A single antiviral to treat multiple opportunistic infections

项目总结/摘要 免疫抑制移植患者对环境病原体的易感性增加， 与供体组织一起移动或驻留在受体中的外来因子。传统疗法针对病毒 从而限制了对特定目标病毒的有效性。Evrys Bio正在开发口服给药， 靶向宿主细胞sirtuin-2蛋白（SIRT 2）的广谱抗病毒药物。体外可行性 在SBIR I期试验中，早期电极导线FLS-359显示出对四个家族的广泛有效性， 给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，FLS-359的SIRT 2靶向作用阻止了病毒药物的获得 在流感模型中的耐药性，并与传统的直接作用的抗病毒药物的抗病毒活性相加。一 原型是在SBIR第二阶段开发的，允许选择一种候选药物（DC）用于研究性新药。 在抗病毒效力方面满足体外目标化合物特征的药物（IND）启用， ADME和体内口服生物利用度、靶向结合和耐受性。DC被命名为EV-100。在这 SBIR第IIB阶段申请，我们要求资金推进EV-100向IND申请。临床试验将 旨在检测EV-100预防人巨细胞病毒（HCMV）感染和疾病的效用 在同种异体造血干细胞移植的成人HCMV血清阳性受者中。进驻中华人民共和 IND申请，我们将建立EV-100剂量、药代动力学参数、疗效和 毒性我们将在大鼠和犬中进行非GLP剂量范围确定安全性研究，并在 鼠HCMV病毒攻击模型，以提供指导，并最大限度地降低给药方案选择的风险， 昂贵的GLP和临床研究。此外，我们还将开展研究，以解决已发表的FDA体外病毒学问题。 支持IND申请的研究建议。这些研究将包括EV-100的评估 对多种实验室和临床HCMV分离株的抗病毒活性，包括EV-100分析 对目前批准的药物具有耐药性的HCMV变体的抑制活性;测试进化 在细胞培养物中增加EV-100浓度的HCMV连续传代期间的病毒耐药性; 评价EV-100与目前批准的抗HCMV药物联合治疗的有效性; EV-100作为HCMV剂量的函数;以及有助于预测EV-100在HCMV感染中的疗效的其他参数。 移植接受者最后，尽管HCMV预防是预期的初始适应症，但广谱抗HCMV治疗是有效的。 抗人类病毒特性是EV-100的潜在突破性特征。药物已经 显示出抑制RNA和DNA病毒，以及可以威胁器官和组织的HCMV。 患者在移植后的存活率。人细胞的体外研究和人源化细胞的体内研究 将在小鼠中进行，以进一步评估EV-100的这种潜在独特的广谱效用。

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.