NextGen Long-acting and targeted combination ART for Children with HIV

NextGen 针对艾滋病毒儿童的长效靶向组合 ART

• 批准号: 9892832
• 负责人: RODNEY J.Y. HO
• 金额: $ 102.69万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-06 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9892832
• 关键词: Abbreviations; Adherence; Adolescent; Adult; Anti-Retroviral Agents; Antiviral Agents; Back; Blood; Cells; Child; Childhood; Clinical; Clinical Paths; Combination Drug Therapy; Communication; Data; Data Set; Deglutition; Development; Development Plans; Disease; Dosage Forms; Dose; Drug Combinations; Drug Kinetics; Drug Targeting; Ensure; Evaluation; Exhibits; FDA approved; Fatigue; Formulation; Funding; Generic Drugs; HIV; HIV Integrase; HIV Protease; Human body; Injectable; Integrase; Integrase Inhibitors; Investigational Drugs; Lead; Lopinavir/Ritonavir; Modeling; National Institute of Allergy and Infectious Disease; Oral; Pharmaceutical Preparations; Phase; Plasma; Plasma Cells; Primates; Process; Proteins; RNA-Directed DNA Polymerase; Research; Resources; Route; Safety; Schedule; Source; Suspensions; Technology; Tenofovir; Testing; Therapeutic; Time; TimeLine; Tissues; United States Food and Drug Administration; United States National Institutes of Health; Update; Validation; Water; Work; anti-viral efficacy; antiretroviral therapy; base; clinical development; combat; first-in-human; industry partner; innovation; interest; meetings; nano; nanoparticle; nanoparticle drug; nanotechnology platform; nonhuman primate; novel drug combination; oral HIV; pediatric human immunodeficiency virus; pharmacokinetic model; physiologically based pharmacokinetics; pill; preclinical development; preference; programs; public-private partnership; research and development; safety study; simian human immunodeficiency virus; success

ABSTRACT The Targeted, Long-acting and Combination Anti-Retroviral Therapeutic (TLC-ART) Program has developed a scalable, drug-combination nano-platform technology called DcNPs (drug combination nanoparticles) that enables the stabilizing of insoluble and soluble short-acting antiretroviral drugs together in an injectable suspension. In nonhuman primates, DcNP is able to transform short-acting oral HIV-drug combinations into long-acting combinations that can be detected in plasma and cells with no lag phase (i.e., rapid peak drug concentrations). This application plans to leverage the novel DcNP technology to develop a safe and effective long-acting combination antiretroviral therapy for children with HIV. A long-acting injectable is urgently needed for children who struggle with adherence issues, including pill fatigue or an inability to swallow. We have established a public-private partnership for the most advanced two active drug TLC-ART platform evaluation intended for adult treatment through UM1 funding from the NIH. With these invaluable resources, we plan to create a long-acting monthly injectable formulation for children that includes three active drugs targeted to two HIV proteins. Our set of milestone-driven aims is based on a defined target product profile (TPP), and will be guided by an external advisory board (EAB) through scheduled and on-demand meetings. The research-focused objectives (Aims 1 and 2) are intended to evaluate a set of four different potential pediatric HIV-drug DcNP combinations and to select a candidate based on studies in juvenile non-human primates to progress to pre-clinical development and seek FDA guidance for an accelerated clinical progression plan (Aims 3-6). The five-year proposal will have EAB and NIAID/DAIDS program oversight to ensure success, and the study results will form a basis to develop safe and effective long-acting antiviral combinations for treatment of young children with HIV.

摘要 靶向、长效和联合抗逆转录病毒治疗(TLC-ART)计划已经制定 一种可扩展的药物组合纳米平台技术，称为DcNPs(药物组合纳米颗粒)， 使不溶性和可溶性短效抗逆转录病毒药物在注射剂中一起稳定 停职。在非人类灵长类动物中，DcNP能够将短效的口服艾滋病毒药物组合转化为 在无滞后期的血浆和细胞中可检测到的长效组合(即快速达峰药物 浓度)。 本应用计划利用DcNP新技术开发一种安全有效的长效 艾滋病毒儿童的联合抗逆转录病毒治疗。儿童急需一种长效注射剂 他们与服药依从性问题作斗争，包括服药疲劳或吞咽困难。 我们已经为最先进的两种活性药物TLC-ART平台建立了公私合作伙伴关系 通过美国国立卫生研究院提供的UM1资金，对成人治疗进行评估。有了这些宝贵的资源， 我们计划为儿童创造一种长效的每月注射配方，其中包括三种活性药物 靶向两种HIV蛋白。 我们的一组里程碑驱动的目标基于定义的目标产品配置文件(TPP)，并将由 外部顾问委员会(EAB)通过预定的和按需召开的会议。以研究为主的目标 (目标1和目标2)旨在评估一套四种不同的可能的儿科艾滋病毒药物DcNP组合 并根据对非人类灵长类幼年动物的研究选择一个候选人，使其进入临床前阶段 制定并寻求FDA的指导，以加快临床进展计划(目标3-6)。 这项为期五年的提案将对EAB和NIAID/DAIDS项目进行监督，以确保成功，该研究 这一结果将为开发安全有效的长效抗病毒药物组合治疗青光眼奠定基础 感染艾滋病毒的儿童。