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

描述（由申请人提供）：HIV-1大流行继续以惊人的速度，显然需要新的预防策略。最近报告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，并证明了降低艾滋病毒传播率的有效性。然而，在两项研究中，iPrEx和CAPRISA 004，其中依从性数据已经详细介绍，有显着差异的反应之间的参与者与高水平的依从性与那些被认为是低依从性。此外，另一项试验FEM-PrEP（一项每日口服FDC TDF/FTC与安慰剂相比的多中心非洲研究）因无效而停止。失败的原因仍有待确定，但周围的问题，坚持方案程序已建议的高怀孕率的参与者在积极arm. Combined，这些试验已经建立了潜在的抗逆转录病毒药物，以有效地防止HIV-1的收购。然而，由于依从性是结果的主要决定因素，人们对每日一次口服治疗或杀微生物剂凝胶的性交相关应用的替代方案感兴趣。八个属性已被确定为下一代PrEP候选人所需的。这些包括1）对于间歇性和长期使用是安全的产品; 2）渗透靶组织的产品; 3）在其渗透部位防止HIV-1传播的抗病毒剂; 4）持久的产品; 5)一种是显示出独特和高耐药性屏障的药物; 6）缺乏显著的药物-药物相互作用的药物; 7）不包括在大多数当前治疗方案中的抗病毒药物;以及8）可负担得起使用和实施的小分子。我们认为，GSK 1265744- LONG ACTING（744-LA）是一种新型HIV-1、SIV和SHIV整合酶链转移抑制剂，具有满足这些标准的潜力。该申请概述了开发744-LA作为有效和潜在革命性PrEP制剂所需的基本和临床前框架。这是基于以下观察结果：6名人类志愿者单次肌内给予400 mg剂量的744-LA，导致所有治疗受试者的血浆药物水平在给药后至少42天保持超过蛋白质调整的IC 90。以5 mg/kg剂量给药的食蟹猴的全身药代动力学表现出与在人体中观察到的相当的特征。重要的是，744的口服制剂已在HIV-1感染个体中作为每日一次单药给药显示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剂量在恒河猴中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 SHIVSF 162 P3的低剂量直肠内和高剂量阴道内激发模型来证明744-LA有效地防止传播，并值得临床开发为新型PrEP试剂。 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经减少了HIV-1的传播，但由于坚持每日口服治疗或在阴道周围施用局部杀微生物剂凝胶的问题，实施中存在挑战，因此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，我们发现了一种新型链转移整合酶抑制剂GSK 1265744-LONG ACTING（744-LA），当单次肌内注射400 mg剂量时，其全身药代动力学与每月一次至每三个月一次的给药一致。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对一组全球相关的HIV-1变体的活性，并在恒河猴体内用SHIVSF 162 P3进行直肠和阴道挑战，以证明其作为革命性的下一代PrEP药物的潜力。

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.