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: 9049665
• 负责人: JAMES C. CLOYD
• 金额: $ 51.41万
• 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 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9049665
• 关键词: Acute; Advanced Development; Amendment; Animals; Appearance; Biological Assay; Biological Availability; Caregivers; Chemistry; Clinical; Clinical Research; Contracts; Cutaneous; Cyclic GMP; Data; Development; Devices; Diazepam; Dose; Drug Formulations; Drug Kinetics; Effectiveness; Emergency treatment; Epilepsy; Exhibits; FDA approved; 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; Phase; Phase I Clinical Trials; Qualifying; Rattus; Research; Research Design; Risk; Route; Safety; Seizures; Subcutaneous Injections; Syringes; System; Technology; Testing; Therapeutic; Time; 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; meetings; nervous system disorder; novel; preference; programs; public health relevance; rectal; research clinical testing; standard of care; subcutaneous; usability

 DESCRIPTION (provided by applicant): The program outlined in this Fast Track application has been designed to accelerate the development and commercialization of the DiazePen(tm) for the treatment of uncontrolled seizures in persons with epilepsy. The envisioned product would replace the current standard of care, diazepam rectal gel (DiaStat(r)), with a novel formulation fo rapid delivery via subcutaneous injection. For this effort, Xeris will use its proprietary formulaton platform (XeriSol(tm)), which has already demonstrated feasibility of a very-low volume, stable diazepam with pharmacokinetics similar to DiaStat(r). Successful completion of the aims will advance development of the DiazePen(tm) through the formulation optimization and nonclinical phase, IND application and manufacture of clinical supplies for a future Phase 1 clinical trial tha 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(tm) 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(r). 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(r) rectal gel. 4. Manufacture two (2) cGMP clinical batches of the drug product formulation in vials for the first clinical trialand 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(tm) auto-injector and the commercial rectal gel applicator (Diastat(r) AcuDial). 6. Prepare and submit an amended IND application to the FDA seeking clearance for a Phase 1 clinical study.

 描述（由申请人提供）：本快速通道申请中概述的计划旨在加速用于治疗癫痫患者不受控制的癫痫发作的 DiazePen(tm) 的开发和商业化。设想的产品将取代目前的护理标准——地西泮直肠凝胶（DiaStat(r)），采用一种通过皮下注射快速给药的新配方。为此，Xeris 将使用其专有配方平台 (XeriSol(tm))，该平台已经证明了极低用量、稳定的地西泮的可行性，其药代动力学与 DiaStat(r) 类似。成功完成这些目标将通过配方优化和非临床阶段、IND 申请以及为 Xeris Pharmaceuticals 赞助的未来 1 期临床试验生产临床用品来推进 DiazePen(tm) 的开发。这项研究与 NINDS 直接相关，NINDS 对开发神经系统疾病的创新疗法明确感兴趣，包括用于治疗神经系统疾病的疗法（药物、生物制剂和/或设备），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地西泮的开发，作为不受控制的癫痫发作的一线家庭治疗。 1. 优化 XeriSol(tm) 非水、可溶、稳定的地西泮配方，以提供所需的药代动力学 (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供应品，并将这些供应品进行短期稳定性研究（实时和加速）。 3. 开展支持 IND 的动物研究：在大鼠中进行的一项为期 14 天的安全耐受性研究，通过每日皮下和皮内注射途径评估三 (3) 种 XeriSol 地西泮制剂。 b.在小型猪中使用 Xeris 的非水地西泮和 DiaStat(r) 进行的 GLP PK 比较研究。本研究将力求证明通过皮内和皮下注射给药的两种产品与 DiaStat(r) 直肠凝胶相比，在各种 PK 参数（包括 Cmax、Tmax 和 AUC）的耐受性方面的药理学可比性。 4. 在小瓶中生产两 (2) 个 cGMP 临床批次的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(tm) 自动注射器和商业直肠凝胶涂抹器 (Diastat(r) AcuDial) 进行全面的风险分析和形成性比较人为因素研究。 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。