Auto-Injectable Diazepam Formulation for Rapid Treatment of Uncontrolled Seizures

 描述（由申请人提供）：本快速通道申请中概述的项目旨在加速DiazePen（TM）的开发和商业化，用于治疗癫痫患者不受控制的癫痫发作。设想的产品将取代目前的护理标准，地西泮直肠凝胶（DiaStat（r）），与一种新的配方，通过皮下注射快速交付。为此，Xeris将使用其专有的配方平台（XeriSol（tm）），该平台已经证明了极低容量、稳定的地西泮的可行性，其药代动力学与DiaStat（r）相似。这些目标的成功完成将通过处方优化和非临床阶段、IND申请和为Xeris Pharmaceuticals申办的未来1期临床试验生产临床供应品来推进DiazePen（TM）的开发。这项研究与NINDS直接相关，NINDS明确对神经系统疾病的创新疗法的开发感兴趣，包括治疗神经系统疾病的治疗剂（药物，生物制剂和/或器械），以及将治疗剂输送到中枢神经系统的技术/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作为不受控制的癫痫发作的一线家庭治疗的发展。1.优化XeriSol（tm）非水溶性、稳定的地西泮制剂，以提供所需的药代动力学（PK）特征，并确认容器密封件的相容性。2.生产至少3个GLP批次的优化制剂非临床供应品，并将这些供应品用于短期稳定性研究（实时和加速）。3.进行IND使能动物研究：a.大鼠14天安全性-耐受性研究，评价每日皮下和皮内注射途径的三（3）种XeriSol地西泮制剂。 B. Xeris非水性地西泮和DiaStat（r）在小型猪中的GLP PK比较研究。本研究将试图证明通过皮内和皮下注射给药的两种产品与DiaStat（r）直肠凝胶相比在耐受性、各种PK参数（包括Cmax、Tmax和AUC）方面的药理学可比性。4.生产两（2）个cGMP临床批次的小瓶制剂制剂，用于第一次临床试验，并将该批次用于ICH合规性长期稳定性研究。5.使用DiazePen（tm）自动注射器和市售直肠凝胶施源器（Diastat（r）AcuDial）进行全面风险分析和形成性比较人为因素研究。6.准备并向FDA提交修正的IND申请，以寻求1期临床研究的批准。

 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.