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

• 批准号: 8508184
• 负责人: CECILIA C CHENG-MAYER
• 金额: $ 159.13万
• 依托单位: AARON DIAMOND AIDS RESEARCH CENTER
• 依托单位国家: 美国
• 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/8508184
• 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

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.

描述（由申请人提供）：HIV-1大流行仍以惊人的速度继续进行，并且显然需要新颖的预防策略。最近已经报道了四项作为暴露前预防（PREP）的抗逆转录病毒药物（ARV）的研究结果，并证明了在降低HIV传播率方面的有效性。但是，在两项研究中，详细介绍了依从性数据的IPREX和CAPRISA 004，在依从性较高的参与者与被认为是低座位者的参与者之间存在巨大差异。此外，另一项试验，fem-prep，是一项非洲每日口服FDC TDF/FTC与安慰剂的多个非洲研究，这是由于徒劳的。失败的原因仍有待定义，但是围绕遵守协议程序的问题是由主动组中参与者的高怀孕率提出的。综上所述，这些试验确定了ARV有效防止HIV-1采集的潜力。但是，由于依从性是结果的主要决定因素，因此人们对每日口服治疗或菌心凝胶的同时应用的应用具有兴趣。对于下一代准备候选者，已确定八个属性是理想的。其中包括1）一种可用于偶发和长期使用的产品； 2）穿透目标组织的一个； 3）一种抗病毒，可在其渗透地点防止HIV-1传播； 4）持久的产品； 5）一个显示独特且高的阻力障碍； 6）缺乏明显的药物相互作用的药物； 7）大多数当前治疗方案中未包括的抗病毒； 8）一个负担得起和实施的小分子。我们认为GSK1265744-长作用（744-LA）是一种新颖的HIV-1，SIV和SHIV整合酶的新颖的链转移抑制剂，具有满足这些标准的潜力。该应用程序概述了开发744-LA作为有效且潜在的革命性准备代理所需的基本和临床前框架。这是基于这样的观察结果，即对六名人类志愿者进行肌内施用的400 mg剂量，导致血浆药物水平超过蛋白质调整后的IC90，至少在所有治疗受试者中至少42天。以5 mg/kg剂量的cymologologologologologologologologologologologologologologologologic猴子中的全身药代动力学表现出与人类所见的概况。重要的是，在HIV-1感染的个体中，744的口服配方表现为每天一次单一疗法的强大抗病毒活性。因此，我们建议证明744具有对代表全球大流行的一组传播分离株的强大抗病毒活性。我们将在恒河猕猴中定义5 mg/kg剂量的药代动力学特征，无论是在直肠和宫颈分泌和组织中。最后，我们将使用R5 SHIVSF162P3在恒河猕猴中使用低剂量的直肠内部和高剂量的阴道内挑战模型，以证明744-LA有效地防止了传播并值得作为一种新型准备剂的临床发展。