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: 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
• 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

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(申请人提供)：艾滋病毒-1大流行仍在以惊人的速度蔓延，显然需要新的预防战略。最近报道了四项关于作为暴露前预防(PrEP)的抗逆转录病毒药物(ARV)的研究结果，并证明了其在降低艾滋病毒传播率方面的有效性。然而，在两项研究中，Iprex和CAPRISA 004详细介绍了依从性数据，高依从性的参与者与那些被认为是低依从者的参与者之间的反应有很大的差异。此外，另一项关于每日口服FDC TDF/FTC与安慰剂的非洲多点研究FE-PrEP因无效而被叫停。失败的原因仍未确定，但活动组参与者的高怀孕率表明了遵守礼仪程序的问题。总而言之，这些试验已经确立了抗逆转录病毒药物有效防止艾滋病毒-1感染的潜力。然而，由于依从性是结果的主要决定因素，人们对替代每日一次的口服治疗或与杀微生物剂凝胶有关的性交应用感兴趣。八种特性已被确定为下一代PrEP候选的理想属性。这些产品包括1)间歇性和慢性使用安全的产品；2)穿透目标组织的产品；3)在穿透部位防止HIV-1传播的抗病毒药物；4)持久的产品； 5)一种表现出独特的高耐药性屏障的药物；6)一种缺乏显著的药物-药物相互作用的药物；7)一种目前大多数治疗方案中没有包括的抗病毒药物；以及8)一种使用和实施起来都负担得起的小分子。我们相信，GSK1265744-Long Active(744-LA)是一种新型的HIV-1、SIV和SIV整合酶的链转移抑制剂，具有满足这些标准的潜力。本申请概述了将744-LA开发为一种有效的、可能具有革命性的PrEP制剂所需的基本和临床前框架。这是基于这样的观察，即6名志愿者肌肉注射400毫克744-LA后，所有受试者的血浆药物水平在给药后至少42天内保持在蛋白质调整后的IC90以上。以5 mg/kg剂量给药的猕猴全身药代动力学与在人类中看到的相似。重要的是，744的口服配方已经显示出强大的抗病毒活性，作为每天一次的单一治疗剂量在HIV-1感染者中。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剂量在恒河猴体内以及在直肠和宫颈分泌物和组织中的药代动力学特征。最后，我们将使用R5 SHIVSF162P3在恒河猴的低剂量直肠内和高剂量阴道内激发模型，证明744-LA有效地防止了传播，值得作为一种新型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预防减少了艾滋病毒-1的传播，尽管由于坚持每日口服治疗或性交周围使用局部杀微生物剂凝胶的问题而在实施中可能面临挑战，并且需要具有长效抗病毒活性的下一代PrEP药物。在与葛兰素史克、Shionogi和ViiV Health Care的合作中，我们已经确定了一种新型链转移整合酶抑制剂GSK1265744-长效(744-LA)，当单次肌肉注射400 mg剂量时，显示出与每月一次至每三个月给药一致的全身药代动力学。该提案概述了一个全面的基础和临床前框架，以展示该制剂在体外对一组全球相关的HIV-1变异株的活性，以及在恒河猴直肠和阴道内用SHIVSF162P3挑战的体内活性，以展示其作为革命性的下一代PrEP制剂的潜力。