A preclinical assessment of monthly intramuscular GSK1265744, an InSTI, as PrEP

每月肌肉注射 GSK1265744（一种 InSTI）作为 PrEP 的临床前评估

基本信息

批准号：
8330127
负责人：
CECILIA C CHENG-MAYER
金额：
$ 49.73万
依托单位：
AARON DIAMOND AIDS RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-10 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8330127
关键词：
Adherence African Anti-Retroviral Agents Antiviral Agents Asses Botswana Cervical Chronic Clinical Clinical Trials Clinical Trials Design Coitus Collaborations Couples Data Depo Provera Development Dose Drug Formulations Drug Interactions Drug Kinetics Effectiveness Epidemic Failure Female Futility Gel HIV HIV-1 Healthcare Heterosexuals Hour Human Human Volunteers In Vitro Individual Inhibitory Concentration 50 Integrase Integrase Inhibitors Intramuscular Local Microbicides Macaca Macaca mulatta Measurement Measures Modality Modeling Monkeys Oral Outcome Participant Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Pharmacodynamics Placebos Plasma Predisposition Pregnancy Rate Prevention Procedures Property Prophylactic treatment Proteins Protocols documentation Reporting Research Personnel Resistance SIV Scientist Sexual Transmission Site Surface Tenofovir Time Tissues Treatment Protocols Vaccines Vagina Vaginal Route of Drug Administration Variant Woman arm base efficacy testing emtricitabine in vivo inhibitor/antagonist interest meetings men men who have sex with men microbicide multidisciplinary next generation novel pandemic disease placebo controlled study pre-clinical prevent rectal research study response simian human immunodeficiency virus small molecule transmission process vaginal transmission

项目摘要

DESCRIPTION (provided by applicant): The HIV-1 pandemic continues at alarming rates and there is a clear need for novel preventative strategies. Results of four studies of antiretroviral agents (ARVs) given as pre-exposure prophylaxis (PrEP) have been recently reported and demonstrated effectiveness in reducing HIV transmission rates. However, in two studies, iPrEx and CAPRISA 004, in which adherence data have been presented in detail, there were dramatic differences in responses between participants with high levels of adherence versus those considered low adherers. Furthermore, another trial, FEM-PrEP, a multisite African study of daily oral FDC TDF/FTC versus placebo was stopped due to futility. Reasons for failure remain to be defined but issues surrounding adherence to protocol procedures have been suggested by the high pregnancy rates of participants in the active arm. Taken together, these trials have established the potential for ARVs to effectively prevent HIV-1 acquisition. However, with adherence being a main determinant of outcome, there is interest in alternatives to once daily oral therapy or coital-related applications of a microbicide gel. Eight properties have been identified as desirable for a next generation PrEP candidate. These include 1) a product that is safe for episodic and chronic use; 2) one that penetrates target tissue; 3) an antiviral that is protective against HIV-1 transmission at the site it penetrates; 4) a product that is long lasting; 5) one that displays a unique and high barrier to resistance; 6) an agent that lacks significant drug-drug interactions; 7) an antiviral that is not included in most current treatment regimens; and 8) a small molecule that is affordable to use and implement. We believe that GSK1265744- LONG ACTING (744-LA), a novel, strand transfer inhibitor of HIV-1, SIV, and SHIV integrase, has the potential to fulfill these criteria. This application outlines a basic and preclinical framework required to develop 744-LA as an effective and potentially revolutionary PrEP agent. This is based on the observation that a single 400 mg dose of 744-LA administered intramuscularly to six human volunteers resulted in plasma drug levels that remained in excess of the protein-adjusted IC90 for at least 42 days post administration in all treated subjects. Systemic pharmacokinetics in cynomologous monkeys dosed at 5 mg/kg demonstrated a comparable profile to that seen in humans. And importantly, the oral formulation of 744 has demonstrated robust antiviral activity dosed as once daily monotherapy in HIV-1 infected individuals. Accordingly, we propose to demonstrate that 744 has robust antiviral activity against a panel of transmitted isolates that are representative of the global pandemic. We will define the pharmacokinetic profile of the 5 mg/kg dose in rhesus macaques both systemically and in rectal and cervical secretions and tissue. Finally we will use the low dose intrarectal and the high dose intravaginal challenge models using R5 SHIVSF162P3 in rhesus macaques to demonstrate that 744-LA effectively prevents transmission and merits clinical development as a novel PrEP agent. PUBLIC HEALTH RELEVANCE: The use of antiretroviral agents for prevention has reduced HIV-1 transmission in 4 recent clinical trials, though challenges in implementation due to issues of adherence to either daily oral therapy or peri-coitally administered topical microbicide gels ar likely and next generation PrEP agents with long-acting antiviral activity are needed. In collaboration with GlaxoSmithKline, Shionogi and ViiV Health Care we have identified a novel strand transfer integrase inhibitor, GSK1265744-LONG ACTING (744-LA) that when given as a single 400 mg dose intramuscularly has demonstrated systemic pharmacokinetics consistent with dosing anywhere from once a month to every three months. This proposal outlines a comprehensive basic and preclinical framework to demonstrate activity of this agent in vitro against a panel of globally relevant HIV-1 variants and in vivo in rhesus macaques challenged both rectally and vaginally with SHIVSF162P3 to demonstrate its potential as a revolutionary next generation PrEP agent.

