A Bioresorbable Subdermal Implant for Sustained Delivery of a Novel Maturation Inhibitor to Prevent HIV Infection

一种生物可吸收皮下植入物，用于持续输送新型成熟抑制剂以预防 HIV 感染

• 批准号: 10249347
• 负责人: John A Moss
• 金额: $ 87.74万
• 依托单位: OAK CREST INSTITUTE OF SCIENCE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-28 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10249347
• 关键词: AIDS prevention; Academia; Address; Adherence; Animal Model; Anti-Retroviral Agents; Area; Automobile Driving; Biodegradation; Biological Markers; Clinical; Clinical Trials; Collaborations; Complex; Coupled; Development; Devices; Digit structure; Dose; Drug Delivery Systems; Drug Kinetics; Evaluation; Excision; Formulation; Frequencies; Fumarates; Generations; Goals; HIV; HIV Infections; Histology; Human; Image; Implant; In Vitro; Individual; Industry; Infection; Inflammation; Injectable; Integrase Inhibitors; Intervention; Kinetics; Knowledge; Longitudinal Studies; Macaca; Macaca mulatta; Mass Spectrum Analysis; Measures; Medical; Methodology; Methods; Modeling; Nucleosides; Oral; Participant; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase I Clinical Trials; Plasma; Prevention; Process; Public Health; RNA-Directed DNA Polymerase; Rattus; Recording of previous events; Regimen; Research; Resistance profile; Reverse Transcriptase Inhibitors; Risk; Route; Safety; Scientific Advances and Accomplishments; Sheep; TMC120-R147681; Techniques; Technology; Tenofovir; Topical application; Ultrasonography; Vagina; Vaginal Ring; Water; Woman; design; efficacy study; emtricitabine; experience; implant design; improved; in vivo; in vivo Model; inhibitor/antagonist; innovation; lead candidate; men; metabolomics; nanomolar; non-nucleoside reverse transcriptase inhibitors; nonhuman primate; novel; pharmacokinetics and pharmacodynamics; pill; pre-clinical; pre-exposure prophylaxis; preclinical development; prevent; programs; prophylactic; rectal; safety study; sheep model; simian human immunodeficiency virus; subcutaneous; success; transmission process; truvada; uptake

PROJECT SUMMARY Pre-exposure prophylaxis (PrEP) using orally or topically delivered antiretroviral (ARV) drugs can prevent HIV infection in susceptible, uninfected individuals. Adherence to the daily or monthly dosing regimens, however, has emerged as a critical factor driving the clinical success of HIV PrEP. The poor adherence of some participant groups in the ASPIRE trial of an intravaginal ring (IVR) delivering the non-nucleoside reverse transcriptase inhibitor (NNRTI) dapivirine (DPV) indicates that multiple barriers to adherence exist, and strategies beyond decreased dosing frequency will be required for successful implementation of an effective non-vaccine, method to prevent HIV infection. “Long-acting” subdermal implant ARV formulations that maintain protection for periods of 6 months, and preferably 1 year, or more may increase adherence by minimizing a product's use demands once the initial product uptake decision is made. We propose a resorbable subdermal implant Sustained/Extended Release Drug Delivery System (SER-DDS) delivering a novel ARV agent from the maturation inhibitor mechanistic class. The implant will be developed through a three-tiered formulation development process employing design, fabrication, and in vitro studies iteratively coupled with in vivo PK, degradation, safety, and efficacy studies in three animal models. The drug is DFH-1160005, a novel betulin-derived, 2nd generation maturation inhibitor (MI) with single-digit nanomolar potency against HIV and a robust resistance profile. The program objectives are to develop a safe and effective SER-DDS for HIV prevention; understand the fundamental pharmacology of sustained, systemic DFH-1160005 delivery in the context of vaginal and rectal HIV infection, and apply rigorous methodologies to characterize implant degradation and evaluate safety and efficacy in preclinical in vivo models. In Aim 1, we will formulate implants, measure drug release in vitro, and conduct PK studies in rats, sheep, and rhesus macaques. In Aim 2, we will investigate SER-DDS degradation and resorption kinetics and mechanisms in vitro and in vivo. In Aim 3, we will evaluate lead candidate SER-DDS safety in sheep and explore efficacy and PK- pharmacodynamic relationships in a non-human primate rectal and vaginal challenge SHIV infection model.

项目摘要 使用口服或局部递送的抗逆转录病毒（ARV）药物的预防前预防（PREP）可以预防HIV 易感性，未感染的个体感染。但是，遵守每日或每月给药方案 已成为推动HIV Prep临床成功的关键因素。某些人的依从性不佳 参与群体的参与者组（IVR）输送非核苷反向的试验 转录酶抑制剂（NNRTI）dapivirine（DPV）表明存在多个依从性，并且 成功实施有效的策略将需要降低给药频率 非疫苗，预防HIV感染的方法。维持的“长效”下植入物ARV公式 保护6个月的时期，优先1年或更长时间，可以通过最大程度地减少依从性 最初的产品吸收决策后，产品的使用需求。 我们提出了一个可吸收的下植入物持续/扩展释放药物输送系统（SER-DDS） 从成熟抑制剂机械类别中传递一种新型的ARV剂。植入物将开发 通过使用设计，制造和体外研究的三层公式开发过程 在三种动物模型中，迭代地与体内PK，降解，安全性和有效性研究相结合。该药物是 DFH-1160005，一种新型的β-衍生的，第二代成熟抑制剂（MI），带有单位纳摩尔 对艾滋病毒的效力和强大的阻力剖面。计划的目标是开发安全和 有效预防艾滋病毒的Ser-DD；了解持续的，系统性的基本药理学 DFH-1160005在阴道和直肠艾滋病毒感染的背景下递送，并将严格的方法应用于 表征植入物降解并评估临床前体内模型中的安全性和效率。在AIM 1中，我们 将制定垂体，在体外测量药物释放，并在大鼠，绵羊和恒河猴中进行PK研究 猕猴。 In Aim 2, we will investigate SER-DDS degradation and resolution kinetics and mechanisms in vitro and in vivo. In Aim 3, we will evaluate lead candidate SER-DDS safety in sheep and explore efficiency and PK- Pharmacomynamic relationships in a non-human primate rectal and vaginal challenge SHIV infection model.