Project Horizon: Hydrogel Injectable Depot System for Next-Generation Long-Acting HIV Prevention and Contraception

项目摘要/摘要 需要开发下一代多用途预防技术(MPTS)，以提供 长效(LA)，同时系统地提供预防艾滋病毒感染和 意外怀孕。我们建议开发一种基于硅水凝胶的新型LA注射库系统 提供多洛替格列韦(DTG)，一种经过验证和有效的艾滋病毒整合酶链转移抑制剂(INSTI)，以及 左旋诺孕酮(LNG)，一种获得许可的避孕药。在项目的第一阶段(R61)(具体目标1-3)， 主要目标是达到证明开发基于颗粒的水凝胶的可行性的里程碑 仓库系统能够为两种药物提供至少3个月的持续时间，更短的尾部药代动力学(PK) 以及无药物-药物相互作用(DDI)。在具体目标1中，我们将进行迭代公式 开发以产生和筛选初步可行性的原型组合，然后对其进行评估 在大鼠和非人灵长类动物模型中临床前特定目标2确定最佳 PK/药效学(PD)简介和安全性和DDI特征，以支持选择领先的MPT 配方。在具体目标3中，我们将与美国艾滋病毒高发地区的潜在最终用户进行接触 以更深入地了解用户对产品属性的偏好。在第二阶段(R33) (具体目标4-6)，主要目标将是扩大产品开发努力，以表征领导 在IND前会议上制定并获得FDA的支持IND的反馈，进行POC避孕 动物实验中的有效性和HIV预防效果，并确定最佳给药方案和靶点 基于最终用户输入的产品配置文件(TPP)。在具体目标4中，配方优化活动将是 执行以改善每种药物的协调PK配置文件和持续时间，并更好地满足产品要求 按最终用户优先顺序排列的属性首选项。临床前概念验证数据将使用RAT生成 避孕效果模型和公认的使用猪尾的重复、低剂量SHV挑战模型 CDC的(阴道内)和恒河猴(直肠内)猕猴。一旦确定了铅的配方，我们将 还起草毒理学测试计划、临床研究设计和临床开发计划，以支持Pre-IND 与FDA会面(具体目标5)。最后，在具体目标6中，我们将在SA3的基础上再接再厉 通过离散选择实验了解用户和提供商对LA MPT的首选产品属性 可注射性，以完善TPP并指导正在进行的产品开发工作。总而言之，这个项目 建议通过临床前概念验证，开发一种可注射的LA MPT，具有强有力的监管途径 未来的临床进步，为下一代艾滋病毒预防和 可能适合最有需要的高危妇女生活方式的避孕产品。

PROJECT SUMMARY/ABSTRACT There is a need to develop next-generation multipurpose prevention technologies (MPTs) that provide long-acting (LA), simultaneous systemic delivery of products for the prevention of HIV acquisition and unintended pregnancy. We propose to develop a novel silica hydrogel-based LA injectable depot system delivering dolutegravir (DTG), a proven and potent HIV integrase strand-transfer inhibitor (INSTI), and levonorgestrel (LNG), a licensed contraceptive agent. In the first (R61) phase of the project (Specific Aims 1-3), the main objective is to achieve milestones demonstrating feasibility of developing a particle-based hydrogel depot system capable of providing at least 3 months duration for both drugs, shorter tail pharmacokinetic (PK) profiles, and no drug-drug interaction (DDI). In Specific Aim 1, we will conduct iterative formulation development to produce and screen prototype combinations for initial feasibility, which will then be evaluated preclinically in Specific Aim 2 in rat and non-human primate models to determine optimal PK/pharmacodynamics (PD) profiles and characterize safety and DDI, to support selection of a lead MPT formulation. In Specific Aim 3, we will engage with potential end-users in a US region with high HIV incidence to gain a more in-depth understanding of user preferences of product attributes. In the second (R33) phase (Specific Aims 4-6), the main objectives will be to expand product development efforts to characterize the lead formulation and obtain IND-enabling feedback from the FDA in a pre-IND meeting, conduct POC contraceptive efficacy and HIV prophylactic efficacy in animal studies, and define the optimal dosing regimen and target product profile (TPP) based on end-user input. In Specific Aim 4, formulation optimization activities will be performed to improve the harmonized PK profile and duration for each drug and to better meet the product attribute preferences prioritized by end users. Preclinical proof-of-concept data will be generated using a rat contraceptive efficacy model and the well-established repeated, low dose SHIV challenge models using pigtail (intravaginal) and rhesus (intrarectal) macaques at CDC. Upon identification of the lead formulation, we will also draft a toxicology testing plan, clinical study design and clinical development plan to support a pre-IND meeting with the FDA (Specific Aim 5). Finally, in Specific Aim 6, we will build upon the formative work of SA3 with a discrete choice experiment to understand user and provider preferred product attributes for the LA MPT injectable, in order to refine the TPP and guide on-going product development efforts. In summary, this project proposes to develop, through preclinical proof-of-concept, a LA MPT injectable with a strong regulatory path for future clinical advancement, providing a significant advancement of a next-generation HIV prevention and contraceptive product that may fit into the lifestyles of at-risk women most in need.