Development of Inhaled CPZEN-45 For Tuberculosis Therapy

项目摘要/摘要 结核病(TB)是一种潜伏的疾病，每年导致150-200万人死亡。这一增长 全球对多重和广泛耐药结核病提出了一个紧急的未得到满足的医疗需求，即 新药和疫苗开发的速度不够。经过十年的研究活动， CPZEN-45，一种卡普扎霉素的衍生物，已被证明是安全和有效的，当通过 动物的皮下途径和肺途径。肺给药途径较多 比皮下给药更可取，因为它是非侵入性的，更容易被重度患者接受 受损的目标患者群体。CPZEN-45准备在正式的临床前和初始阶段开发 临床研究。建议在支持扩大规模和向现有产品进行技术转让方面 制造规范(CGMP)制造设施、现行良好实验室规范的表现 (CGLP)临床前毒理学研究和研究性新药(IND)申请的准备 支持I期单剂耐受性升级研究的文件将符合美国食品和药物管理局 美国食品药品监督管理局(FDA)对产品审批的要求。完成IND所需的实验 材料如下：具体目标1-喷雾干燥CPZEN-45的放大和技术转让(放大， 向cGMP环境进行技术转让，开发有效的分析方法)；具体目标2- CGMP大鼠和狗14天毒理学研究(气雾剂特性，大鼠和狗研究，验证 生物分析方法)；具体目标3--文件编制和项目管理，以支持IND前工作 与FDA的会议(化学、制造和控制；数据管理；临床前毒理学 研究；数据管理，第一阶段-方案开发；耐受性和单剂量递增研究 药代动力学)。

PROJECT SUMMARY/ABSTRACT Tuberculosis (TB) is an insidious disease that kills between 1.5–2.0 million people annually. The increase in multiple and extensively drug-resistant TB globally presents an urgent unmet medical need that is underserved by the pace of new drug and vaccine development. Following a decade of research activity, CPZEN-45, a caprazamycin derivative, has been shown to be safe and efficacious when administered via both the subcutaneous and pulmonary routes in animals. The pulmonary route of administration is more desirable than subcutaneous delivery because it is non-invasive and more acceptable to the severely compromised target patient population. CPZEN-45 is poised for development in formal preclinical and initial clinical studies. It is proposed that in supporting scale up and technical transfer to a current Good Manufacturing Practice (cGMP) manufacturing facility, the performance of current Good Laboratory Practice (cGLP) preclinical toxicology studies and preparation of Investigational New Drug (IND) Application documents to support a Phase I single-dose escalating tolerability study would meet U.S. Food and Drug Administration (FDA) requirements for product approval. The experiments required to complete the IND materials are as follows: Specific Aim 1—Scale up and technical transfer of spray dried CPZEN-45 (scale up, technical transfer to a cGMP environment, development of validated analytical methods); Specific Aim 2— cGMP rat and dog 14-day toxicology studies (aerosol characterization, rat and dog studies, validated bioanalytical methods); Specific Aim 3—Document preparation and project management to support pre-IND meeting with the FDA (chemistry, manufacturing, and controls; data management; preclinical toxicology studies; data management, Phase I—Protocol development; single-dose escalation study of tolerability and pharmacokinetics).