Pre-IND Development of an Arenavirus Antiviral

摘要 禽流感病毒是一个不同的家族。有几种物种与严重的 人类中的阿拉伯病毒性出血热(AVHF)，其病死率高达 30%。人类感染新城疫病毒通常是通过接触物质发生的。 被感染的啮齿类动物的排泄物污染，尽管是直接的人与人之间的传播 传播可能发生在临床环境中。老年人感染引起的中枢性心衰 据估计，世界范围内的拉萨病毒每年在非洲造成超过30万人感染， 其中15%-20%的住院患者死亡，而幸存者通常遭受永久性 后遗症。阿根廷出血热(AHF)也有类似的结果，由 感染了朱宁病毒。一种针对JUNV的预防性疫苗已经开发出来， 然而，目前还没有针对拉萨或其他人类出血热的疫苗。 禽流感病毒和广谱疫苗对当前和新兴的有效 阿拉伯病毒不太可能被开发出来。利巴韦林是唯一可用的抗病毒药物，可以 有效治疗ArenaVirus感染(特别是在前6天静脉注射 然而，有严重的副作用，包括血小板减少和贫血。vt.给出 有限的治疗和预防选择，高死亡率，潜在的 人畜共患病和人与人之间的传播，以及地理上 移植和生物武器化六种禽流感病毒已被确认为 A类病原体。我们已经确定了一系列新的进入抑制剂，包括 具有亚纳摩尔、广谱病毒活性的类药物候选化合物， 它们在体内表现出显著的疗效。在此，我们建议进行第二阶段研究，以提供 支持IND的主要候选研究，包括CMC、原料药工艺化学和纵向扩展 以及体外和体内毒性和安全性研究。

Summary Arenaviruses comprise a diverse family. Several species are associated with severe arenaviral hemorrhagic fever (AVHF) in humans that exhibit case-fatality rates as high as 30%. Human infection with arenaviruses typically occurs through contact with materials contaminated with the excretions of an infected rodent although direct human- to-human transmission may occur in clinical settings. AVHF resulting from infection with the Old World arenavirus Lassa is estimated to cause over 300,000 annual infections in Africa, of which 15-20% of hospitalized patients die while survivors often suffer permanent sequelae. Similar outcomes are observed with Argentine hemorrhagic fever (AHF), caused by infection with Junin virus. A prophylactic vaccine has been developed against JUNV, however, no vaccines are available against Lassa or the other human hemorrhagic fever arenaviruses and broad-spectrum vaccines effective against both current and emerging arenaviruses are unlikely to be developed. Ribavirin, the only available antiviral, can be effective in treating arenavirus infection (particularly with IV administration in the first 6 days), however, there are serious side effects including thrombocytopenia and anemia. Given the limited treatment and prophylactic options, the high mortality rate, the potential for both zoonotic and human-to-human transmission, and the potential for geographical transplantation and bio- weaponization six arenaviruses have been recognized as Category A pathogens. W e have identified a novel chemical series of entry inhibitors including drug-like candidate compounds with sub-nanomolar, broad spectrum arenavirus activity, which exhibit remarkable in vivo efficacy. Here we propose Phase IIb studies to provide IND-enabling studies of the lead candidate, including CMC, API process chemistry and scale up as well as in vitro and in vivo toxicity and safety studies.