Development of Inhaled CPZEN-45 For Tuberculosis Therapy

开发用于结核病治疗的吸入式 CPZEN-45

• 批准号: 10116257
• 负责人: Anthony James Hickey
• 金额: $ 148.36万
• 依托单位: RESEARCH TRIANGLE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10116257
• 关键词: Aerosols; Animal Model; Animals; Bioavailable; Canis familiaris; Cavia; Cessation of life; Chemistry; Clinical Research; Communicable Diseases; Data; Development; Disease; Dose; Drug Kinetics; Environment; Extreme drug resistant tuberculosis; HIV; Incidence; Inhalation; International; Investigational Drugs; Investigational New Drug Application; Lung; Medical; Methods; Minimum Inhibitory Concentration measurement; Multi-Drug Resistance; Multidrug-Resistant Tuberculosis; Mycobacterium tuberculosis; NOEL; Organism; Patients; Performance; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Population; Preparation; Product Approvals; Rattus; Research Activity; Research Institute; Route; Safety; Subcutaneous Injections; Techniques; Toxic effect; Toxicology; Tuberculosis; United States Food and Drug Administration; Validation; analytical method; co-infection; data management; drug development; experimental study; first-in-human; good laboratory practice; in vivo; manufacturing facility; meetings; mouse model; novel therapeutics; patient population; porcine model; pre-clinical; preclinical study; protocol development; respiratory; scale up; subcutaneous; tuberculosis treatment; vaccine development

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).

项目概要/摘要 结核病 (TB) 是一种隐匿性疾病，每年导致 1.5 至 200 万人死亡。增加的 全球范围内的多重耐药结核病提出了一个未得到满足的迫切医疗需求： 新药和疫苗开发的步伐不够。经过十年的研究活动， CPZEN-45 是一种卡普拉霉素衍生物，已被证明通过以下途径给药时是安全有效的： 动物的皮下途径和肺部途径。肺部给药途径较多 比皮下注射更可取，因为它是非侵入性的并且更容易被重症患者接受 受损的目标患者群体。 CPZEN-45 已准备好进行正式的临床前和初步开发 临床研究。建议在支持现有良好项目的扩大规模和技术转让方面 生产规范 (cGMP) 生产设施，当前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 支持第一阶段单剂量逐步递增耐受性研究的文件将符合美国食品和药物管理局的要求 产品批准的管理 (FDA) 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 环境的技术转移、开发经过验证的分析方法）；具体目标 2— cGMP 大鼠和狗 14 天毒理学研究（气溶胶表征、大鼠和狗研究、验证 生物分析方法）；具体目标 3——支持 IND 前的文件准备和项目管理 与 FDA 会面（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——协议开发；单剂量递增研究的耐受性和 药代动力学）。