A single antiviral to treat multiple opportunistic infections

项目摘要/摘要 免疫抑制的移植患者对环境病原体以及 与供体组织一起旅行或居住在受者体内的不定性剂。传统疗法针对的是病毒 并因此仅限于针对特定病毒的有效性。Evrys Bio正在开发口服药物， 针对宿主细胞sirtuin-2蛋白(SIRT2)的广谱抗病毒药物。在体外的可行性是 在SBIR第一阶段展示了早期领先的FLS-359，对四个家族表现出广泛的有效性 给免疫抑制的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靶向SIRT2阻止了病毒药物的获得 在流感模型中具有抗药性，与传统的直接作用抗病毒药物相比，抗病毒活性是相加的。一个 原型是在SBIR第二阶段开发的，允许选择候选药物(DC)进行研究 药物(IND)-在抗病毒效力和抗病毒能力方面满足体外目标化合物概况的使能 ADME和体内口服生物利用度、靶向接合和耐受性。DC被命名为EV-100。在这 SBIR第二阶段B申请，我们请求资金，以推动EV-100向IND提交申请。临床试验将 旨在测试EV-100对预防人类巨细胞病毒(HCMV)感染和疾病的效用 接受同种异基因造血干细胞移植的成年HCMV阳性受者。晋级到 IND备案，我们将建立EV-100剂量、药代动力学参数、疗效和 毒性。我们将在大鼠和狗身上进行非GLP剂量范围寻找安全性研究，并在 小鼠HCMV病毒挑战模型提供指导并通过选择给药方案将风险降至最低 昂贵的全科医生和临床研究。此外，我们将进行研究，以解决已发表的FDA体外病毒学 研究支持IND申请的建议。这些研究将包括对EV-100的评估 多个实验室和临床分离株的抗病毒活性，包括对EV-100的分析 对目前批准的药物具有抗药性的人巨细胞病毒变种的抑制活性；进化测试 通过增加细胞培养中EV-100的浓度来提高HCMV连续传代过程中的病毒耐药性； 结合目前批准的抗巨细胞病毒药物对EV-100有效性的评估；EV-100的描绘 100作为HCMV剂量的函数；以及有助于预测EV-100在 移植受者。最后，尽管预防巨细胞病毒是预定的初始适应症，但广谱的 针对人类病毒的抗病毒特性是EV-100的一个潜在的突破性特征。这种药已经被 除了能对器官和组织构成威胁的巨细胞病毒外，还能抑制RNA和DNA病毒 移植后患者的存活率。人体细胞的体外研究和人源化的体内研究 将在小鼠身上进行实验，以进一步评估EV-100这一潜在的独特的广谱用途。

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.