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：
10165884
负责人：
JEFFREY S GLENN
金额：
$ 74.55万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-05 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10165884
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和治疗方面的集体学术和行业经验开发一种令人兴奋的新型抑制剂，具有抗甲型流感病毒的广谱活性 (IAV) 优先病原体——针对 IND 我们的先导分子 LNA9 是一种短的 15 个碱基锁定核酸。 (LNA)“gapmer”，专门针对由独特的 RNA 二级结构组成的重要 IAV 包装信号我们最近发现并发现在所有检查的 IAV 亚型中都是保守的结构，包括 1918 年大流行流感、高路径禽流感 (H5N1) 和 2009 年“猪流感”(H1N1) 具有核酸酶抗性。硫代磷酸酯骨架和内部 RNAse H 激活序列，旨在催化在体外，LNA9 能以 nM 水平显着抑制 IAV 包装。在感染之前或之后添加时的浓度，以及在-12下体内鼻内（IN）施用LNA9时的浓度，感染后 8 小时和 36 小时完全阻止 IAV 对小鼠的致死作用。临床阶段药物： 1) 进一步扩展病毒学数据包， a) 证明抗病毒活性 b) 为 LNA9 的高值提供额外的证据与其他直接作用的抗病毒药物相比，在体外和体内都不会产生耐药性；确定LNA9的最小体内有效剂量以及感染前后的天数给药可以挽救流感死亡；d) 在第二次验证中证明 LNA9 的功效雪貂模型，包括预防传播：2) 实现最佳的传递和监测方法体内临床前研究：a) 证明静脉注射的体内功效，以补充目前的已证实的 IN 途径；b) 建立监测分布和清除动力学的分析方法 LNA9 体内给药后；c) 通过 IN 和进行小鼠、大鼠和狗单剂量 PK 研究 IV 途径；3) 制造 LNA9，以支持所需的 IND 启用和初步临床研究：合成 5g 非 GMP LNA9 和 10g GMP LNA9；和 b) 进行最终释放/稳定性研究；产品 (API)；4) 进行初步体外 ADME-Tox 和临床前动物安全测试；完成支持 IND 的 GLP 安全药理学和多剂量 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 IND 前会议包。我们的多学科团队 - 包括学术界和行业合作伙伴，在以下领域拥有丰富的专业知识病毒学、流感生物学、寡核苷酸化学、肺部制剂和递送、监管事务、和成功的早期药物开发非常适合我们提案的成功实现。具体目标将产生一种令人兴奋的新药，能够针对这一关键优先事项提供保护病原体，包括威胁数百万人的毒性最强的菌株。