IND-Enabling Studies for Arenavirus Preclinical Candidate

总结 沙粒病毒包括一个不同的家庭。几个物种与严重的 人类的沙粒病毒出血热（AVHF）。人感染沙粒病毒 典型地通过与被动物排泄物污染的材料接触而发生 虽然在临床环境中可能发生人与人之间的直接传播， 据估计，由旧大陆沙粒病毒拉沙感染引起的AVHF可导致 西非每年有30多万例感染，其中15-20%的住院患者 死亡，而幸存者往往遭受永久性后遗症。静脉内施用 非特异性抗病毒剂利巴韦林（标签外）已被用于拉沙病毒感染， 西非。然而，它已被证明提供有限的疗效和显著的风险， 严重的副作用包括血小板减少和贫血。考虑到有限的治疗 和预防选择，死亡率/发病率，潜在的人畜共患病和 人传人、地域移植和生物武器化 六种沙粒病毒被认为是A类病原体。为了提供 有效和特异性的抗病毒治疗拉沙和其他沙粒病毒出血热在这里，我们 建议完成IND使能性研究和高级非临床研究， 具有亚纳摩尔广谱沙粒病毒活性的临床前候选进入抑制剂， 具有可证明的药物样特征，其表现出显著的体内治疗功效。

Summary Arenaviruses comprise a diverse family. Several species are associated with severe arenaviral hemorrhagic fever (AVHF) in humans. 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 Western Africa, of which 15-20% of hospitalized patients die while survivors often suffer permanent sequelae. The intravenous administration of the nonspecific antiviral agent has been adopted ribavirin (off-label) for Lassa virus infections in Western Africa. However, it has been shown to provide limited efficacy and a significant risk for serious side effects including thrombocytopenia and anemia. Given the limited treatment and prophylactic options, the mortality/morbidity rate, the potential for both zoonotic and human-to-human transmission, geographical transplantation and bio-weaponization six arenaviruses have been recognized as Category A pathogens. In order to provide a potent and specific antiviral to treat Lassa and other arenavirus hemorrhagic fevers here we propose the completion of IND-enabling studies and advanced nonclinical studies for an oral preclinical candidate entry inhibitor with sub-nanomolar broad spectrum arenavirus activity and demonstrable drug-like features that exhibits remarkable in vivo therapeutic efficacy.