical candidate; commercial application; commercialization; design; dosage; effective therapy; in vivo; lead optimization; mitochondrial dysfunction; novel drug combination; novel therapeutics; pharmacokinetics and pharmacodynamics; phase 2 study; side effect; symptom treatment

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.

Neuroene Therapeutics 是一家生物技术公司，旨在开发和商业化安全有效的 癫痫的治疗方法。每 26 人中就有 1 人在一生中患上癫痫病，但是目前可用的抗癫痫药物 癫痫药物 (AED) 存在一些问题和责任，导致市场需求未得到满足，例如 (1) 不 控制了 40% 的癫痫患者的癫痫发作，(2) 目前的 AED 只能治疗癫痫症状， 不改变基础疾病，（3）不良影响。 我们发现了新的抗癫痫化合物，可以保护线粒体和神经元健康， 已成功完成第一阶段 STTR：我们通过精心设计优化了先导化合物 和合成，现在具有出色的血清半衰期（5.6 小时，而之前的 t1/2 为 1 小时）、保留、 和小鼠体内的口服生物利用度（100%），以及与我们之前相比增加的抗癫痫活性 带领。我们现在的目标是完成先导化合物的 IND 研究。 Neuroene Therapeutics 的最终目标是为患有以下疾病的患者开发新一代 AED 耐药性癫痫和当前药物治疗产生严重副作用的患者。有 尽管线粒体功能障碍是癫痫的一个主要促成因素，但目前尚无针对线粒体功能障碍的 AED。 针对替代作用机制，并且与当前 AED 相比具有较低的治疗剂量 上市意味着这种新疗法可能更有效且潜在副作用更少。 建立最佳口服制剂以及药代动力学（PK）和药效（PD）关系 啮齿动物将揭示先导化合物的最佳剂量策略和最佳癫痫子集 使未来能够在高等哺乳动物和人类中研究这种潜在的口服 AED。 目标 1. 合成、ADMET 和配方。我们的最终目标是生产一种安全的 AED 人类口服。口服生物利用度至少为 80% 的优化口服制剂将是 发表。目标 2.口服剂量和大脑生物利用度。我们将确定口服最大耐受剂量 (MTD)、先导化合物在啮齿动物中的最佳剂量和给药方案。先导化合物应具有 没有可观察到的基因或慢性毒性，并且将在脑组织中维持显着的 CMAX，具有良好的目标 选择性。目标 3：抗癫痫功效。将评估先导化合物的抗癫痫功效 多种啮齿动物癫痫发作模型。该先导化合物将被认为对以下啮齿动物模型有效 药物抵抗性癫痫，通过在低于 MTD 的剂量下减少癫痫发作的发生率，以及 PD（治疗持续时间） 急性抗癫痫作用）与 PK 相关。 在第二阶段研究结束时，先导化合物将被认为是可行的新一代 AED 基于实现体内功效和 PK/PD 里程碑，允许在高等哺乳动物中进行研究 人体研究预 IND 申请所需的。将寻求与制药和生物技术的合作伙伴关系 治疗剂进入人体临床试验并完成产品的商业化。