Project 1: PREVENT Program Critical Path Project

项目 1：预防计划关键路径项目

• 批准号: 9276582
• 负责人: Daniel Tuse
• 金额: $ 107.45万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9276582
• 关键词: AIDS prevention; Animals; Biological Assay; Carbopol; Characteristics; Chemistry; Clinic; Clinical; Clinical Protocols; Clinical Research; Clinical Trials; Critical Pathways; Cyclic GMP; Development; Documentation; Dosage Forms; Ensure; Feedback; Formulation; Gel; Goals; Guidelines; HIV; HIV vaccine; HIV-1; Human; Human Herpesvirus 2; Investigational Drugs; Investigational New Drug Application; Licensure; Marines; Methodology; Methods; Mus; Nicotiana; Oryctolagus cuniculus; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology Study; Phase; Plants; Prevention; Production; Proteins; Published Comment; Rattus; Recombinants; Recovery; Regulation; Research; Risk; Rodent; Route; Safety; Skin; Suggestion; System; Toxicology; Training; United States Food and Drug Administration; Vagina; Viral; Virus; base; cGMP production; clinical efficacy; efficacy study; genotoxicity; immunotoxicity; in vivo; inhibitor/antagonist; irritation; manufacturing process; meetings; microbial; microbicide; novel; pre-clinical; preclinical safety; preclinical study; programs; prototype; rectal; rectal microbicide; safety study; transmission process

The overall goal of the Critical Path Project ("CPP"; Project 1) is to coordinate cGMP- compliant Drug Substance and Drug Product manufacture and release, manage preclinical safety and efficacy studies, and develop and integrate regulatory documents for submission of an Investigational New Drug (IND) application to US Food and Drug Administration (FDA), in support of an investigative clinical trial. Project 1 will establish the manufacturing methodology for the new product and help define an accelerated development path towards demonstration of clinical efficacy and product licensure. The novel active pharmaceutical ingredient (API) of our microbicide is Griffithsin (GRFT), a marine algal natural protein for which we have developed and scaled an efficient recombinant manufacturing process. GRFT is the most potent HIV-1 entry inhibitor known and also has high activity against other viruses that may be co-transmitted with HIV, such as HSV-2. Through our collaborators in the PREVENT Program, we have produced more than 200 g of GRFT for research use, and developed effective and stable microbicide gel dosage forms. These prototype gels have been evaluated for initial safety in an ex vivo human explant system, physicochemical stability and API release characteristics with very encouraging results. In Aim 1 of this Project, we will apply methods we have successfully used to date to further optimize the API manufacturing process for maximum yield and recovery. The manufacturing process will be brought to compliance with FDA cGMP guidelines, together with supporting documentation. Compliant API will be used to cGMP manufacture the rectal gel final dosage form optimized in Core B. In Aim 2, the safety and tolerability of the rectal gel product will be determined in regulation-compliant toxicology in 3 animal species, with endpoints to include topical and systemic safety, tolerability, irritation, sensitivity and immunotoxicity. Preliminary Chemistry, Manufacturing and Controls (CMC) and safety information along with a draft clinical Protocol will be discussed with FDA in a pre-IND meeting. Agency feedback will assist us in finalizing an IND application, activation of which by FDA will allow us to initiate a first-in-humans clinical trial of the GRFT microbicide in Project 3.

关键路径项目的总体目标（“ CPP”；项目1）是协调CGMP- 合规药物和药物产品制造和释放，管理 临床前的安全性和功效研究，并制定和整合监管文件 为了向美国食品和药物提出调查新药（IND） 管理（FDA），支持一项调查性临床试验。项目1将建立 新产品的制造方法，并有助于定义加速 发展临床功效和产品许可的发展路径。 我们菌心的新型活性药物成分（API）是Griffithsin（GRFT）， 我们已经开发并缩放有效的海洋藻类天然蛋白 重组制造过程。 GRFT是已知的最有效的HIV-1进入抑制剂，并且对 可能与HIV共同传播的其他病毒，例如HSV-2。通过我们的 预防计划中的合作者，我们生产了200克GRFT 用于研究，并开发了有效且稳定的杀菌剂凝胶剂型。 这些原型凝胶已被评估为在体内人类外植体中的初始安全性 系统，物理化学稳定性和API释放特性，非常令人鼓舞 结果。在该项目的AIM 1中，我们将应用我们已成功使用的方法 进一步优化API制造过程，以最大收益和恢复。这 制造过程将符合FDA CGMP指南， 以及支持文档。合规API将用于CGMP 制造在Core B中优化的直肠凝胶最终剂型的形式。在AIM 2中，安全性 直肠凝胶产物的耐受性将在符合调节符合条件中确定 3种动物物种的毒理学，其中包括局部和系统安全， 耐受性，刺激性，灵敏度和免疫毒性。初步化学， 制造和控制（CMC）以及安全信息以及草案临床 协议将与FDA在一次预定会议上讨论。代理商反馈将协助 我们在最终确定IND应用程序时，FDA的激活将使我们能够启动 项目3中GRFT菌心的首次人类临床试验。