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在研乙肝新药CRV431联合CMX157表现出强力协同抗HBV效应

2016-09-13  来源:艾兰博曼医学网  作者:无聊的猫  编辑:faliuxue
导读
专注于抗病毒治疗开发并商业化的生物制药公司 ContraVir 近日宣布,旗下具有功能性治愈慢乙肝潜能的联合用药方案向前迈出了重要的一步。公司在研的最优亲环蛋白抑制剂 CRV431 在临床前研究

专注于抗病毒治疗开发并商业化的生物制药公司 ContraVir 近日宣布,旗下具有功能性治愈慢乙肝潜能的联合用药方案向前迈出了重要的一步。公司在研的最优亲环蛋白抑制剂 CRV431 在临床前研究中表现出了强效的抗乙肝病毒活性,包括同公司的另一款产品——高度有效的替诺福韦前体药物 CMX157 联合使用时表现出了协同效应。CMX157 目前正在泰国进行 Phase 2 期临床研究。

该亲环蛋白抑制剂 CRV431 的临床前研究结果是在由美国肝病研究学会(AASLD)/欧洲肝病研究协会(EASL)关于新型慢乙肝治疗药物发现与进展联合会议上公布的,发言的标题为“CRV431: An Optimized Cyclophilin Inhibitor with Multiple Anti-HBV Activities, High Selectivity Index, and Synergy with CMX157”。

人类肝细胞(AD38)体外研究结果显示,多重剂量的亲环蛋白抑制剂 CRV431 联合 CMX157 能够协同的抑制HBV的复制,通过检测HBV DNA 下降的水平来衡量。这些数据是首次体现这些药物具有协同的抗 HBV 活性,这也证实了 ContraVir 认为 CRV431 跟 CMX157 的联合通过靶向病毒生命周期的不同阶段或能更有效的杀灭乙肝病毒的信念。

“这项研究证实了我们的想法,并证实我们拥有的两个抗 HBV 产品的联合治疗将是独一无二并且强有力的资产,而且这两者的联合还可能具有功能性治愈慢乙肝的潜能,” ContraVir CEO James Sapirstein 表示。“ CRV431 展示了具有作用于被认为治愈HBV必要的多个关键位点的潜能。正如我们看到其他病毒性疾病被成功治愈,通过跟一个成熟的药物如替诺福韦/CMX157进行联合将会释放这些药物的潜力并使我们更接近于HBV的治愈。”、

跟其他相关临床发现一样,研究数据还对 CRV431 的体外抗HBV活性进行了描述。更重要的是,通过以 CC50/IC50率计算,CRV431 要比其他所有已知的亲环蛋白抑制剂具有最广泛的选择指数。这种优化选择指数可能跟最佳的一类治疗指数相关,因此,具有增强的临床抗HBV作用。其他单药 CRV431 体外用药的发现包括以下:

  亲环蛋白通过肝细胞常见的牛磺胆酸钠共转运多肽(NTCP)受体途径独立抑制病毒的摄取 ;

  相较其他相关的亲环蛋白抑制剂如阿拉泊韦(alisporovir),CRV431 在AD38细胞中具有更强的抑制细胞内 HBV DNA的能力;

  通过感染或转染的Huh7细胞抑制血清 HBV 抗原 HBeAg 和 HBsAg 和/或的产生。降低或清除这些抗原被认为是治愈慢乙肝方案的关键要求。

在大鼠和小鼠进行的体内研究中,更突出显示 CRV431 的附加特性。剂量研究显示 CRV431 适合口服用药,相较于环孢菌素A其口服药代动力学获得明显改善,CRV431 是由环孢菌素A的母体所衍生。此外,在一个肝纤维化老鼠模型中,给予老鼠口服 CRV431 显示可以减少肝纤维化区域并呈现剂量依赖效应。这种效应独立于该药的病毒抑制效应,而有可能是 CRV431 跟宿主亲环蛋白(多种促纤维化的机制)的相互作用产生的。

