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

我们的目标是利用我们在抗病毒研究和行业方面的集体学术和行业经验 开发一种具有广谱抗甲型流感病毒活性的激动型新型抑制剂 (IAV)优先病原体--针对IND。我们的前导分子LNA9是一个短小的15碱基锁定的核酸 (LNA)专门针对IAV包装信号(由独特的RNA秒级组成--Gapmer)- 我们最近发现的一种结构，在所有被检查的IAV亚型中都是保守的， 包括1918年大流行流感、高途径禽类(H5N1)和2009年的“猪”(H1N1)。LNA9具有核酸酶抗性 硫化骨架和内部核糖核酸酶H激活序列，旨在催化 干扰并降低其目标IAV包装信号。在体外，LNA9在NM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，鼻内(IN)给药LNA9在-12， 感染后8小时和36小时可完全阻止IAV对小鼠的致死作用。我们现在寻求将LNA9开发成一个 临床阶段药物：1)进一步扩展病毒学数据包，通过a)展示针对 新增IAV高致病株和耐药株；b)为LNA9‘S高毒株提供额外证据 与其他直接作用的抗病毒药物相比，在体外和体内形成抗药性的障碍；c) 确定LNA9在体内的最小有效剂量以及感染前后的天数 用药可以挽救流感死亡；以及d)在第二次验证中展示LNA9的S疗效 雪貂模型，包括预防传播：2)实现最佳投放和监测方法 体内临床前研究，通过：a)证明静脉注射的体内疗效，以补充目前 经验证的路线；b)建立分析方法，以监测分布和清除动力学 体内给药后的LNA9；以及c)通过IN和 IV路线；3)制造LNA9以支持必要的IND使能和初步临床研究，由a) 合成5g非GMP LNA9和10g GMP LNA9；以及b)进行最终释放/稳定性研究 产品(原料药)；4)进行初步的体外ADME-Tox和临床前动物安全性试验；5) 完成IND-Enabling GLP安全药理学和多剂14天升级啮齿动物和非 啮齿动物毒性研究、临床发展计划和IND前期会议包。 我们的多学科团队--包括在以下领域拥有卓越专长的学者和行业伙伴 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， 以及成功的早期药物开发--非常适合这一提议。成功地完成了我们的 特定的目标将产生一种令人兴奋的新药，能够提供对这一关键优先事项的保护 病原体，包括威胁数百万人的最强毒力菌株。 好了！

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. !