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.

项目概要 该拟议项目的长期目标是提供一种创新的、最终用户知情的艾滋病毒暴露前检测方法 长效预防植入系统 (LAPIS) 形式的预防 (PrEP) 产品。青金石优惠 超越现有 PrEP 传递系统并与年轻人保持一致的属性组合 女性偏好：用户独立性、自由裁量权、长期保护（1年）以及有利的零保 药物的指令释放动力学、治疗窗内的可逆性、多种抗逆转录病毒药物的递送 （抗逆转录病毒药物），以及对用过的植入物进行生物侵蚀以避免强制去除。植入物具有独特的可回收性， 如果需要，在药物输送期间，但在药物耗尽后保持静止和生物降解 药物。以这种方式，在出现不良反应或使用者希望的情况下，可以逆转药物输送 停止。植入技术还将药物输送特性与生物降解脱钩 性质并可以实现药物释放的零级动力学。 LAPIS平台可以适应不同的 类别的活性药物成分 (API)，还能够提供组合抗逆转录病毒药物 PrEP，从而解决提高疗效的潜力（如口服给药所证明的那样）并提供 对抗逆转录病毒病毒（ARV）耐药的艾滋病毒株具有更高的屏障。提出的具体目标是： (1) 开发种植体系统 用于为 HIV PrEP 提供抗逆转录病毒药物，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 LAPIS 的安全性、药代动力学 (PK) 和体内药物消耗曲线 在临床前研究中； (3) 测试 LAPIS 在预防野生型和 ARV- 方面的预防功效 抗性猿猴人类免疫缺陷病毒 (SHIV) 通过阴茎途径在非人类体内传播 灵长类动物（NHP）。重要的是，拟议的工作将利用早期项目取得的成就 开发植入平台并将在以下关键方面继续开展这项工作： 长期活跃 药物成分 (API) 交付（长达 1 年）、双 API 交付、药物消耗表征 NHP 的概况和预防效果评估。我们既定且互补的团队将使用 以里程碑为驱动的研究策略，具有明确的预期交付成果，指导产品的进展 开发和临床转化。