The Development of a Rectal Enema as Microbicide (DREAM) Program addresses the critical need to develop a highly effective, safe, and more behaviorally-congruent alternative for the prevention of rectal HIV infection. The overall goal of the program is to develop a single dose pericoital enema to deliver a tenofovir (TFV) prodrug capable of providing one week of HIV protection. This strategy (1) builds upon proven high levels of efficacy of TFV-based pre-exposure prophylaxis (PrEP) in adherent persons, (2) directly targets adherence as the greatest weakness of PrEP regimens, and (3) employs an array of innovative tools which we have refined in two prior U19 IPCP rectal microbicide programs. Given the common practice of rectal douching with an enema prior to receptive anal sex, we selected the enema as a dosing strategy requiring little behavioral change compared to oral and other topical approaches. Rectal delivery also reduces systemic exposure compared to oral and injectable approaches. We plan pharmacokinetic enhancements to (1) increase TFV bioavailability to colon tissue CD4+ cells by optimizing one of three competing TFV prodrugs with far greater tissue and cellular uptake than TFV itself - TFV disoproxil fumarate, TFV alafenamide fumarate, and CMX157 - and (2) explore sustained product release. Beyond the primary goal of producing a single PrEP enema candidate, two secondary themes are intrinsic to the success of this program as indicated in goals 2 and 3 below. The Program integrates four projects (Pre-Clinical, Tissue modeling, Clinical, IND-enabling) and three cores (Administrative, Regulatory, and Analytical) to achieve the overarching Program Goals: Goal 1: Develop a rectally-applied, HIV preventive TFV prodrug enema using a competitive pipeline process reducing multiple candidates through mouse, macaque, and pre-phase I human studies. Goal 2: Develop data-driven dosing recommendations for non-human primate to human studies (allometric scaling) based on both multi-compartment pharmacokinetics and antiretroviral pharmacodynamics. Goal 3: Build models enabling clinical trial simulation based on actual TFV target tissue (and other compartment) concentrations integrated with viral dynamic models to enhance future study design/efficiency.
A safe, effective HIV pre-exposure prophylaxis strategy with high levels of adherence is urgently needed to protect men and women at highest risk of HIV infection from anal sex, where transmission risk per sex act far exceeds that of cervical-vaginal transmission. We propose development of an enhanced TFV prodrug enema to take advantage of common enema use associated with anal sex and the proven efficacy of TFV. Project 1: Clinical Optimization of a Tenofovir Enema and Adherence Tracking Project Leader: Craig Hendrix DESCRIPTION: The Development of a Rectal Enema As Microbicide (DREAM) Program addresses the critical need to develop a highly effective, safe, and acceptable microbicide enema with the promise of greater adherence as a more behaviorally-transparent alternative for the prevention of rectal HIV infection. The overall goal of the program is to develop a single dose rectal enema to deliver a tenofovir (TFV) prodrug capable of providing one week of protection. This strategy builds upon proven high levels of efficacy of TFV-based pre-exposure prophylaxis (PrEP) in adherent persons and directly targets the greatest weakness of PrEP regimens - prophylactic failure due to poor adherence. Given the common practice of rectal douching with an enema prior to receptive anal sex, we have selected a dosing strategy which requires little or no behavioral change compared to other oral and topical approaches. Topical delivery also significantly reduces systemic exposure compared to oral and injectable approaches. We propose pharmacokinetic enhancements to increase TFV bioavailability and provide sustained release. Three TFV prodrugs with far greater tissue and cellular uptake than TFV itself - TFV disoproxil fumarate, TFV alafenamide fumarate (TAF, formerly GS7340), and CMX157 - have been selected for study. Integrated with 3 other projects and 3 cores in the DREAM Program, Project 1 involves a series of clinical studies to achieve the following specific aims: Aim 1: Determine the combination of TFV dose and enema tonicity best able to achieve our colon tissue target drug concentrations. Aim 2: Compare TFV enema dosing before and after to recommend dose timing and the impact of semen on tissue drug concentrations. Aim 3: Evaluate the use of biomarkers for both enema dosing and sexual activity to provide objective evidence of adherence to protocol prescribed dosing. Aim 4: Provide clinical samples (plasma, PBMC, colon tissue/cells, rectal fluid) to support method development and assay validation in Project 2, Project 3, and Core C.
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