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（由应用程序提供）：该快速应用中概述的程序旨在加速地西培（TM）的开发和商业化，以治疗癫痫患者的不受控制的癫痫发作。设想的产品将取代当前的护理标准，地西epam直肠凝胶（DIASTAT（R）），并通过皮下注射快速递送了新型的配方。为此，Xeris将使用其专有配方平台（Xerisol（TM）），该平台已经证明了具有类似于DIXSTAT（R）的药代动力学的非常低体积的稳定地氮杂剂的可行性。成功完成目标将通过公式优化和非临床阶段，IND应用和制造临床供应的临床供应将在未来的1阶段1临床试验中提高地西培（TM）的开发。这项研究与Ninds直接相关，该NIND对神经系统疾病的创新治疗剂的开发非常感兴趣，包括治疗神经系统疾病的治疗（药物，生物药物和/或设备），以及为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，以显着提高自动注射地西epa的开发，以作为一种不受控制的癫痫发作的一线，在家治疗。 1。优化Xerisol（TM）非水，固体，稳定的地西epam配方，以提供所需的药代动力学（PK）剖面并确认容器关闭的兼容性。 2。制造优化公式的非临床供应至少三（3）个GLP批次，并将这些供应置于短期稳定性研究（实时和加速）中。 3。进行辅助动物研究：一项14天的安全性研究研究，通过每日皮下和皮内注射途径，评估三（3）个Xerisol地西epam的大鼠。 b。与Xeris的非水分地西ep和diacstat（R）的迷你猪中的比较GLP PK研究。这项研究将寻求证明通过皮内和皮下注射施用的两种产品与耐受性相比，与直肠（R）（R）直肠凝胶相比，各种PK参数（包括CMAX，TMAX和AUC）之间的药理可比性。 4.在第一次临床试验中，在小瓶中制造了两（2）个CGMP临床批次，并将该批量放置在ICH符合ICH符合的长期稳定性研究中。 5。进行全面的风险分析和形成性比较人为因素研究地西培（TM）自动注射器和商业直肠凝胶施加器（DIASTAT（R）辅助）。 6.准备并向FDA提交修订的IND申请，以寻求1阶段临床研究的许可。