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

项目范围：用于下一代长效艾滋病毒预防和避孕的水凝胶注射储库系统

• 批准号: 10090563
• 负责人: Meredith R Clark
• 金额: $ 105.3万
• 依托单位: EASTERN VIRGINIA MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-12 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10090563
• 关键词: AIDS prevention; Alpha Particles; Animal Model; Animals; Antiviral Agents; Biological; Centers for Disease Control and Prevention (U.S.); Clinical; Clinical Research; Contraceptive Agents; Contraceptive methods; Coupled; Data; Development; Development Plans; District of Columbia; Dose; Drug Delivery Systems; Drug Interactions; Drug Kinetics; Drug Screening; Encapsulated; Evaluation; Feedback; Female; Focus Groups; Formulation; Future; HIV; HIV Integrase; HIV risk; Half-Life; Hour; Hydrogels; In Vitro; Incidence; Individual; Injectable; Integrase; Interview; Lead; Levonorgestrel; Life Style; Macaca; Modeling; Pharmaceutical Preparations; Pharmacodynamics; Phase; Plasma; Population; Prevention; Property; Prophylactic treatment; Provider; Rattus; Regimen; Reproductive Health; Research; Research Design; Rheology; Rhesus; Risk; Risk Assessment; Safety; Silicon Dioxide; System; Tail; Technology; Testing; Toxicology; Vagina; Woman; Work; anti-viral efficacy; base; biomaterial compatibility; clinical development; cohort; contraceptive efficacy; design; drug release profile; experimental study; first-in-human; improved; in vivo; inhibitor/antagonist; innovation; meetings; next generation; nonhuman primate; novel; phase III trial; pre-clinical; pre-clinical assessment; preference; preservation; product development; prophylactic; prototype; rectal; sexually active; silochrome; simian human immunodeficiency virus; unintended pregnancy

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.

项目摘要/摘要 有必要开发提供下一代多功能预防技术（MPT） 长效（LA），同时全身交付产品，以预防艾滋病毒收购和 意外怀孕。我们建议开发一种新型的基于二氧化硅水凝胶的LA可注射仓库系统 提供DoluteGravir（DTG），这是一种经过验证且有效的HIV整合酶Strand-Transfer抑制剂（Insti），并且 Levonorgestrel（LNG），有执照的避孕剂。在项目的第一个（R61）阶段（特定目标1-3）， 主要目的是实现建立基于粒子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，较短的尾部药代动力学（PK） 轮廓，没有药物相互作用（DDI）。在特定目标1中，我们将进行迭代配方 开发以生成和筛选原型组合以供初始可行性，然后将评估 在大鼠和非人类灵长类动物模型中的特定目标2中临床上的临床上，以确定最佳 PK/药效学（PD）概况并表征安全性和DDI，以支持选择铅MPT 配方。在特定目标3中，我们将与艾滋病毒发病率高的美国地区的潜在最终用户互动 要对产品属性的用户偏好有更深入的了解。在第二（R33）阶段 （特定目标4-6），主要目标是扩大产品开发工作以表征铅 在预定的会议上进行POC避孕药，并从FDA获得配方并从FDA获得索引反馈 在动物研究中的疗效和HIV预防疗效，并定义最佳剂量方案和靶标 基于最终用户输入的产品配置文件（TPP）。在特定目标4中，配方优化活动将是 执行以改善每种药物的统一PK剖面和持续时间，并更好地满足产品 最终用户优先级的属性首选项。临床前概念验证数据将使用大鼠生成 避孕功效模型和使用辫子的重复重复，低剂量的SHIV挑战模型 CDC处的（阴道内）和恒河猴（内部）猕猴。识别铅配方后，我们将 还起草了毒理学测试计划，临床研究设计和临床开发计划，以支持预先指导 与FDA会面（特定目标5）。最后，在特定目标6中，我们将基于SA3的形成性工作 通过一个离散选择实验来了解La Mpt的用户和提供商首选产品属性 可以注射，以完善TPP并指导正在进行的产品开发工作。总之，这个项目 提议通过临床前概念验证开发具有强大调节路径的LA MPT 未来的临床进步，为下一代艾滋病毒预防和 避孕产品可能适合最需要的高危女性的生活方式。