Advancing a broad-spectrum anti-influenza A virus RNA packaging inhibitor to an IND

将广谱抗甲型流感病毒 RNA 包装抑制剂推进 IND

基本信息

批准号：
9973144
负责人：
JEFFREY S GLENN
金额：
$ 111.3万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-17 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9973144
关键词：
Animals Antiviral Agents Biology Birds Canis familiaris Chemistry Clinical Clinical Research Complement Data Development Plans Disease Dose Drug Kinetics Drug resistance Family suidae Ferrets Formulation Frequencies Goals Half-Life Hour In Vitro Industry Infection Influenza Influenza A Virus, H1N1 Subtype Influenza A Virus, H5N1 Subtype Influenza A virus Influenza prevention Intranasal Administration Intravenous Ion Channel Kinetics Lead Liver Lung Measurable Mediating Methods Modeling Monitor Mus Muscle Nature Neuraminidase Neuraminidase inhibitor Oligonucleotides Oseltamivir Pathogenicity Pharmaceutical Preparations Pharmacology Plasma Prevention RNA Rattus Regulatory Affairs Research Resistance Resistance development Ribonuclease H Rodent Route Safety Signal Transduction Structure Testing Therapeutic Time Toxic effect Vertebral column Viral Packaging Virulent Virus Virus Diseases analytical method animal safety anti-influenza anti-viral efficacy base clinical development design drug development experience in vivo industry partner inhibitor/antagonist lead candidate locked nucleic acid man meetings mortality multidisciplinary mutant novel novel therapeutics nuclease pandemic influenza phosphorothioate pre-clinical preclinical study prevent priority pathogen research and development resistant strain safety testing transmission process viral RNA virology weapons

项目摘要

Our goal is to leverage our collective academic and industry experience in antiviral research and development to advance an exciting novel inhibitor with broad-spectrum activity against the influenza A virus (IAV) Priority Pathogen—towards an IND. Our lead molecule, LNA9, is a short 15 base locked nucleic acid (LNA) “gapmer” that specifically targets an essential IAV packaging signal composed of a unique RNA second- ary structure that we recently discovered and found to be conserved across all examined subtypes of IAV, including 1918 pandemic flu, high path avian (H5N1) and 2009 `swine' (H1N1). LNA9 has a nuclease-resistant phosphorothioate backbone and an internal RNAse H activating sequence that is designed to catalytically disrupt and degrade its target IAV packaging signal. In vitro, LNA9 dramatically inhibits IAV packaging at nM concentrations when added before or after infection, and in vivo, intranasal (IN) administration of LNA9 at -12, 8, and 36 hours post infection completely prevents IAV lethality in mice. We now seek to develop LNA9 into a clinical stage drug by: 1) Further expanding the virology data package by a) demonstrating activity against additional highly pathogenic and drug resistant strains of IAV; b) providing additional evidence for LNA9's high barrier to the development of resistance compared to other direct-acting antivirals in vitro and in vivo; c) determining the minimum in vivo effective dose, and number of days before or after infection that LNA9 administration can rescue from influenza mortality; and d) demonstrating LNA9's efficacy in second validated ferret model, including prevention of transmission: 2) Enabling the optimal delivery and monitoring methods for in vivo preclinical studies by: a) demonstrating the in vivo efficacy of IV delivery to complement the currently proven IN route; b) establishing the analytical methods to monitor the distribution and clearance kinetics of LNA9 following in vivo administration; and c) performing mouse, rat, and dog single dose PK studies via IN and IV routes; 3) Manufacturing LNA9 to support the requisite IND-enabling and initial clinical studies by a) synthesizing 5g of non-GMP LNA9, and 10g of GMP LNA9; and b) performing the final release/stability studies of the product (API); 4) Performing initial in vitro ADME-Tox and preclinical animal safety testing; and 5) Completing the IND-enabling GLP safety pharmacology and multiple dose 14-day escalation rodent and non- rodent toxicity studies, a clinical development plan, and pre-IND meeting package. Our multidisciplinary team--including academics and industry partners with demonstrated expertise in virology, influenza biology, oligonucleotide chemistry, pulmonary formulation and delivery, regulatory affairs, and successful early drug development—is ideally suited for this proposal. Successful accomplishment of our specific aims will yield an exciting novel drug capable of conferring protection against this key Priority Pathogen, including its most virulent strains that threaten millions. !

我们的目标是利用我们在抗病毒研究方面的集体学术和行业经验以及开发以促进一种激动人心的小说抑制剂，具有针对影响病毒的宽光谱活性（iav）优先病原体 - 特征。我们的铅分子LNA9是一个短的15个碱基锁定核酸（lna）“ gapmer”，该“ gapmer”专门针对由独特的RNA第二次组成的必需IAV包装信号我们最近发现并发现在所有检查的IAV亚型中构成的ARY结构，包括1918年的大流动流感，高路径（H5N1）和2009猪（H1N1）。 LNA9具有抗核酸酶的耐药性磷酸座主链和内部RNase H激活序列，该序列旨在催化破坏并降解其目标IAV包装信号。在体外，LNA9急剧抑制NM的IAV包装感染前或之后添加时浓度，在体内，鼻内（IN）在-12时施用LNA9 感染后8和36小时完全阻止了小鼠的IAV致死性。我们现在寻求将LNA9发展成一个临床阶段药物：1）进一步扩大病毒学数据包，a）证明活动的活动 IAV的其他高度致病性和抗药性菌株； b）提供LNA9高的其他证据与其他直接作用抗病毒药在体外和体内相比，阻力发展的障碍； c）确定最小体内有效剂量以及感染前或之后的天数行政管理可以从影响力中救出； d）证明LNA9在第二次验证中的效率雪貂模型，包括预防传输：2）实现最佳输送和监视方法体内临床前研究作者：a）证明静脉输送的体内效率以完成当前在路线上经过证明； b）建立分析方法来监视的分布和清除动力学 LNA9在体内给药后； c）通过IN和 IV路线； 3）制造LNA9通过A支持必要的成分和初步临床研究合成5G非GMP LNA9和10g GMP LNA9的合成； b）执行最终版本/稳定性研究产品（API）; 4）进行初始体外ADME-TOX和临床前动物安全测试； 5）完成辅助GLP安全药理学和多剂量的14天升级啮齿动物和非 - 啮齿动物毒性研究，临床开发计划和预印度会议计划。我们的多学科团队 - 包括学术界和行业合作伙伴，具有证明的专业知识病毒学，影响，寡核苷酸化学，肺配方和递送，监管事务，和成功的早期药物开发 - 非常适合该建议。成功实现我们的具体目标将产生一种令人兴奋的新型药物，能够针对此关键优先级进行会议保护病原体，包括威胁着数百万美元的最有毒菌株。呢