Project 1: PREVENT Program Critical Path Project

项目 1：预防计划关键路径项目

基本信息

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
项目类别：
财政年份：
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

项目摘要

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（“CPP”；项目 1）的总体目标是协调 cGMP- 合规原料药和药品的生产和放行、管理临床前安全性和有效性研究，并制定和整合监管文件向美国食品药品监督管理局提交研究性新药 (IND) 申请管理（FDA），支持研究性临床试验。项目1将建立新产品的制造方法并帮助定义加速临床疗效示范和产品许可的发展路径。我们的杀菌剂的新型活性药物成分 (API) 是 Griffithsin (GRFT)，一种海洋藻类天然蛋白质，我们为此开发并规模化了一种高效的重组制造过程。 GRFT 是已知最有效的 HIV-1 进入抑制剂，并且具有高活性其他可能与 HIV 共同传播的病毒，例如 HSV-2。通过我们的 PREVENT 计划的合作者，我们已经生产了超过 200 克 GRFT 用于研究用途，并开发了有效且稳定的杀菌剂凝胶剂型。这些原型凝胶已在离体人体外植体中进行了初步安全性评估系统、理化稳定性和 API 释放特性非常令人鼓舞结果。在本项目的目标 1 中，我们将应用迄今为止已成功使用的方法进一步优化 API 制造工艺，实现最大产量和回收率。这制造过程将符合 FDA cGMP 指南，连同支持文档。合规API将用于cGMP 制造在核心 B 中优化的直肠凝胶最终剂型。在目标 2 中，安全性直肠凝胶产品的耐受性将在符合法规的情况下确定 3 种动物的毒理学，终点包括局部和全身安全性，耐受性、刺激性、敏感性和免疫毒性。初步化学，制造和控制 (CMC) 和安全信息以及临床草案协议将在 IND 前会议上与 FDA 讨论。机构反馈将有所帮助我们完成 IND 申请，FDA 激活该申请将使我们能够启动项目3中GRFT杀菌剂的首次人体临床试验。