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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要该项目的重点是开发一种用于治疗病毒出血热的广谱抗病毒药物由旧世界和新世界竞技病毒引起的疾病。没有FDA批准的疗法由这些病毒引起的治疗感染，出血热舞台病毒被列为NIAID 类别的优先病原体。我们的小分子药物LHF-535是一种研究新药（IND）针对LASSA病毒的口服抗病毒疗法，这是一种旧世界的体育症病毒，导致LASSA热。药物靶向LASSA病毒包膜糖蛋白，并用作病毒抑制剂。在这个项目中，我们的目标要组装一个数据包以扩展LHF-535标记的指示，以包括新的感染世界出血热竞技病毒junín病毒和男子气概病毒，介绍预先提出的建议 FDA更充分地表征了发展的体属性的基因型和表型特征对LHF-535的耐药性，并为静脉内（i.v.）给药制定LHF-535。为了实现这些目标，提出了以下特定目标：1）定义LHF-535对新世界的抗病毒活性出血热病毒。 Junín病毒和Machupo病毒在南方的不同地区是内在的美国，在那里引起零星的严重疾病爆发，并具有高发病率和死亡率。我们将使用建立良好的豚鼠感染模型，以定义抗病毒效率并确定药代动力学 - 药效关系。 2）确定LHF-535的性质，出现和病毒病毒。我们将评估LHF-535抑制表达慢病毒假型感染的能力朱恩病毒的包膜糖蛋白包含特定设计的氨基酸取代。朱恩病毒耐LHF-535具有抗性的变体也将通过LHF-535细胞中的串行通道以及通过从LHF-535治疗失败的动物中分离病毒。协助监测抗病毒的发展在最初的临床效率研究中的阻力，我们还将生成和测试扩展的通用库 LASSA病毒包膜中的变体糖蛋白。 3）开发i.v. LHF-535的公式。静脉管理在口服不可行的情况下提供了一种药物输送的选择。我们还将探讨I.V.提供的快速药物暴露的可能性管理可能会增强治疗效率，特别是在疾病晚期。配方开发将包括评估抗病毒效率（包括固定剂量和加载剂量策略），毒理学和安全药理学。总之，我们的研究将增强LHF-535的临床价值和效率，跨多个指示和支持并告知II期临床试验。 LHF-535旨在改善全球健康，并充当医学对策与出血热轨迹构成的生物恐怖威胁。