Auto-Injectable Diazepam Formulation for Rapid Treatment of Uncontrolled Seizures

用于快速治疗失控癫痫发作的自动注射地西泮制剂

• 批准号: 9440793
• 负责人: JAMES C. CLOYD
• 金额: $ 79.72万
• 依托单位: XERIS PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9440793
• 关键词: Acute; Advanced Development; Amendment; Animals; Appearance; Biological Assay; Biological Availability; Caregivers; Chemistry; Clinical; Clinical Research; Clinical Trials; Contracts; Crystallization; Cutaneous; Cyclic GMP; Data; Development; Devices; Diazepam; Dose; Drug Kinetics; Effectiveness; Emergency treatment; Epilepsy; Exhibits; FDA approved; Formulation; Future; Gel; Home environment; Human; Injectable; Injection of therapeutic agent; Intravenous; Lead; Life; Manufactured Supplies; Measurement; Methodology; Methods; Miniature Swine; Modeling; National Institute of Neurological Disorders and Stroke; Needles; Neuraxis; Particulate Matter; Patients; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Pharmacology Study; Phase; Phase I Clinical Trials; Rattus; Research; Research Design; Risk; Route; Safety; Seizures; Subcutaneous Injections; Syringes; System; Technology; Testing; Therapeutic; Time; Toxicology; Update; Vial device; absorption; analytical method; base; commercialization; comparative; design; experience; improved; in vitro Assay; in vivo Model; innovation; interest; intradermal injection; liquid chromatography mass spectrometry; manufacturing facility; nervous system disorder; novel; preference; programs; rectal; research clinical testing; social; standard of care; subcutaneous; usability

The program outlined in this Fast Track application has been designed to accelerate the development and commercialization of the DiazePen™ for the treatment of uncontrolled seizures in persons with epilepsy. The envisioned product would replace the current standard of care, diazepam rectal gel (DiaStat®), with a novel formulation for rapid delivery via subcutaneous injection. For this effort, Xeris will use its proprietary formulation platform (XeriSol™), which has already demonstrated feasibility of a very-low volume, stable diazepam with pharmacokinetics similar to DiaStat®. Successful completion of the aims will advance development of the DiazePen™ through the formulation optimization and nonclinical phase, IND application and manufacture of clinical supplies for a future Phase 1 clinical trial that will be sponsored by Xeris Pharmaceuticals. This research is directly relevant to the NINDS which is explicitly interested in the development of innovative therapeutics for neurological disorders, including therapeutics (drugs, biologics, and/or devices) for treatment of neurological disorders, and technologies/methodologies to deliver therapeutics to the central nervous system. This proposal envisions six main objectives to significantly advance development of an auto-injectable diazepam as a first-line, at-home treatment for uncontrolled seizures. 1. Optimize XeriSol™ non-aqueous, soluble, stable diazepam formulations to provide the desired pharmacokinetic (PK) profile and confirm container-closure compatibility. 2. Manufacture at least three (3) GLP batches of non-clinical supplies of the optimized formulations and place these supplies on a short term stability study (real-time and accelerated). 3. Conduct IND-enabling animal studies: a. A 14-day safety-tolerability study in rats evaluating three (3) XeriSol diazepam formulations by daily subcutaneous and intradermal routes of injection. b. A comparative GLP PK study in mini pigs with Xeris’ non-aqueous diazepam and DiaStat®. This study will seek to demonstrate pharmacological comparability between the two products administered via intradermal and subcutaneous injection with respect to tolerability various PK parameters including Cmax, Tmax, and AUC compared to DiaStat® rectal gel. 4. Manufacture two (2) cGMP clinical batches of the drug product formulation in vials for the first clinical trial and place this batch on an ICH-compliant long-term stability study. 5. Conduct a comprehensive risk analysis and formative comparative human factors study with a DiazePen™ auto-injector and the commercial rectal gel applicator (Diastat® AcuDial). 6. Prepare and submit an amended IND application to the FDA seeking clearance for a Phase 1 clinical study.

本快速通道申请中概述的计划旨在加速开发和 DiazePen™ 的商业化，用于治疗癫痫患者不受控制的癫痫发作。这 设想的产品将取代当前的护理标准，地西泮直肠凝胶 (DiaStat®)，采用一种新颖的 通过皮下注射快速递送的制剂。为此，Xeris 将使用其专有配方 平台 (XeriSol™)，该平台已经证明了极低体积、稳定的地西泮的可行性 药代动力学与 DiaStat® 相似。目标的顺利完成，将有力推动我省发展 DiazePen™通过配方优化和非临床阶段、IND申请和制造 未来一期临床试验的临床用品将由 Xeris Pharmaceuticals 赞助。这项研究 与 NINDS 直接相关，NINDS 对开发创新疗法明确感兴趣 神经系统疾病，包括用于治疗神经系统疾病的疗法（药物、生物制剂和/或装置） 疾病以及向中枢神经系统提供治疗的技术/方法。 该提案设想了六个主要目标，以显着推进自动注射剂的开发 地西泮作为一线家庭治疗不受控制的癫痫发作。 1. 优化 XeriSol™ 非水、可溶、稳定的地西泮配方，以提供所需的效果 药代动力学 (PK) 曲线并确认容器密封兼容性。 2. 生产至少三 (3) 个 GLP 批次的优化配方的非临床用品并放置 这些提供短期稳定性研究（实时和加速）。 3. 开展支持 IND 的动物研究： 一个。一项针对大鼠的 14 天安全耐受性研究，每天评估三 (3) 种 XeriSol 地西泮制剂 皮下和皮内注射途径。 b.在小型猪中使用 Xeris 的非水地西泮和 DiaStat® 进行的 GLP PK 比较研究。这项研究 将寻求证明两种产品之间的药理学可比性 皮内和皮下注射对各种 PK 参数的耐受性，包括 Cmax、 与 DiaStat® 直肠凝胶相比的 Tmax 和 AUC。 4. 生产两 (2) 个 cGMP 临床批次的小瓶药品制剂，用于首次临床试验 并将该批次进行符合 ICH 的长期稳定性研究。 5. 使用 DiazePen™ 进行全面的风险分析和形成性比较人为因素研究 自动注射器和商用直肠凝胶涂抹器 (Diastat® AcuDial)。 6. 准备并向 FDA 提交修订后的 IND 申请，寻求 1 期临床研究的许可。