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

项目总结 这一拟议项目的长期目标是提供创新的、终端用户知情的艾滋病毒预暴露 长效预防植入系统(LIPIS)形式的预防(PrEP)产品。Lapis报价 超越PrEP现有传递系统并与年轻男性保持一致的属性组合 女性偏好：用户独立性、裁量权、长期保护(1年)，以及有利的零利率 药物的有序释放动力学、治疗窗口的可逆性、多种抗逆转录病毒药物的输送 (抗逆转录病毒药物)，以及对废弃植入物的生物侵蚀，以绕过强制性移除。植入物是唯一可回收的， 如果需要，在给药期间，但在其他情况下保持静止并在耗尽后生物降解 那药。以这种方式，在出现不良反应或使用者的愿望的情况下，可以逆转药物输送 对停产的指控。植入技术还将药物输送特性与生物降解性分离 并能实现药物释放的零级动力学。Lapis平台可以容纳不同的 活性药物成分(原料药)的类别，并使联合抗逆转录病毒药物的交付 Prep，从而解决了提高疗效的可能性(如口服剂量所示)，并提供了 对抗逆转录病毒HIV毒株的屏障更高。建议的具体目标是：(1)开发植入物系统 用于HIV PrEP的抗逆转录病毒药物的皮下注射，持续1年，以支持依从性，安全性， 和有效性；(2)评价青金石的安全性、药代动力学(PK)和体内药物耗竭情况 在临床前研究中；以及(3)测试青金石预防野生型和ARV的效果。 耐药猴-人类免疫缺陷病毒(SIV)经阴茎途径在非人类体内传播 灵长类(NHP)。重要的是，拟议的工作将利用在早期方案期间取得的成就 开发植入平台，并将在以下关键方面加强这项工作：长期积极 原料药(原料药)交付(最长1年)、双原料药交付、药物耗竭表征 国家卫生保健计划的概况和预防效果的评价。我们的成熟和互补的团队将使用 以里程碑为导向的研究战略，以明确的预期交付成果指导产品进度 发展和临床翻译。

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.