Auto-Injectable Diazepam Formulation for Rapid Treatment of Uncontrolled Seizures

在此快速通道应用程序中概述的程序旨在加速开发， DiazePen™用于治疗癫痫患者不受控制的癫痫发作的商业化。的 设想的产品将用一种新的药物替代目前的护理标准，地西泮直肠凝胶（DiaStat®）， 用于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™），该平台已经证明了非常低体积的稳定地西泮的可行性， 与DiaStat®相似的药代动力学。这些目标的顺利完成将推动 DiazePen™通过处方优化和非临床阶段，IND申请和生产 为Xeris Pharmaceuticals申办的未来1期临床试验提供临床用品。本研究 与NINDS直接相关，NINDS明确对开发创新疗法感兴趣， 神经系统疾病，包括用于治疗神经系统疾病的治疗剂（药物、生物制剂和/或器械） 疾病和向中枢神经系统递送治疗剂的技术/方法。 该提案设想了六个主要目标，以显着推进自动注射的发展 地西泮作为治疗不受控制的癫痫发作的一线家庭治疗方法。 1.优化XeriSol™非水、可溶、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-密封件相容性。 2.生产至少三（3）批优化制剂的非临床供应品的GLP批次，并放置 对这些供应品进行短期稳定性研究（实时和加速）。 3.进行IND启用动物研究： a.大鼠14天安全性-耐受性研究，每日评价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Xenis非水性安定和DiaStat®进行的比较GLP PK研究。本研究 将寻求证明两种产品之间的药理学可比性， 皮内和皮下注射对于耐受性的各种PK参数， Tmax和AUC。 4.生产两（2）个cGMP临床批次的小瓶制剂制剂，用于首次临床试验 并将该批次进行ICH合规性长期稳定性研究。 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 自动注射器和市售直肠凝胶施用器（Diastat® AcuDial）。 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。

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.