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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：
9095165
负责人：
Daniel Tuse
金额：
$ 87.87万
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/9095165
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 Drug Packaging Ensure Feedback Formulation Gel Goals Guidelines HIV HIV vaccine HIV-1 Human Human Herpesvirus 2 Investigational Drugs Investigational New Drug Application Licensure Marines Marketing Methodology Methods Mus Nicotiana Oryctolagus cuniculus Pharmaceutical Preparations Pharmacologic Substance Pharmacology 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 Work base cGMP production clinical efficacy genotoxicity immunotoxicity in vivo inhibitor/antagonist irritation manufacturing process meetings microbial microbicide novel pre-clinical preclinical efficacy 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”；Project 1）的总体目标是协调cGMP-