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: 10318950
• 负责人: SEAN M AMBERG
• 金额: $ 111.8万
• 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/10318950
• 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; Epidemic; Evaluation; FDA approved; Formulation; GP2 gene; Gene Library; Genotype; Glycoproteins; Goals; In Vitro; Infection; Intravenous; 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; Virulence; Virus; Vomiting; Washington; World Health Organization; anti-viral efficacy; antiviral drug development; biodefense; clinical development; clinical efficacy; drug resistant virus; efficacy study; genetic variant; genome sequencing; global health; high risk; human pathogen; improved; in vivo; intravenous administration; medical countermeasure; meetings; mortality; mouse model; 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.

项目摘要 本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 由旧世界和新世界沙粒病毒引起的疾病。没有FDA批准的治疗方法 治疗由这些病毒引起的感染，出血热沙粒病毒被列为NIAID A类优先病原体。我们的小分子药物LHF-535是一种研究性新药（IND） 针对拉沙病毒的口服抗病毒治疗，拉沙病毒是一种引起拉沙热的旧大陆沙粒病毒。药物 靶向拉沙病毒包膜糖蛋白并作为病毒进入抑制剂发挥作用。在这个项目中，我们的目标 将组装一个数据包，以扩展LHF-535的标签适应症，以包括新的 世界出血热沙粒病毒Junín病毒和Machupo病毒，通过以下方式解决IND前的建议 FDA更全面地描述了沙粒病毒的基因型和表型特征， 针对LHF-535的抗性，并配制用于静脉内（i. v.）局为了实现这些目标， 本研究的主要目的如下：1）确定LHF-535对新世界的抗病毒活性 出血热沙粒病毒。胡宁病毒和马丘波病毒是南方不同地区的地方病 在美国，它们会引起具有高发病率和死亡率的严重疾病的零星爆发。我们将使用 确定抗病毒疗效和确定药代动力学的成熟豚鼠感染模型- 药效学关系2)确定LHF-535抗性的性质、出现和毒力 病毒我们将评估LHF-535抑制表达LHF的慢病毒假型的感染性的能力。 胡宁病毒的包膜糖蛋白，含有专门设计的氨基酸取代。胡宁病毒 对LHF-535具有抗性的变体也将通过在LHF-535处理的细胞中连续传代和通过 从LHF-535治疗失败的动物中分离病毒。协助监察抗病毒药物的发展 在最初的临床疗效研究中，我们还将生成和测试一个扩大的遗传文库， 拉沙病毒包膜糖蛋白内的变体。3)开发LHF-535的静脉注射制剂。静脉 给药在口服给药不可行的情况下提供了药物递送的选择。我们 还将探讨静脉注射给药提供的快速药物暴露可能增强 治疗效果，特别是在疾病的晚期阶段。制剂开发将包括评价 抗病毒疗效（包括固定剂量和负荷剂量策略）、毒理学和安全药理学。 总之，我们的研究将提高LHF-535在多种适应症中的临床价值和疗效， 支持并通知II期临床试验。LHF-535旨在改善全球健康，并作为一种 针对出血热沙粒病毒造成的生物恐怖主义威胁的医学对策。