Development of Rectal Enema As Microbicide (DREAM)

描述(由申请人提供)：开发直肠灌肠作为杀微生物剂(DREAM)计划解决了开发一种高效、安全和更符合行为的替代方案来预防直肠艾滋病毒感染的迫切需要。该计划的总体目标是开发一种单剂口周灌肠，以提供能够提供一周艾滋病毒保护的替诺福韦(TFV)前体药物。这一策略(1)建立在基于TFV的暴露前预防(PrEP)在依从者中已被证明的高水平疗效的基础上，(2)直接将坚持作为PrEP方案的最大弱点，以及(3)采用一系列创新工具，我们在之前的两个U19 IPCP直肠杀菌剂计划中对这些工具进行了改进。考虑到在接受肛交前用灌肠冲洗直肠的普遍做法，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，需要很少的行为改变。与口服和注射方法相比，直肠分娩也减少了全身暴露。我们计划进行药代动力学增强，以(1)通过优化三种竞争的TFV前药之一来提高TFV对结肠组织CD4+细胞的生物利用度，这三种TFV前药的组织和细胞摄取量远远高于TFV本身-TFV富马酸二异丙酯、TFV富马酸丙二醇酯和CMX157-以及(2)探索产品的持续释放。除了产生一个单一的PrEP灌肠候选者的主要目标外，如下面的目标2和3所示，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：开发一种直肠应用的、预防艾滋病毒的TFV前体药物灌肠，使用竞争性流水线流程，通过小鼠、猕猴和前期I期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，为非人类灵长类动物对人类的研究(异速生长比例法)制定数据驱动的剂量建议。目标3：建立能够根据TFV目标组织(和其他隔间)的实际浓度进行临床试验模拟的模型，并与病毒动态模型相结合，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.