Advanced development of a viral entry inhibitor as a therapeutic for arenavirus hemorrhagic fever

病毒进入抑制剂治疗沙粒病毒出血热的最新进展

• 批准号: 10539278
• 负责人: SEAN M AMBERG
• 金额: $ 106.37万
• 依托单位: KINETA, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10539278
• 关键词: Address; Advanced Development; Africa; Amino Acid Substitution; Amino Acids; Animals; Antiviral Agents; Antiviral resistance; Arenavirus; Argentinian Hemorrhagic Fever; Attenuated; Biological Products; Bioterrorism; Bolivian Hemorrhagic Fever; Bolivian Hemorrhagic Fever Virus; Category A pathogen; Cavia; Cells; Characteristics; Clinical; Coupled; Data; Development; Disease; Disease Outbreaks; Dose; Drug Delivery Systems; Drug Exposure; Drug Interactions; Drug Kinetics; Drug Targeting; Drug resistance; Engineering; Evaluation; FDA approved; Formulation; GP2 gene; Gene Library; Genotype; Glycoproteins; Goals; In Vitro; Infection; Intravenous; Intubation; Investigational Drugs; Investigational New Drug Application; Junin virus; Label; Lassa Fever; Lassa virus; Modeling; Molecular; Monitor; Morbidity - disease rate; Mutation; National Institute of Allergy and Infectious Disease; National Security; Nature; Old World Arenaviruses; Oral; Oral Administration; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pharmacology Study; Phase I Clinical Trials; Phase II Clinical Trials; Phenotype; Population; Public Health; Recommendation; Regimen; Research Priority; Resistance; Resistance development; Safety; Serial Passage; South America; Surveys; Tacaribe Complex Viruses; Tacaribe virus; Testing; Therapeutic; Toxicology; Transmembrane Domain; Treatment Efficacy; Unconscious State; Universities; Utah; Variant; Viral; Viral Genome; Viral Hemorrhagic Fevers; Viral Physiology; Virulence; Virus; Vomiting; Washington; World Health Organization; anti-viral efficacy; antiviral drug development; biodefense; clinical development; clinical efficacy; drug resistant virus; efficacy study; epidemic potential; genetic variant; genome sequencing; global health; high risk; human pathogen; improved; in vivo; intravenous administration; medical countermeasure; mortality; mouse model; pre-Investigational New Drug meeting; research and development; small molecule; viral entry inhibitor; viral resistance; virus envelope

PROJECT SUMMARY This project is focused on developing a broad-spectrum antiviral drug for treating viral hemorrhagic fever diseases caused by Old World and New World arenaviruses. There are no FDA-approved therapeutics for treating infections caused by these viruses, and hemorrhagic fever arenaviruses are listed as NIAID Category A priority pathogens. Our small-molecule drug, LHF-535, is an investigational new drug (IND)-ready oral antiviral therapeutic against Lassa virus, an Old World arenavirus that causes Lassa fever. The drug targets the Lassa virus envelope glycoprotein and functions as a viral entry inhibitor. In this project, our goals are to assemble a data package to expand the labeled indication for LHF-535 to include infection with the New World hemorrhagic fever arenaviruses Junín virus and Machupo virus, address pre-IND recommendations by the FDA to more fully characterize the genotypic and phenotypic characteristics of arenaviruses that develop resistance to LHF-535, and formulate LHF-535 for intravenous (i.v.) administration. To achieve these goals, the following Specific Aims are proposed: 1) Define the antiviral activity of LHF-535 against New World hemorrhagic fever arenaviruses. Junín virus and Machupo virus are endemic in distinct regions of South America, where they cause sporadic outbreaks of severe disease with high morbidity and mortality. We will use well-established guinea pig infection models to define antiviral efficacy and to determine pharmacokinetic- pharmacodynamic relationships. 2) Determine the nature, emergence, and virulence of LHF-535-resistant viruses. We will evaluate the ability of LHF-535 to inhibit the infectivity of lentiviral pseudotypes expressing envelope glycoproteins of Junín virus that contain specifically engineered amino acid substitutions. Junín virus variants that are resistant to LHF-535 will also be identified by serial passage in LHF-535-treated cells and by isolating viruses from animals that fail LHF-535 treatment. To assist in monitoring the development of antiviral resistance during initial clinical efficacy studies, we will also generate and test an expanded library of genetic variants within the Lassa virus envelope glycoprotein. 3) Develop an i.v. formulation for LHF-535. Intravenous administration provides an option for drug delivery in situations where oral administration is not feasible. We will also explore the possibility that the rapid drug exposure provided by i.v. administration might enhance therapeutic efficacy, particularly in late stages of disease. Formulation development will include evaluation of antiviral efficacy (including fixed-dose and loading-dose strategies), toxicology, and safety pharmacology. Together, our studies will enhance the clinical value and efficacy of LHF-535 across multiple indications and support and inform Phase II clinical trials. LHF-535 is intended to both improve global health and serve as a medical countermeasure to the bioterrorism threat posed by hemorrhagic fever arenaviruses.

项目总结 该项目致力于开发一种治疗病毒性出血热的广谱抗病毒药物。 由旧世界和新世界禽流感病毒引起的疾病。目前还没有FDA批准的治疗方法 治疗由这些病毒引起的感染，以及出血热阿拉伯病毒被列为NIAID A类优先病原体。我们的小分子药物LHF-是一种可用于研究的新药(IND) 拉沙病毒的口服抗病毒疗法，拉沙病毒是一种引起拉沙热的东半球阿拉伯病毒。这种药 以拉萨病毒包膜糖蛋白为靶标，发挥病毒进入抑制作用。在这个项目中，我们的目标是 将组装一个数据包以扩大LHF的标签适应症-包括感染新的 世界出血热病毒Junín病毒和Machupo病毒，通过 FDA将更全面地描述发展成阿雷诺病毒的基因和表型特征 对LHF-的抗性，并配制静脉注射用LHF-。行政管理。为了实现这些目标， 提出了以下具体目标：1)确定LHF-抗新世界的抗病毒活性 出血热病毒。Junín病毒和Machupo病毒在南方不同地区流行 在美国，它们造成严重疾病的零星暴发，发病率和死亡率都很高。我们将使用 建立完善的豚鼠感染模型来确定抗病毒效果并确定药代动力学- 药效学关系。2)确定LHF抗性的性质、出现和毒力 病毒。我们将评估LHF-对慢病毒假型表达的感染性的抑制能力 Junín病毒的包膜糖蛋白，含有特殊设计的氨基酸替代。Junín病毒 对LHF耐药的变异体也将通过LHF处理的细胞中的连续传代和 从LHF治疗失败的动物身上分离病毒。协助监测抗病毒药物的开发情况 在最初的临床疗效研究期间，我们还将生成和测试扩展的基因库 拉萨病毒包膜糖蛋白内的变异体。3)发展静脉注射。LHF-的配方。静脉注射 在口服给药不可行的情况下，给药提供了一种选择。我们 还将探索由静脉注射提供的快速药物暴露的可能性。政府可能会加强 治疗效果，特别是在疾病的晚期。配方制定将包括评估 抗病毒疗效(包括固定剂量和加载剂量策略)、毒理学和安全药理学。 总之，我们的研究将提高LHF的临床价值和疗效-跨多个适应症和 支持并通报第二阶段临床试验。LHF-旨在改善全球健康并充当 应对出血热禽流感病毒生物恐怖主义威胁的医学对策。