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

摘要 靶向、长效和联合抗逆转录病毒治疗（TLC-ART）计划已经开发 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）， 能够使不溶性和可溶性短效抗逆转录病毒药物一起稳定在注射剂中 悬浮液在非人灵长类动物中，DcNP能够将短效口服HIV药物组合转化为 可以在血浆和细胞中检测到的没有迟滞期的长效组合（即，快速达峰药物 浓度）。 该申请计划利用新颖的DcNP技术开发一种安全有效的长效 联合抗逆转录病毒治疗艾滋病毒感染儿童。儿童急需长效注射剂 这些人有坚持服药的问题，包括药丸疲劳或无法吞咽。 我们已经建立了公私合作的最先进的两个活性药物TLC-ART平台 通过NIH资助的UM 1，用于成人治疗的评估。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制剂，其中包括三种活性药物 针对两种HIV蛋白质。 我们的一系列里程碑驱动的目标是基于定义的目标产品概况（TPP），并将以 外部咨询委员会（EAB）通过预定和按需会议。以研究为重点的目标 (Aims 1和2）旨在评估一组四种不同的潜在儿科HIV-药物DcNP组合 并根据在幼年非人灵长类动物中的研究选择候选人，以进展到临床前 制定并寻求FDA对加速临床进展计划的指导（目标3-6）。 这项为期五年的提案将由EAB和NIAID/DAIDS项目监督，以确保成功， 研究结果将为开发安全有效的长效抗病毒药物组合治疗年轻人提供基础。 感染艾滋病毒的儿童。

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.