Development of Rectal Enema As Microbicide (DREAM)

描述（由申请人提供）：直肠灌肠作为杀微生物剂（DREAM）计划的开发解决了开发一种高效，安全和更符合行为的替代方法来预防直肠HIV感染的迫切需要。该计划的总体目标是开发一种单剂量的会阴灌肠剂，以提供能够提供一周艾滋病毒保护的替诺福韦（TFV）前药。该策略（1）建立在已证明的基于TFV的暴露前预防（PrEP）在依从性人群中的高水平疗效基础上，（2）直接针对依从性作为PrEP方案的最大弱点，（3）采用了一系列创新工具，我们在之前的两个U19 IPCP直肠杀微生物剂项目中对其进行了改进。考虑到在接受肛交之前用灌肠剂进行直肠冲洗的常见做法，我们选择灌肠剂作为与口服和其他局部方法相比几乎不需要行为改变的给药策略。与口服和注射方法相比，直肠给药也减少了全身暴露。我们计划药代动力学增强，以（1）通过优化组织和细胞摄取远大于TFV本身的三种竞争性TFV前药之一（TFV富马酸二异山梨酯、TFV富马酸艾拉酚胺和CMX 157），增加TFV对结肠组织CD 4+细胞的生物利用度，以及（2）探索持续的产品释放。除了生产单一PrEP灌肠剂候选物的主要目标之外，两个次要主题对于该计划的成功是内在的，如下面的目标2和3所示。该计划整合了四个项目（临床前，组织建模，临床，IND使能）和三个核心（管理，监管和分析），以实现总体计划目标：目标1：使用竞争性管道过程开发一种正确应用的HIV预防性TFV前药灌肠剂，通过小鼠，猕猴和I期前人体研究减少多个候选药物。 目标2：根据多室药代动力学和抗逆转录病毒药效学，为非人灵长类动物至人类研究（异速生长比例）制定数据驱动的给药建议。 目标3：基于实际TFV靶组织（和其他隔室）浓度与病毒动力学模型相结合，构建能够进行临床试验模拟的模型，以增强未来研究设计/效率。

DESCRIPTION (provided by applicant): 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.