"NextGen Long-acting Platform: Targeted Combination Antiretrovirals"

“下一代长效平台：靶向组合抗逆转录病毒药物”

• 批准号: 10234129
• 负责人: Rachel Ann Bender Ignacio
• 金额: --
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10234129
• 关键词: AIDS clinical trial group; Acquired Immunodeficiency Syndrome; Address; Anti-Retroviral Agents; B-Lymphocytes; Biological Assay; Blood; Blood Cells; Cells; Characteristics; Clinical; Clinical Data; Clinical Research; Clinical Trials; Clinical Trials Data Monitoring Committees; Clinical Trials Unit; Combination Drug Therapy; Communication; Complex; Data; Databases; Development; Diphosphates; Dose; Drug Combinations; Drug Kinetics; Enrollment; Ensure; Excipients; FDA approved; Formulation; Funding; Future; HIV; Hour; Human; Injectable; Institutional Review Boards; Investigational Drugs; Kinetics; Lead; Leadership; Lipids; Liposomes; Lopinavir; Lopinavir/Ritonavir; Lymphoid Cell; Lymphoid Tissue; Medical center; Modeling; Monitor; Mononuclear; Nucleotides; Oral; Participant; Performance; Peripheral Blood Mononuclear Cell; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Physiology; Plasma; Plasma Cells; Pre-Clinical Model; Protease Inhibitor; Recording of previous events; Regulatory Pathway; Research; Reverse Transcriptase Inhibitors; Safety; Sampling; Services; Sex Differences; Site; Subcutaneous Injections; Suspensions; Technology; Tenofovir; Testing; Time; TimeLine; Translational Research; United States National Institutes of Health; Universities; Washington; Water; Woman; antiretroviral therapy; arm; base; cohort; design; experience; first-in-human; human data; human study; innovation; lipid nanoparticle; lymph nodes; men; multidisciplinary; nanoparticle; next generation; nonhuman primate; novel; open label; pre-clinical; preclinical study; programs; response; statistics; success

The Targeted Long-acting Combination Antiretroviral Therapy (TLC-ART) Program has discovered a novel platform that can stabilize insoluble and soluble antiretroviral drugs together in a nanosuspension which provides long-acting (LA) plasma and cell concentrations in pre-clinical studies. The lead formulation (called TLC-ART 101) combines three FDA-approved drugs (active pharmaceutical ingredients, APIs) that are available generically lopinavir (LPV), ritonavir (RTV) and tenofovir (TFV). While TLC-ART 101 may not be developed as a commercial product, substantial pre-clinical data exists and the program has received favorable regulatory pathway guidance from the FDA. TLC-ART 101 is years ahead of other TLC-ART formulations in development. In this application, we propose a first-in-human, hypothesis-driven, clinical trial to provide human data about this novel, next generation, LA drug-combination platform technology. The trial will address multiple questions about the human pharmacokinetics (PK) and safety of this new platform. The project will be managed by an experienced, multi-disciplinary Study Leadership Team. The clinical trial will conducted by the staff at the UW AIDS Clinical Trials Unit (a Division of AIDS-approved research site affiliated with the AIDS Clinical Trials Group), overseen by an independent Data Monitoring Committee, and monitored by independent monitors. The proposed trial is an open-label, single-arm study with a pharmacologically- guided dose and duration adaptive design. The trial's hypothesis is that the TLC-ART drug-combination nanoparticle platform is safe and able to transform the PK of three short-acting generic and physically diverse antiretroviral drugs to create a LA concentration-time course in human plasma and cells. The primary objectives of the clinical trial are: 1) To characterize the plasma concentration-time course and PK of a single dose of the three APIs of TLC-ART 101 (LPV, RTV, and TFV) administered by sub-cutaneous injection, and 2) To characterize the safety and tolerability of a single subcutaneous injection of TLC-ART 101. The trial also has 4 exploratory mechanistic objectives that will provide information about the cell-targeting characteristics of TLC-ART 101 (meaning intracellular blood and lymphoid cells have equal or higher API concentrations than plasma), as well as exploring whether there are sex differences in the PK parameters of the 3 APIs. Twelve to 16 healthy persons without HIV will be enrolled in dose cohorts of 4, monitored carefully for safety, and undergo intensive PK sampling (18 timepoints over 35 days) for plasma API concentrations using a sensitive, validated assay done under GLP. Intracellular API and TFV-diphosphate concentrations from blood mononuclear cells and lymph node mononuclear cells (in a subset) will be compared to plasma concentrations to address the cell-targeting characteristics of the platform technology. The 3-year proposal includes major milestones and a timeline that will be closely monitored to ensure success of this innovative clinical trial. These human data will form a basis to develop more potent highly active LA antiviral combinations with this platform.

靶向长效联合抗逆转录病毒治疗(TLC-ART)计划发现了一种新的 可以在纳米悬浮液中将不溶性和可溶性抗逆转录病毒药物稳定在一起的平台， 在临床前研究中提供长效(LA)血浆和细胞浓度。铅配方(称为 TLC-ART 101)结合了FDA批准的三种药物(活性药物成分，原料药) 一般可用洛比那韦(LPV)、利托那韦(RTV)和替诺福韦(TFV)。而TLC-ART 101可能不是 作为一种商业产品，存在大量的临床前数据，该计划已收到 FDA提供了有利的调控途径指导。TLC-ART 101领先其他TLC-ART多年 正在开发中的配方。在这项应用中，我们提出了一项首个人类、假设驱动的临床试验，以 提供有关这一新颖的下一代洛杉矶药物组合平台技术的人力数据。审判将会 解决有关这一新平台的人体药代动力学(PK)和安全性的多个问题。这个 该项目将由一个经验丰富的多学科研究领导团队进行管理。临床试验将 由华盛顿大学艾滋病临床试验股(艾滋病批准研究网站附属的一个部门)的工作人员进行 与艾滋病临床试验小组)，由一个独立的数据监测委员会监督和监测 由独立的监视器。拟议的试验是一项开放标签的单臂研究，具有药理学- 指导剂量和持续时间适应性设计。该试验的假设是TLC-ART药物组合 纳米颗粒平台是安全的，能够转化PK的三种短效通用型和物理多样性 抗逆转录病毒药物在人体血浆和细胞中产生LA浓度-时间过程。初级阶段 临床试验的目标是：1)表征单次给药后的血药浓度-时间进程和PK TLC-ART 101的三种原料药(LPV、RTV和TFV)皮下注射的剂量，和2) 研究TLC-ART 101单次皮下注射的安全性和耐受性。审判还包括 有4个探索性的机械目标，将提供关于细胞靶向特征的信息 TLC-ART 101(意味着细胞内血液和淋巴细胞的原料药浓度等于或高于 血浆)，并探讨3种API的PK参数是否存在性别差异。12点到 16名健康的未感染艾滋病毒的人将被纳入4个剂量队列，仔细监测安全性，以及 使用灵敏的、 根据GLP进行验证的化验。血液中细胞内API和TFV-二磷酸盐浓度 单核细胞和淋巴结单核细胞(在一个子集中)将与血浆浓度进行比较 以解决平台技术的细胞靶向特性。这份为期3年的提案包括主要 里程碑和时间表将受到密切监测，以确保这项创新临床试验的成功。这些 人体数据将为利用该平台开发更有效、高活性的LA抗病毒药物组合奠定基础。