Pre-IND Development of an Arenavirus Antiviral

沙粒病毒抗病毒药物的 IND 前开发

基本信息

批准号：
9914982
负责人：
Gregory William Henkel
金额：
$ 100万
依托单位：
ARISAN THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-02-10 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9914982
关键词：
ABCB1 gene ABCG2 gene Acids Africa Anemia Animals Antiviral Agents Arenavirus Arenavirus Infections Argentinian Hemorrhagic Fever Binding Proteins Canis familiaris Cardiac Case Fatality Rates Category A pathogen Cavia Cell Line Cells Chemicals Chemistry Chinese Hamster Ovary Cell Chromosome abnormality Clinical Clinical Pathology Crystallization Detection Development Dose Engineering Enzymes Equilibrium Evaluation Excipients Excretory function Exhibits FDA approved Family Formulation G-Protein-Coupled Receptors Geography Glycoproteins Goals Healthcare Systems High Pressure Liquid Chromatography Human In Vitro Infection Intestines Ion Channel Junin virus Liquid substance Liver Extract Manuals Maximum Tolerated Dose Methods Modeling Morbidity - disease rate No-Observed-Adverse-Effect Level Old World Arenaviruses Oral Organic solvent product Outcome Particle Size Pathogenicity Patients Pharmaceutical Preparations Pharmacologic Substance Phase Phenotype Polymorph Preventive vaccine Process Rattus Recovery Ribavirin Running Safety Series Serum Sodium Chloride Solid Solubility Solvents Stomach Survivors Suspensions Tablets Testing Therapeutic Therapeutic Index Thrombocytopenia Time Toxic effect Toxicokinetics Toxicology Transplantation Vaccines Vesicular stomatitis Indiana virus Viral Hemorrhagic Fevers Visual Zoonoses analytical method aqueous base capsule dosage experimental study in vivo infected vector rodent inhibitor/antagonist lead candidate method development mortality nanomolar neurobehavioral novel novel therapeutics patch clamp pathogen pre-clinical preclinical study prophylactic safety study scale up screening side effect surfactant transmission process weapons

项目摘要

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.

概括沙粒病毒由一个多样化的家族组成。有几个物种与严重的人类沙粒病毒性出血热 (AVHF) 的病死率高达 30%。人类感染沙粒病毒通常是通过接触材料发生的尽管直接人传人，但仍被受感染啮齿动物的排泄物污染传播可能发生在临床环境中。旧病感染引起的 AVHF 据估计，世界沙粒病毒拉沙每年在非洲造成超过 30 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的痛苦后遗症。阿根廷出血热 (AHF) 也观察到类似的结果，通过感染胡宁病毒。已开发出针对 JUNV 的预防性疫苗，然而，没有针对拉沙热或其他人类出血热的疫苗对当前和新兴的沙粒病毒和广谱疫苗均有效沙粒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有效治疗沙粒病毒感染（特别是在前 6 个月内静脉注射）天），然而，存在严重的副作用，包括血小板减少和贫血。给定有限的治疗和预防选择、高死亡率、潜在的人畜共患病和人际传播，以及地理传播的潜力移植和生物武器化六种沙粒病毒已被认为是 A类病原体。我们已经确定了一系列新型化学进入抑制剂，包括具有亚纳摩尔、广谱沙粒病毒活性的类药物候选化合物，表现出显着的体内功效。在此，我们提出 IIb 期研究以提供主要候选药物的 IND 支持研究，包括 CMC、API 工艺化学和放大以及体外和体内毒性和安全性研究。