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

项目总结/摘要 需要开发下一代多用途预防技术， 长效（LA），同时全身递送产品，用于预防HIV感染， 意外怀孕我们建议开发一种新的硅水凝胶为基础的LA注射贮库系统 递送dolutegravir（DTG），一种经证实的有效的HIV整合酶链转移抑制剂（CDFI），和 左炔诺孕酮（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）， 主要目标是实现里程碑，证明开发基于颗粒的水凝胶的可行性 能够为两种药物提供至少3个月持续时间的储药系统，较短的尾药代动力学（PK） 没有药物相互作用（DDI）。在具体目标1中，我们将进行迭代公式化 开发，以生产和筛选原型组合的初步可行性，然后将进行评估 在大鼠和非人灵长类动物模型中的临床前特异性目标2中，以确定最佳 PK/药效学（PD）特征并描述安全性和DDI，以支持选择主要MPT 公式化。在具体目标3中，我们将与美国艾滋病高发地区的潜在最终用户进行接触 更深入地了解用户对产品属性的偏好。第二阶段（R33） （具体目标4-6），主要目标将是扩大产品开发工作，以表征电极导线 在IND前会议上从FDA获得IND支持反馈，进行POC避孕 有效性和HIV预防有效性，并确定最佳给药方案和目标 根据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 旨在改善每种药物的协调PK特征和持续时间， 最终用户优先考虑的属性偏好。将使用大鼠生成临床前概念验证数据 避孕效果模型和完善的重复，低剂量SHIV攻击模型，使用猪尾 （阴道内）和恒河猴（直肠内）猕猴。在确定了主要配方后，我们将 还起草毒理学试验计划、临床研究设计和临床开发计划，以支持IND前申请 与FDA会面（具体目标5）。最后，在具体目标6中，我们将在SA 3的基础上进行构建 通过离散选择实验，了解用户和供应商对LA MPT的首选产品属性 注射，以完善TPP和指导正在进行的产品开发工作。总之，这个项目 建议通过临床前概念验证开发一种具有强大监管路径的LA MPT注射剂， 未来的临床进展，为下一代艾滋病毒预防提供了重大进展， 避孕产品，可能适合最需要的高危妇女的生活方式。

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.