Development of Rectal Enema As Microbicide (DREAM)

描述（由申请人提供）：直肠灌肠剂作为杀微生物剂的开发（DREAM）项目解决了开发一种高效、安全、更符合行为的替代方案来预防直肠HIV感染的关键需求。该项目的总体目标是开发一种单剂量的头周灌肠剂，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)建立在基于tfv的暴露前预防（PrEP）对依从者的高水平有效性的基础上，(2)直接针对依从性，这是PrEP方案的最大弱点，(3)采用了一系列创新工具，这些工具是我们在之前的两个U19 IPCP直肠杀微生物剂项目中改进的。考虑到接受性肛交前直肠灌洗灌肠的常见做法，我们选择灌肠作为一种剂量策略，与口服和其他局部方法相比，它需要很少的行为改变。与口服和注射方式相比，直肠给药也减少了全身暴露。我们计划通过优化三种TFV前药中的一种（TFV富马酸二氧吡酯、TFV富马酸丙胺和CMX157）来提高TFV对结肠组织CD4+细胞的生物利用度，并探索产品的持续释放。除了生产一种单一的PrEP灌肠候选剂的主要目标之外，以下目标2和3所示的两个次要主题是该计划成功的内在因素。该计划整合了四个项目（临床前、组织建模、临床、ind启用）和三个核心项目（行政、监管和分析），以实现总体计划目标：目标1：通过小鼠、猕猴和I期前人体研究，使用竞争性管道工艺开发一种直肠应用的艾滋病毒预防性TFV前药灌肠剂。目标2：基于多室药代动力学和抗逆转录病毒药效学，为非人类灵长类动物对人类研究（异速缩放）制定数据驱动的剂量建议。目标3：建立基于实际TFV靶组织（和其他隔室）浓度的临床试验模拟模型，并结合病毒动力学模型，以提高未来的研究设计/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.