A single antiviral to treat multiple opportunistic infections

单一抗病毒药物可治疗多种机会性感染

基本信息

批准号：
10602319
负责人：
Stacy Remiszewski
金额：
$ 100万
依托单位：
EVRYS BIO, LLC
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：
2014-06-15 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10602319
关键词：
Address Adenoviruses Adult Alabama Allogenic American Antiviral Agents Asthma BK Virus Biological Availability Canis familiaris Cell Culture Techniques Cell Transplantation Cells Chemicals Clinical Clinical Investigator Clinical Research Clinical Trials Clinical Trials Design Clinical effectiveness Collaborations Communities Controlled Study Cytomegalovirus Cytomegalovirus Infections DNA Viruses Data Disease Dose Drug Kinetics Drug resistance Economic Burden Effectiveness Evaluation Evolution Excretory function Family Funding General Hospitals Graft Rejection HIV Health Hematopoietic Stem Cell Transplantation Hepatic Hepatitis B Hepatitis Viruses Herpesviridae Human Human Herpesvirus 4 Immune system Immunosuppression In Vitro Individual Industry Infection Influenza A virus Investigational Drugs Laboratories Lead Letters Liver London Lung Marketing Metabolism Modeling Morbidity - disease rate Mus Opportunistic Infections Oral Oral Administration Organ Organ Transplantation Organoids Patient Selection Patients Pharmaceutical Preparations Phase Plasma Polyomavirus Predisposition Primary Infection Prophylactic treatment Proteins Publishing RNA Viruses Rattus Recommendation Regimen Reporting Resistance Resistance development Rheumatism Risk Serial Passage Serum Sirtuins Small Business Innovation Research Grant Testing Therapeutic Therapeutic Intervention Therapeutic immunosuppression Time Tissue Donors Toxic effect Toxicology Transplant Recipients Transplantation Transplantation and Immune System Travel Universities Variant Viral Viral Drug Resistance Viral Physiology Virus Virus Diseases Virus Latency absorption acquired drug resistance clinic ready clinical development clinical practice college commercialization cost design drug candidate drug development drug resistant influenza efficacy study good laboratory practice high risk immunosuppressed in vivo in vivo Model infection risk inhibitor manufacture meetings member mortality pathogen post-market prevent product development prototype resistant strain respiratory virus risk minimization safety practice safety study seropositive standard of care targeted treatment traditional therapy translational study virology

项目摘要

PROJECT SUMMARY/ABSTRACT Immunosuppressed transplant patients have heightened susceptibility to environmental pathogens as well as adventitious agents traveling with donor tissues or resident in the recipient. Traditional therapies target the virus and are thereby limited in effectiveness to the specific virus targeted. Evrys Bio is developing orally administered, broad-spectrum antivirals that target the host-cell sirtuin-2 protein (SIRT2). In vitro feasibility was demonstrated in SBIR Phase I for an early lead, FLS-359, showing broad effectiveness against four families of viruses posing problems for immunosuppressed transplant patients: herpesviruses, polyomaviruses, hepatitis viruses, and respiratory viruses. Additionally, SIRT2-targeting with FLS-359 blocked acquisition of viral drug resistance in an influenza model and was additive in antiviral activity with traditional direct-acting antivirals. A prototype was developed in SBIR Phase II, allowing selection of a Drug Candidate (DC) for Investigational New Drug (IND)-enablement that satisfied the in vitro Target Compound Profile with respect to antiviral potency and ADME, and in vivo oral bioavailability, target engagement, and tolerability. The DC is designated EV-100. In this SBIR Phase IIB application, we request funding to advance EV-100 toward an IND filing. The clinical trial will be designed to test the utility of EV-100 for prophylaxis of human cytomegalovirus (HCMV) infection and disease in adult HCMV-seropositive recipients of an allogeneic hematopoietic stem cell transplant. To advance to the IND filing, we will establish relationships between EV-100 dose, pharmacokinetic parameters, efficacy, and toxicity. We will conduct non-GLP dose range finding safety studies in rats and dogs, and efficacy studies in murine HCMV viral challenge models to provide guidance and minimize risk with dosing regimen selection for costly GLP and clinical studies. In addition, we will perform studies to address published FDA in vitro virology study recommendations that will support an IND filing. These studies will include the assessment of EV-100 antiviral activity versus multiple laboratory and clinical HCMV isolates, including the analysis of EV-100 inhibitory activity toward HCMV variants that are resistant to currently approved drugs; testing for the evolution of viral drug resistance during serial passage of HCMV in increasing concentrations of EV-100 in cell culture; evaluation of EV-100 efficiency in combination with currently approved anti-HCMV drugs; delineation of EV- 100 as a function of HCMV dose; and additional parameters that help to predict the efficacy of EV-100 in transplant recipients. Finally, although HCMV prophylaxis is the intended initial indication, the broad-spectrum antiviral profile against human viruses is a potential breakthrough feature of EV-100. The drug has already been shown to inhibit both RNA and DNA viruses in addition to HCMV that can threaten both the organ and the survival of the patient following a transplant. In vitro studies in human cells and in vivo studies in humanized in mice will be performed to further evaluate this potentially unique broad-spectrum utility of EV-100.

项目摘要/摘要免疫抑制的移植患者对环境病原体以及与供体组织或接收者居民一起旅行的不定代理。传统疗法针对病毒因此，对特定病毒的有效性有限。 evrys bio正在口头管理，靶向宿主细胞Sirtuin-2蛋白（SIRT2）的广谱抗病毒药。体外可行性是在SBIR第一阶段证明了早期领先，FLS-359，对四个家庭的效率广泛为免疫抑制移植患者带来问题的病毒：疱疹病毒，多瘤病毒，肝炎病毒和呼吸道病毒。此外，使用FLS-359的sirt2靶向病毒药物的收购流感模型中的抗性，并具有传统直接作用抗病毒药的抗病毒活性。一个原型是在SBIR II期开发的，允许选择候选药物（DC）进行研究在抗病毒效力和 Adme和体内口服生物利用度，目标参与度和耐受性。 DC被指定为EV-100。在这个 SBIR阶段IIB应用程序，我们要求资金将EV-100推向IND申请。临床试验将旨在测试EV-100对人类巨细胞病毒（HCMV）感染和疾病预防的实用性在成年的HCMV - 呼吸阳性受体中，同种异体造血干细胞移植。前进到 IND提交，我们将建立EV-100剂量，药代动力学参数，功效和功效之间的关系毒性。我们将进行非GLP剂量范围，以找到大鼠和狗的安全性研究，以及在鼠类HCMV病毒挑战模型，以提供指导并通过选择给药方案的选择来最大程度地降低风险昂贵的GLP和临床研究。此外，我们将进行研究以解决已发表的体外病毒学的FDA 研究建议将支持IND申请。这些研究将包括对EV-100的评估抗病毒活性与多个实验室和临床HCMV分离株，包括对EV-100的分析对当前批准药物具有抵抗力的HCMV变体的抑制活性；测试进化在细胞培养中，HCMV串联eV-100浓度浓度的串行过程中，病毒耐药性的耐药性；评估EV-100效率与当前批准的抗HCMV药物的结合；描述ev- 100作为HCMV剂量的函数；以及有助于预测EV-100的其他参数移植接受者。最后，尽管预防HCMV是预期的初始指示，但广谱针对人类病毒的抗病毒特征是EV-100的潜在突破特征。该药物已经除HCMV外，还可以抑制RNA和DNA病毒，从而威胁器官和移植后患者的存活率。人类细胞和体内研究的体外研究在小鼠中，将进行进一步评估EV-100的潜在独特的广谱实用程序。