Ultra-long Acting Transcutaneously Refillable Islatravir Nanofluidic Implant for HIV Pre-Exposure

摘要 长效(LA)暴露前预防(PrEP)策略提供了改善对 最大限度地预防艾滋病毒的治疗方案。零级释放动力学的关键属性，长期 药物递送、用户独立给药、治疗决定权、长期使用的安全性和可取回性 成功实施临床广泛PrEP的理想标准。到目前为止，洛杉矶的PrEP战略还没有 充分满足上述标准。我们的目标是通过开发一种超 长效司拉他韦(ISL)植入物，释放持续时间至少2年 不间断地进行持久和安全的艾滋病毒预防，不依赖于用户的坚持。为了实现这一目标，我们 提出了一种经皮可再充填的纳米流控释药植入物，用于持续治疗 和持续的ISL释放。NanoDDI包括新获得专利的纳米流体膜，以及用于快速、 微创经皮药物再充填。通过注射器手动进行灌装，无需任何 复杂的泵或设备，以延长植入物的使用寿命超过2年。该纳米流体膜用于 通过被动扩散控制药物释放的纳米通道，无需泵送机制，允许 离散的、长期的、用户独立的给药。与注射剂或其他LA聚合策略不同，NanoDDI 避免爆裂和腐烂释放。零级释放动力学与生理条件无关， 不考虑个体间的异质性。重要的是，NanoDDI满足了用户的自由裁量权偏好 且剂量持续时间较长。 在这里，我们将检验这样一个假设，即来自NanoDDI的持续和持续的ISL传递将实现预防性 持续两年的药物水平，并有效防止非人类灵长类动物(NHP)中的希沃克病毒感染。这 提案概述了开发NanoDDI作为HIV PrEP的基础的全面临床前框架 平台，利用团队在临床前和临床艾滋病毒PrEP、长效药物输送、药物 配方和抗逆转录病毒药理。我们的目标是1)开发和优化NanoDDI和ISL配方 2)评估NanoDDI-ISL的药代动力学(PK)、耐受性和安全性 在NHP工作2年，并评估经皮药物再灌装的效果；3)综合 评价NanoDDI-ISL在4种猴HIV传播途径中的PrEP效果，即直肠、阴茎、 阴道和静脉注射。 我们的多学科团队在长效给药方面的合作艾滋病毒PrEP研究方面有着坚实的历史 植入，并将获得默克公司的科学技术支持和药物供应的这项研究。我们将使用 里程碑驱动研究方法将NanoDDI-ISL技术推向临床的最终目标 翻译。

Abstract Long-acting (LA) pre-exposure prophylactic (PrEP) strategies offer the promise of improving adherence to therapeutic regimen for maximal HIV preventive efficacy. Key attributes of zero-order release kinetics, long-term drug delivery, user-independent dosing, therapeutic discretion, safety for chronic use and retrievability are desirable criteria for successful widespread clinical PrEP implementation. To date, LA PrEP strategies do not sufficiently address the aforementioned criteria. Our goal is to address these limitations by developing an ultra- long acting islatravir (ISL) delivery implant with an unprecedented release duration of at least 2 years uninterrupted for durable and safe HIV prevention independent of user adherence. To achieve this goal, we propose the NanoDDI, a transcutaneously refillable subcutaneous nanofluidic drug delivery implant for sustained and constant ISL release. The NanoDDI comprises a newly patented nanofluidic membrane, and ports for rapid, minimally invasive transcutaneous drug refilling. Refilling is performed manually via a syringe without any complex pumps or equipment to extend implant use duration beyond 2 years. The nanofluidic membrane use nanochannels to control drug release through passive diffusion without pumping mechanisms, permitting discrete, long-term user-independent dosing. Unlike injectables or other LA polymeric strategies, NanoDDI avoids burst and decay release. Zero-order release kinetics is achieved independent of physiological conditions, regardless of interindividual heterogeneity. Importantly, the NanoDDI addresses user preferences for discretion and longer dose duration. Here we will test the hypothesis that constant and sustained ISL delivery from NanoDDI will achieve preventative drug levels for a 2-year duration and effectively prevent SHIV infection in non-human primates (NHP). This proposal outlines a comprehensive preclinical framework fundamental for developing NanoDDI as a HIV PrEP platform, leveraging the team’s experience in pre-clinical and clinical HIV PrEP, long-acting drug delivery, drug formulation, and antiretroviral pharmacology. We aim 1) to develop and optimize NanoDDI and ISL formulation for sustained and constant release; 2) to assess pharmacokinetics (PK), tolerability, and safety of NanoDDI-ISL for 2 years in NHP and evaluate effectiveness of transcutaneous drug refilling; and 3) to comprehensively evaluate PrEP efficacy of NanoDDI-ISL in NHPs using 4 routes of simian HIV transmission, namely rectal, penile, vaginal and intravenous. Our multidisciplinary team has a solid history of collaborative HIV PrEP studies with long-acting drug delivery implants and will receive Merck’s scientific and technical support and drug supply for this study. We will use a milestone-driven research approach to advance the NanoDDI-ISL technology towards the ultimate goal of clinical translation.