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Preclinical development of a Nipah Virus inhibitor

尼帕病毒抑制剂的临床前开发

基本信息

批准号：
10761349
负责人：
SEAN EKINS
金额：
$ 29.51万
依托单位：
COLLABORATIONS PHARMACEUTICALS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10761349
关键词：
2019-nCoV Acute African Green Monkey Animals Anti-Infective Agents Antimalarials Antiviral Agents Binding Blood Body Weight Body Weight decreased Cavia Cessation of life Combined Modality Therapy Country Data Democratic Republic of the Congo Disease Disease Outbreaks Dose Drug Kinetics Ebola Ebola virus FDA approved Family Feedback Future Glycoproteins Goals Government Hamsters Human In Vitro India Infection Inflammatory Injections Intellectual Property Intravenous Investments Legal patent Malaysia Marburgvirus Marketing Maximum Tolerated Dose Modeling Monitor Morbidity - disease rate Mus Nipah Virus Oral Orphan Drugs Paramyxovirus Pharmaceutical Preparations Pharmacologic Substance Phase Preparation Privatization Respiratory Disease Route SARS-CoV-2 inhibitor Science Sodium Chloride Taxes Testing Time Tissues Toxicology Viral Viral Physiology Virus Virus Inhibitors Virus Replication Water Work bat-borne clinical development coronavirus disease cytokine release syndrome efficacy evaluation efficacy study efficacy testing future outbreak in vitro activity in vivo inhibitor intraperitoneal manufacture meter nervous system disorder nonhuman primate novel pandemic virus pathogen preclinical development preclinical study pyronaridine remdesivir small molecule

项目摘要

Project Summary SARS-CoV-2 has led to an increased urgency to develop treatments for additional emerging viruses and potentially provide broader spectrum antivirals in order to anticipate pandemic viruses. Nipah virus (NiV) is a bat-borne pathogen (family Paramyxoviridae) that results in acute and often fatal (recent outbreaks in India have demonstrated case fatality ~70%) respiratory and neurological disease for which there is currently no FDA approved treatment. There have been very few small molecule antivirals that have demonstrated activity against NiV either in vitro or in vivo. These include favipiravir (EC90 15.87- 123.8 µM) which resulted in survival in the hamster model and remdesivir (EC90 50-100 nM) when dosed daily by the intravenous (IV) route in the African green monkey (AGM) model resulting in their survival. We recently identified the antiviral activity of pyronaridine (EC50 = 65.57 nM and CC50 3.65 µM) for NiV (Malaysia strain, Patent No. 17/092,058). We have also shown that pyronaridine has efficacy against Ebola in vitro and efficacy in vivo in mice and guinea pig. Additionally, pyronaridine has demonstrated promising activity in vitro against Marburg virus and in vivo efficacy against SARS-CoV-2 in mice. We have recently shown that pyronaridine is lysosomotropic and binds to the Ebola glycoprotein as well as decreases the inflammatory cytokine storm in mice induced by SARS-CoV-2. We now propose to assess the oral maximum tolerated dose and pharmacokinetics prior to performing efficacy studies in the hamster model of NiV. If we are successful in demonstrating in vivo efficacy, we will file an orphan drug designation and a preIND with the FDA. If we demonstrate statistically significant efficacy in Phase I we will then perform efficacy testing in Phase II using the African Green Monkey model for NiV, perform IND enabling toxicology studies and manufacture GMP grade pyronaridine tertraphosphate. Our ultimate aim is to bring a treatment to market for NiV which can be stockpiled by the USA and other countries in preparation for future outbreaks.

项目摘要 SARS-CoV-2已经导致开发针对其他新出现病毒的治疗方法的紧迫性增加，潜在地提供更广谱的抗病毒药物，以预测大流行性病毒。尼帕病毒（NiV）是一种蝙蝠传播的病原体（副粘病毒科），导致急性和往往致命（最近在印度爆发，已证实病死率约为70%）呼吸系统和神经系统疾病，目前FDA尚无此类疾病的治疗方法批准的治疗。很少有小分子抗病毒药物已经证明了对 NiV在体外或体内。这些包括法匹拉韦（EC 90 15.87- 123.8 µM），其导致仓鼠模型和remdesivir（EC 90 50-100 nM），每日通过静脉（IV）途径给药，绿色猴（AGM）模型，导致其存活。我们最近发现咯萘啶的抗病毒活性 (EC50= 65.57 nM和CC 50 3.65 µM）。我们还表明，咯萘啶在体外具有抗埃博拉病毒的功效，在小鼠和豚鼠体内具有抗埃博拉病毒的功效。此外，本发明还咯萘啶已证明有希望的体外抗马尔堡病毒活性和体内抗 SARS-CoV-2小鼠。我们最近发现咯萘啶是亲溶酶体的，与埃博拉病毒结合，糖蛋白以及减少由SARS-CoV-2诱导的小鼠中的炎性细胞因子风暴。我们现在建议在进行疗效研究前评估口服最大耐受剂量和药代动力学在仓鼠模型中如果我们成功证明体内功效，我们将提交孤儿药并获得FDA的PreIND认证。如果我们在I期研究中证明具有统计学显著性疗效，在II期使用非洲绿色猴模型进行NiV的有效性试验，进行IND启用毒理学研究和生产GMP级咯萘啶四磷酸盐。我们的最终目标是美国和其他国家可以储存NiV，为未来的治疗做准备。爆发