Combination HIV Antiretroviral Rectal Microbicide Program

联合HIV抗逆转录病毒直肠杀微生物剂（CHARM）计划解决了开发一种安全有效的直肠杀微生物剂以预防通过无保护肛交获得的HIV感染的迫切需要。该项目的总体目标是开发一种针对直肠的抗逆转录病毒复合杀微生物剂配方。候选杀微生物剂将包括替诺福韦、UC 781以及替诺福韦和UC 781的组合。该计划有三个科学项目和三个科学核心来支持这一目标。项目1将使用一系列试验（包括结直肠细胞系和人类肠道外植体组织）对杀微生物剂的安全性和有效性进行临床前评价，并将由匹兹堡大学的Charlene Dezzutti博士进行。项目2将利用最近开发的HIV感染转基因小鼠模型，在体内动物模型中评估产品的功效，并将由德克萨斯大学的维克托加西亚-马丁内斯博士承担。项目3将进行一系列1期前人体研究，提供候选杀微生物剂的安全性、药代动力学和有效性的初步数据。这些研究的一个特别优势是能够对体内暴露于杀微生物剂产品的参与者的肠外植体进行离体/体外感染研究。临床研究将在匹兹堡大学、加州大学洛杉矶分校和约翰霍普金斯医学院进行。核心A将为研究提供行政支持。核心B将提供法规和信息学支持，并将由CONRAD（我们本次提交的公司申办者）的执行董事亨利加贝尔尼克博士指导。位于匹兹堡大学的核心C将成为配方开发核心。核心C将由丽莎罗汉博士领导，并将开发直肠特异性制剂，并将在项目1-3的迭代过程中进行评价。希望在该项目结束时，将产生一种或多种直肠特异性抗逆转录病毒杀微生物剂，可以在未来的I期直肠安全性研究中进行临床评估。

The Combination HIV Antiretroviral Rectal Microbicide (CHARM) program addresses the critical need to develop a safe and effective rectal microbicide for the prevention of HIV infection acquired through unprotected anal intercourse. The overall goal of the project is to develop a rectal specific formulation of a combination antiretroviral microbicide. The candidate microbicides will include tenofovir, UC781, and a combination of tenofovir and UC781. The Program has three scientific projects and 3 scientific cores to support this goal. Project 1 will undertake the preclinical evaluation of microbicide safety and efficacy using a range of assays including colorectal cell lines and human intestinal explant tissue and will be conducted by Dr. Charlene Dezzutti at the University of Pittsburgh. Project 2 will exploit a recently developed transgenic murine model of HIV infection to evaluate product efficacy in an in vivo animal model and will be undertaken by Dr. Victor Garcia-Martinez at the University of Texas. Project 3 will undertake a series of pre-Phase 1 human studies that will provide preliminary data on the safety, pharmacokinetics, and efficacy of the microbicide candidates. A particular strength of these studies will be the ability to conduct ex vivo / in vitro infection studies on intestinal explants from participants who have been exposed to the microbicide product in vivo. The clinical studies will be undertaken at the University of Pittsburgh, UCLA, and the Johns Hopkins School of Medicine. Core A will provide administrative support for the study. Core B will provide regulatory and informatics support and will be directed by Dr. Henry Gabelnick who is the Executive Director of CONRAD, our corporate sponsor for this submission. Core C, based at the University of Pittsburgh, will be the Formulation Development Core. Core C will be led by Dr. Lisa Rohan and will develop rectal specific formulations that will be evaluated in an iterative process in Projects 1-3. It is hoped that by the end of the program, one or more rectal specific antiretroviral microbicides will have been generated that can be clinically evaluated in future Phase 1 rectal safety studies.