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

• 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
• 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

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， 开发一种令人兴奋的新型抑制剂，具有广谱抗甲型流感病毒活性 (IAV)我们的先导分子LNA 9是一个短的15个碱基的锁核酸 (LNA)特异性靶向由独特的RNA第二部分组成的必需IAV包装信号的“gapmer”， 我们最近发现并发现在所有检测的IAV亚型中保守的结构， 包括1918年大流行性流感、高致病性禽流感（H5 N1）和2009年“猪流感”（H1N1）。LNA 9具有核酸酶抗性， 在一个实施方案中，所述RNA酶包含硫代磷酸骨架和内部RNA酶H激活序列，所述内部RNA酶H激活序列被设计成催化 破坏并降解其目标IAV包装信号。在体外，LNA 9在nM时显著抑制IAV包装 在感染之前或之后添加时的浓度，以及在体内，在-12 ° C下鼻内（IN）施用LNA 9， 感染后8和36小时完全防止IAV在小鼠中的致死性。我们现在寻求将LNA 9开发成 临床阶段药物：1）进一步扩大病毒学数据包，通过a）证明抗 IAV的另外的高致病性和耐药性菌株; B）为LNA 9的高致病性和耐药性提供另外的证据， 与其他直接作用的抗病毒药物相比，在体外和体内形成耐药性的屏障; c） 确定最小体内有效剂量，以及LNA 9 d）证明LNA 9在第二次验证中的功效， 雪貂模式，包括预防传播：2）使最佳的交付和监测方法， 体内临床前研究通过：a）证明IV递送补充目前的药物的体内功效， 经证实的IN途径; B）建立分析方法以监测以下物质的分布和清除动力学： c）通过IN和LNA 9进行小鼠、大鼠和狗单剂量PK研究， IV途径; 3）通过a）生产LNA 9以支持必要的IND使能和初始临床研究 合成5g非GMP LNA 9和10 g GMP LNA 9;和B）进行最终释放/稳定性研究 产品（API）; 4）进行初始体外ADME-Tox和临床前动物安全性测试;以及5） 完成IND使能GLP安全性药理学和多次给药14天递增啮齿动物和非 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-包括学者和行业合作伙伴，在以下方面具有专业知识： 病毒学，流感生物学，寡核苷酸化学，肺部制剂和递送，法规事务， 和成功的早期药物开发-非常适合这个提议。成功完成我们的 特定的目标将产生一种令人兴奋的新药，能够保护人们免受这一关键优先事项的影响 病原体，包括其最致命的菌株，威胁数百万人。 !