Long-Acting Prevention Implantable System (LAPIS) for HIV Pre-Exposure Prophylaxis (PrEP)

用于 HIV 暴露前预防 (PrEP) 的长效预防植入系统 (LAPIS)

• 批准号: 10010563
• 负责人: Leah Johnson
• 金额: $ 78.56万
• 依托单位: RESEARCH TRIANGLE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-06 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10010563
• 关键词: 2' -deoxyadenosine; Achievement; Address; Adherence; Adult; Adverse reactions; Anti-Retroviral Agents; Antiretroviral resistance; Biodegradation; Bypass; Centers for Disease Control and Prevention (U.S.); Characteristics; Devices; Dose; Drug Delivery Systems; Drug Kinetics; Effectiveness; Evaluation; Excision; Formulation; Goals; HIV; HIV Infections; HIV antiretroviral; HIV resistance; Heterosexuals; Implant; In Vitro; Incidence; Infection; International; Intervention; Kinetics; Lead; Macaca mulatta; Modeling; Mutation; New Zealand; North Carolina; Nucleosides; Oral; Oryctolagus cuniculus; Pattern; Pharmaceutical Preparations; Pharmacologic Substance; Polymers; Population; Prevention; Prodrugs; Property; Research; Research Institute; Resistance; Reverse Transcriptase Inhibitors; Route; Safety; Science; Social Behavior; System; Tail; Technology; Tenofovir; Testing; Therapeutic; Universities; Virus Diseases; Woman; Work; cis-female; clinical translation; combat; drug release kinetics; drug release profile; drug resistant virus; implant design; in vivo; innovation; low and middle-income countries; manufacturing process; mechanical properties; men; men who have sex with men; multidisciplinary; mutant; nonhuman primate; novel; penis; pre-exposure prophylaxis; preclinical study; preference; prevent; product development; programs; prophylactic; prototype; research and development; scale up; simian human immunodeficiency virus; subcutaneous; transgender women; transmission process; viral transmission; young man; young woman

PROJECT SUMMARY The long-term goal of this proposed project is to deliver an innovative, end-user-informed HIV pre-exposure prophylaxis (PrEP) product in the form of a Long-Acting Prevention Implantable System (LAPIS). LAPIS offers a combination of attributes that surpass existing delivery systems for PrEP and align with young men and women's preferences: user independence, discretion, long-term protection (1 year), as well as favorable zero- order release kinetics of drugs, reversibility over the therapeutic window, delivery of multiple antiretrovirals (ARVs), and bioerosion of the spent implant to bypass obligatory removal. The implant is uniquely retrievable, if needed, for the duration of drug delivery, but otherwise remains stationary and biodegrades after depletion of the drug. In this manner, reversal of drug delivery is possible in the case of adverse reactions or a user's desire for discontinuation. The implant technology also decouples drug delivery characteristics from biodegradation properties and can achieve zero-order kinetics of drug release. The LAPIS platform can accommodate different classes of active pharmaceutical ingredients (APIs) and also enables the delivery of combination ARVs for PrEP, thereby addressing the potential for increased efficacy (as demonstrated for oral dosing) and providing a higher barrier for ARV-resistant HIV strains. The proposed specific aims are: (1) To develop an implant system for delivery of ARVs for HIV PrEP, subcutaneously inserted and lasting 1 year to support adherence, safety, and effectiveness; (2) To evaluate safety, pharmacokinetics (PK), and in vivo drug depletion profiles of LAPIS in preclinical studies; and (3) To test the prophylactic efficacy of LAPIS in preventing wild-type and ARV- resistant simian-human immunodeficiency virus (SHIV) transmission via the penile route within nonhuman primates (NHPs). Importantly, the proposed work will leverage achievements made during earlier programs in developing the implant platform and will build upon this work in the following key aspects: long-term active pharmaceutical ingredient (API) delivery (up to 1 year), delivery of dual APIs, characterization of drug depletion profiles, and evaluation of prophylactic efficacy in NHPs. Our established and complementary team will use a Research Strategy that is milestone-driven, with clear expected deliverables guiding progress of product development and clinical translation.

项目摘要 这个拟议项目的长期目标是提供创新的，最终用户的艾滋病毒预曝光前 以长效预防植入系统（LAPIS）的形式进行预防（PREP）产品。青金石提供 超过现有的递送系统的属性组合，与年轻人和年轻人保持一致 妇女的偏好：用户独立性，酌处权，长期保护（1年）以及有利的零 订单释放药物动力学，治疗窗口上的可逆性，多个抗逆转录病毒 （ARV）和用过的植入物的生物侵蚀以绕过强制性清除。植入物是独特的，可检索的， 如果需要，在药物递送期间 药物。以这种方式，在不良反应或用户的愿望的情况下，药物输送的逆转是可能的 用于中断。植入技术还将药物输送特性从生物降解中解脱出来 性质并可以实现药物释放的零级动力学。青金石平台可以容纳不同的 活性药物成分（API）类别，还可以递送组合ARV 准备，从而解决了提高功效的潜力（如口服剂量所证明的）并提供 抗ARV抗HIV菌株的较高障碍。拟议的特定目的是：（1）开发植入物系统 为了提供艾滋病毒预备的ARV，皮下插入并持续1年以支持依从性，安全性， 和有效性； （2）评估安全性，药代动力学（PK）和青金石的体内药物耗竭概况 在临床前研究中； （3）测试青金石在防止野生型和ARV-的预防性疗效 通过非人类的阴茎路线传播的抗性猿猴 - 人类免疫缺陷病毒（SHIV） 灵长类动物（NHP）。重要的是，拟议的工作将利用在早期计划中取得的成就 开发植入物平台，并将在以下关键方面以这项工作为基础：长期活跃 药物成分（API）输送（最多1年），双API的递送，药物耗竭的表征 NHP中预防疗效的轮廓和评估。我们建立和补充的团队将使用 具有里程碑驱动的研究策略，具有明确的预期可交付成果指导产品的进度 开发和临床翻译。