Combination HIV Antiretroviral Rectal Microbicide Program

HIV 抗逆转录病毒直肠杀菌剂组合计划

• 批准号: 7663393
• 负责人: IAN Michael MCGOWAN
• 金额: $ 224.07万
• 依托单位: MAGEE-WOMEN'S RES INST AND FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-23 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7663393
• 关键词: Combination; HIV; Antiretroviral; Rectal; Microbicide

DESCRIPTION (provided by applicant): 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. PROJECT 1: Nonclinical Strategies for Refining Combination Rectal Formulations (Dezzutti, C) PROJECT 1 DESCRIPTION (provided by applicant): In the face of the existing HIV-1 epidemic, an effective mix of prevention modalities are needed to begin to reduce the incidence of HIV-1. This includes the used of topical microbicides. These are products that would be used to prevent the sexual transmission of HIV-1; including receptive anal intercourse. Project 1, Nonclinical Strategies for Refining Combination Rectal Formulations, of this U19 will strive to ensure that a safe and effective rectal microbicide will be developed. To date, the Phase 2b trials of "first generation" microbicide products, nonoxynol-9, SAVVY, cellulose sulfate, and Carraguard, have either failed to show effectiveness or showed harm and were halted early. This has led the way to using "second generation" microbicide products that encompass the antiretroviral (ARV) drugs, UC781 and tenofovir. We have developed an innovative testing algorithm to evaluate safety and effectiveness of ARV rectal microbicide (RM) formulations that will be developed by this U19 (Core C). This includes the use of a polarized colorectal explant culture system which to date has generated results that has been reflective of nonhuman primate and human Phase 1 clinical safety data as well as predictive of nonhuman primate and human Phase 2b clinical effectiveness data. It is of interest to determine if these RM formulations are effective independent of coitus as well as in the presence of semen. Finally, in anticipation of developing combinations of microbicides that will have multiple mechanisms of action to improve preventative effectiveness, molecules that block or prevent the fusion of HIV-1 with the target cell will be tested for antagonism or synergy with the ARV drugs. The ultimate goal of this work will be to ensure that what is developed in this U19 for RM will be safe and have the potential to be highly effective when tested in a clinical trial.

描述（由申请人提供）：联合HIV抗逆转录病毒直肠杀微生物剂（CHARM）计划解决了开发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感染的迫切需求。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。 项目1：改良直肠联合制剂的非临床策略（Dezzutti，C） 项目1描述（由申请人提供）：面对现有的HIV-1流行病，需要一种有效的预防方式组合，以开始降低HIV-1的发病率。这包括使用局部杀微生物剂。这些产品将用于预防HIV-1的性传播，包括接受性肛交。U19的项目1，改进组合直肠制剂的非临床策略，将努力确保开发安全有效的直肠杀微生物剂。迄今为止，“第一代”杀微生物剂产品壬苯醇醚-9、SAVVY、硫酸纤维素和Carraguard的2b期试验要么未能显示出有效性，要么显示出危害，并提前停止。这导致使用“第二代”杀微生物剂产品，包括抗逆转录病毒药物UC 781和替诺福韦。我们开发了一种创新的测试算法，以评估将由U19（核心C）开发的ARV直肠杀微生物剂（RM）制剂的安全性和有效性。这包括使用极化结直肠外植体培养系统，迄今为止，该系统产生的结果反映了非人灵长类动物和人类I期临床安全性数据，并预测了非人灵长类动物和人类2b期临床有效性数据。确定这些RM制剂是否独立于性交以及在精液存在下有效是有意义的。最后，为了开发出具有多种作用机制以提高预防效果的杀微生物剂组合，将测试阻断或防止HIV-1与靶细胞融合的分子与ARV药物的拮抗作用或协同作用。这项工作的最终目标是确保在U19中开发的RM是安全的，并且在临床试验中测试时具有高度有效的潜力。