Treatment of status epilepticus and refractory status epilepticus with intravenous topiramate.

静脉注射托吡酯治疗癫痫持续状态和难治性癫痫持续状态。

• 批准号: 10696918
• 负责人: Pavel Klein
• 金额: $ 33.51万
• 依托单位: PREVEP, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-21 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10696918
• 关键词: Treatment; status; epilepticus; refractory; intravenous

Abstract Status epilepticus (SE) is a common neurologic emergency that fails to respond to first- and second-line anti-seizure medications (ASMs) in about one third of instances, thus progressing to refractory SE (RSE). Patients with RSE are at grave risk for neurological morbidity and mortality. The recently completed NIH-funded Established SE Treatment Trial (ESETT) highlights the need for improved SE therapies. In that study, >50% of people who failed to respond to the first line agent (i.e. a benzodiazepine; BDZ also failed to respond to the commonly used intravenous (i.v.) second-line agents (e.g. fosphenytoin, valproate, or levetiracetam (LEV)). An improved second-line injectable ASM, with higher likelihood to terminate SE than presently-available injectable ASMs, is thus an important unmet medical need. Of the currently available ASMs, topiramate (TPM) is an attractive medication to evaluate for seizure suppression in treatment-resistant SE given (1) its multimodal mechanism of action, (2) favorable data from parenteral administration in cases of highly resistant SE, and (3) its potential for neuroprotection. Oral and nasogastric tube TPM can ameliorate RSE and super-refractory SE (SRSE, a condition where seizures persist for more than 24 hours) where numerous other ASMs have failed. Yet, TPM is not clinically available for i.v. administration, which is the route of choice in SE treatment. We (PrevEp, Inc.) developed a novel, intellectual property-protected i.v. TPM formulation (PrevEp004) using the FDA-approved excipient meglumine, which provides excellent i.v. tolerability and enables rapid TPM administration across ages for treatment of SE/RSE. We now propose to test the PrevEp004 capacity to terminate SE/RSE. We will (1) measure the tolerability and efficacy of i.v. TPM (PrevEp004) in comparison to i.v. LEV in the rat lithium-pilocarpine model of established SE, following treatment with a BDZ to mimic a realistic clinical situation, using a randomized, blinded design with continuous video EEG monitoring of treatment outcome; (2) measure plasma and brain pharmacokinetics (PK) of the most effective dose of i.v. TPM in rats in order to determine effective drug plasma and brain concentrations to target in clinical trials; (3) further optimize the novel i.v. formulation of PrevEp004 (i.v. TPM), and establish a GMP manufacturing process for the i.v. formulation to enable clinical trial supply; (4) Evaluate the toxicity of the i.v. TPM formulation in rats by conducting a GLP compliant multiple dose toxicity study with i.v. administration of PrevEp004; and (5) prepare a pre-IND meeting with the FDA to enable clinical trials using data obtained from aims 1-4. The pilocarpine experiments and PK studies will be done by Dr. Goodkin at UVA. The pharmaceutical development will be done with Dr. Rogawski at UCD. Expected outcome: Within two years of funding we will (a) test PrevEp004 tolerability and efficacy in an etiologically realistic rat SE model; (b) develop a suitable PrevEp004 formulation and characterize its safety; and (c) conduct a pre-IND meeting to enable the future conduct of a phase I and Ila program in volunteers and SE/RSE patients as a step toward the first-in-human proof of concept (PoC) study, which will be the basis of a subsequent SBIR phase II application. Beyond the scope of this proposal, PrevEp004 may also serve as an i.v. TPM replacement that can be used in instances where patients (>2 million in US) who apply TPM for seizure or migraine management cannot tolerate enteric medication (e.g. after gastrointestinal surgery).

抽象的 癫痫持续状态 (SE) 是一种常见的神经系统急症，约三分之一的病例对一线和二线抗癫痫药物 (ASM) 无效，从而进展为难治性癫痫持续状态 (RSE)。 RSE 患者面临神经系统发病和死亡的严重风险。最近完成的 NIH 资助的既定 SE 治疗试验 (ESETT) 强调了改进 SE 疗法的必要性。在这项研究中，超过 50% 的人对一线药物（即苯二氮卓类药物）没有反应；BDZ 对常用的静脉注射 (i.v.) 二线药物（例如磷苯妥英、丙戊酸或左乙拉西坦 (LEV)）也没有反应。改进的二线注射 ASM 比目前可用的二线注射 ASM 更有可能终止 SE 因此，可注射的 ASM 是一个重要的未满足的医疗需求。在目前可用的 ASM 中，托吡酯 (TPM) 是一种有吸引力的药物，可用于评估难治性 SE 的癫痫发作抑制作用，因为 (1) 其多模式作用机制，(2) 在高度耐药性 SE 病例中肠外给药的有利数据，以及 (3) 其神经保护潜力。口腔和鼻饲管 TPM 可以改善 RSE 以及超级难治性 SE（SRSE，一种癫痫发作持续超过 24 小时的病症），许多其他 ASM 都失败了。然而，TPM 尚未在临床上用于静脉注射。给药，这是SE治疗的选择途径。我们（PrevEp, Inc.）开发了一种新颖的、受知识产权保护的静脉注射药物。 TPM 配方 (PrevEp004) 使用 FDA 批准的赋形剂葡甲胺，提供优异的 静脉注射耐受性，并能够跨年龄段快速进行 TPM 管理来治疗 SE/RSE。我们现在建议测试 PrevEp004 终止 SE/RSE 的能力。我们将 (1) 测量静脉注射的耐受性和功效。 TPM (PrevEp004) 与 i.v. 相比已建立的 SE 大鼠锂-毛果芸香碱模型中的 LEV，经过 BDZ 治疗以模拟真实的临床情况 根据情况，采用随机、盲法设计，对治疗结果进行连续视频脑电图监测； (2) 测量静脉注射最有效剂量的血浆和脑药代动力学（PK）。在大鼠中进行 TPM，以确定临床试验中目标的有效药物血浆和脑浓度； (3)进一步优化小说i.v.制定 PrevEp004（i.v. TPM），并建立 GMP 生产工艺 静脉注射制剂以实现临床试验供应； (4) 评估静脉注射的毒性。通过静脉注射进行符合 GLP 标准的多剂量毒性研究，在大鼠中配制 TPM 制剂。 PrevEp004 的管理； (5) 与 FDA 准备一次 IND 前会议，以便能够使用从目标 1-4 获得的数据进行临床试验。毛果芸香碱实验和 PK 研究将由 Goodkin 博士在 紫外线。药物开发将由都柏林大学的 Rogawski 博士完成。预期结果：在资助后的两年内，我们将 (a) 在病因学上真实的大鼠 SE 模型中测试 PrevEp004 的耐受性和功效； (b) 开发合适的 PrevEp004 制剂并表征其安全性； (c) 召开 IND 前会议，以便将来能够在志愿者中开展第一阶段和 Ila 计划， SE/RSE 患者是迈向首次人体概念验证 (PoC) 研究的一步，该研究将成为后续 SBIR II 期应用的基础。除了本提案的范围之外，PrevEp004 也可以作为静脉注射药物。 TPM 替代品可用于应用 TPM 治疗癫痫或偏头痛的患者（美国超过 200 万）无法耐受肠道药物的情况（例如胃肠道药物治疗后） 外科手术）。