Combination HIV Antiretroviral Rectal Microbicide Program

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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.