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

用于 HIV 暴露前预防 (PrEP) 的长效预防植入系统 (LAPIS)

• 批准号: 10581520
• 负责人: Leah Johnson
• 金额: $ 66.25万
• 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 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581520
• 关键词: 2' -deoxyadenosine; Achievement; Address; Adherence; Adult; Adverse reactions; Anti-Retroviral Agents; Antiretroviral resistance; Behavioral Research; 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; 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; Reverse Transcriptase Inhibitors; Route; Safety; Science; Social Behavior; Specific qualifier value; System; Tail; Technology; Tenofovir; Testing; Therapeutic; Universities; Virus Diseases; Work; breakthrough infection; cis-female; clinical translation; combat; drug release kinetics; drug release profile; drug resistant virus; forgetting; 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; safety assessment; 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一个创新的，最终用户知情的艾滋病毒暴露前 长效预防植入式系统（LAPIS）形式的预防（PrEP）产品。LAPIS提供 超越现有PrEP输送系统并与年轻男性保持一致的属性组合， 女性的偏好：用户独立性，自由裁量权，长期保护（1年），以及有利的零- 药物的顺序释放动力学，治疗窗的可逆性，多种抗逆转录病毒药物的递送 （抗逆转录病毒药物）和生物侵蚀的废植入物绕过强制性删除。植入物是唯一可回收的， 如果需要的话，在药物递送的持续时间内，但是在其它方面保持静止并且在耗尽药物之后生物降解。 流毒以这种方式，在不良反应或使用者期望的情况下，药物递送的逆转是可能的 停药植入技术还使药物输送特性与生物降解特性相结合 性质，并可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（API）的类别，也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潜力（如口服给药所证明的），并提供了 对抗逆转录病毒药物耐药的艾滋病毒株的屏障更高。提出的具体目标是：（1）开发一种种植系统 用于提供抗逆转录病毒药物治疗HIV PrEP，皮下插入并持续1年，以支持依从性，安全性， （2）评价LAPIS的安全性、药代动力学（PK）和体内药物消耗特征 在临床前研究中;和（3）测试LAPIS在预防野生型和ARV- 耐药猴-人免疫缺陷病毒（SHIV）通过阴茎途径在非人类中传播 灵长类动物（NHP）。重要的是，拟议的工作将利用在2010年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建立这项工作： 药物成分（API）输送（长达1年）、双重API输送、药物消耗表征 特征，并评估NHP的预防功效。我们的成熟和互补的团队将使用 研究战略是里程碑驱动的，具有明确的预期可交付成果，指导产品的进展 发展和临床翻译。