James Sapirstein 推断,“我们受到这些研究结果的高度鼓舞,这些研究结果将确保支持我们对 CRV431 进行更深入的临床研究,并跟CMX157在人体中进行联合用药研究。我们期待着继续进行 CRV431 的临床前研究开发,并在2017年的最后季度进行临床研究。”


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ContraVir乙肝新药CRV431联用或能功能性治愈慢乙肝


ContraVir慢乙肝新药CRV431基础研究数据介绍




英文原文

ContraVir Reports New CRV431 Data Highlighting Synergistic Activity with CMX157 Against Hepatitis B

EDISON, N.J., Sept. 12, 2016 /PRNewswire/ -- ContraVir Pharmaceuticals, Inc. (NASDAQ: CTRV), a biopharmaceutical company focused on the development and commercialization of targeted antiviral therapies, today announced that it has taken a major step forward in its pursuit of a potentially curative combination therapy for chronic hepatitis B (HBV). The Company presented new preclinical data profiling the robust anti-HBV activity of its potentially best-in-class cyclophilin inhibitor CRV431, including evidence of synergy with CMX157, ContraVir's highly potent prodrug of tenofovir, when the two drugs are used together. CMX157 is currently in Phase 2 clinical trials in Thailand.

The peer-reviewed findings were presented at a joint meeting sponsored by the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) called HBV Treatment Endpoints Workshop: From Discovery to Regulatory Approval, in a poster titled, "CRV431: An Optimized Cyclophilin Inhibitor with Multiple Anti-HBV Activities, High Selectivity Index, and Synergy with CMX157."

Human liver cells (AD38) treated in vitro with multiple combinations of CRV431 and CMX157 showed synergistic inhibition of HBV replication, as measured by a reduction in HBV DNA. These data are the first to demonstrate synergistic activity of these drugs against HBV, confirming ContraVir's belief that a combination of CRV431 and CMX157 may be more effective at killing the virus by potently targeting multiple stages of the viral life cycle.

"This study validates our approach and the significant opportunity we have to leverage our two HBV assets to create a uniquely powerful combination therapy and potential functional cure for hepatitis B," said James Sapirstein, CEO of ContraVir. "On its own, CRV431 demonstrates the potential to address multiple key endpoints thought to be essential for curing HBV. As we have seen with other successfully cured viral diseases, combination with a proven backbone therapy like tenofovir/CMX157 may unlock the full potential of these drugs and bring us closer to an HBV cure."

Data from the study also describe the in vitro anti-HBV activity of CRV431, as well as other clinically relevant findings. Importantly, CRV431 was shown to have the widest selective index of any known cyclophilin inhibitor, calculated by CC50/IC50 ratio. This optimized selective index may correlate with a best-in-class therapeutic index, and therefore, enhanced clinical utility against HBV. Other key findings for CRV431 monotherapy in vitro include:

Cyclophilin-independent inhibition of viral uptake by liver cells through its common route, the sodium taurocholate co-transporting polypeptide (NTCP) receptor;

Significantly greater potency compared to a related cyclophilin inhibitor, alisporovir, as measured by inhibition of intracellular HBV DNA in AD38 cells; and

Inhibition of production and/or secretion of HBV antigens HBeAg and HBsAg by infected or transfected Huh7 cells. Reduction or elimination of these antigens is considered to be a key requirement for a curative HBV regimen.

In vivo studies in rats and mice highlighted additional characteristics of CRV431 that enhance its profile. Dosing studies showed that CRV431 is suitable for oral dosing, demonstrating a significantly improved oral pharmacokinetic profile compared to cyclosporine A, the parent molecule from which CRV431 is derived. Additionally, in a mouse model of liver fibrosis, orally-administered CRV431 was shown to reduce the area of fibrosis in a dose dependent manner. This activity is independent of viral inhibition and instead may be a result of CRV431's interaction with host cyclophilins, which are implicated in multiple pro-fibrotic mechanisms.

Mr. Sapirstein concluded, "We are highly encouraged by these findings, which clearly support further development of CRV431 into IND-enabling studies and ultimately into clinical development in human combination studies with CMX157. We expect to continue preclinical development of CRV431, with a potential IND filing in the last quarter of 2017."



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