描述（由申请人提供）：HIV-1 大流行继续以惊人的速度发展，显然需要新的预防策略。最近报道了四项抗逆转录病毒药物（ARV）作为暴露前预防（PrEP）的研究结果，并证明了其在降低艾滋病毒传播率方面的有效性。然而，在 iPrEx 和 CAPRISA 004 两项详细提供了依从性数据的研究中，高依从性参与者与低依从性参与者之间的反应存在显着差异。此外，另一项试验 FEM-PrEP 是一项针对每日口服 FDC TDF/FTC 与安慰剂的多地点非洲研究，由于无效而停止。失败的原因仍有待确定，但积极组参与者的高妊娠率表明了有关遵守方案程序的问题。总而言之，这些试验证实了 ARV 有效预防 HIV-1 感染的潜力。然而，由于坚持是结果的主要决定因素，因此人们对每日一次口服疗法或性交相关应用杀菌剂凝胶的替代方案感兴趣。八项特性已被确定为下一代 PrEP 候选者所期望的。其中包括 1) 可以安全地间歇性和长期使用的产品； 2) 一种能够穿透目标组织的物质； 3) 一种抗病毒药物，可防止 HIV-1 在其渗透部位传播； 4) 持久的产品； 5）表现出独特且高抵抗力的一种； 6) 缺乏显着药物间相互作用的药物； 7) 目前大多数治疗方案中不包含的抗病毒药物； 8) 易于使用和实施的小分子。我们相信 GSK1265744-长效 (744-LA) 是一种新型 HIV-1、SIV 和 SHIV 整合酶链转移抑制剂，有可能满足这些标准。该申请概述了将 744-LA 开发为有效且具有潜在革命性的 PrEP 药物所需的基本和临床前框架。这是基于以下观察结果：对六名人类志愿者进行单次 400 mg 剂量的 744-LA 肌肉注射，导致所有接受治疗的受试者在给药后至少 42 天的血浆药物水平仍然超过蛋白质调整的 IC90。食蟹猴中 5 mg/kg 剂量的全身药代动力学表现出与人类相似的特征。重要的是，744 的口服制剂在 HIV-1 感染者中每日一次单药治疗中表现出强大的抗病毒活性。因此，我们建议证明 744 对代表全球大流行的一组传播分离株具有强大的抗病毒活性。我们将确定 5 mg/kg 剂量在恒河猴全身以及直肠和宫颈分泌物和组织中的药代动力学特征。最后，我们将在恒河猴中使用 R5 SHIVSF162P3 进行低剂量直肠内和高剂量阴道内激发模型，以证明 744-LA 能有效预防传播，值得作为新型 PrEP 药物进行临床开发。公共卫生相关性：在最近的 4 项临床试验中，使用抗逆转录病毒药物进行预防已减少了 HIV-1 的传播，尽管由于坚持每日口服治疗或性交周围施用的局部杀菌剂凝胶的问题而导致实施过程中存在挑战，并且可能会出现下一代需要具有长效抗病毒活性的 PrEP 药物。我们与 GlaxoSmithKline、Shionogi 和 ViiV Health Care 合作，发现了一种新型链转移整合酶抑制剂 GSK1265744-LONG ACTING (744-LA)，当以单次 400 mg 剂量肌肉注射时，已证明全身药代动力学与每次给药一致。每月至每三个月一次。该提案概述了一个全面的基础和临床前框架，以证明该药物在体外针对一组全球相关的 HIV-1 变体的活性，以及在接受 SHIVSF162P3 直肠和阴道挑战的恒河猴体内的活性，以证明其作为革命性的下一代 PrEP 的潜力代理人。