EASL2015:影响HBV核心抑制剂NVR 3-778用核苷类似物或其他HBV CORE抑

StephenW

RS-2217
Viral hepatitis
Hepatitis B & D - clinical (Therapy, new compounds, resistance)

EFFECT OF THE COMBINATION OF THE HBV CORE INHIBITOR NVR 3-778 WITH NUCLEOSIDE ANALOGS OR OTHER HBV CORE INHIBITORS ON THE INHIBITION OF HBV DNA REPLICATION IN HEPG2.2.15 CELLS
Angela Lam* 1, Christine Espiritu1, Osvaldo Flores1, George Hartman1, Klaus Klumpp1
1Novira Therapeutics Inc., Doylestown, United States


Corresponding author’s email: [email protected]


Background and Aims:
NVR 3-778 represents a new class of HBV core inhibitors and is in clinical development for the treatment of chronic hepatitis B.  The availability of NVR 3-778 as an HBV replication inhibitor with a new mechanism of action allows the assessment of the potential for increased antiviral potency that could be achieved in combination treatment with other antiviral agents.  Different classes of HBV core inhibitors may also show benefit in combination.
Methods:
HepG2.2.15 cells contain stably integrated HBV DNA and generate infectious HBV particles.  These cells were used to investigate the interaction between NVR 3-778 and nucleoside analogs Lamivudine (LMV), Tenofovir (TFV) and Entecavir (ETV).  The combination of NVR 3-778 with another core inhibitor, NVR 3-7484 was also assessed.  The reduction of HBV DNA in the cell culture supernatant was determined after cells were incubated with different concentrations of NVR 3-778 and a nucleoside analog or other core inhibitor in a checkerboard format for 6 days.  Cell viability was assessed by the determination of intracellular ATP concentrations.  MacSynergy II was used to evaluate the effect of compound combinations.
Results:
HBV DNA replication was monitored by measuring levels of secreted, encapsidated HBV DNA in HepG2.2.15 cell supernatant.  NVR 3-778, NVR 3-7484, LMV, TFV and ETV inhibited HBV DNA replication with mean EC50 values of 0.47 µM, 0.52 µM, 0.11 µM, 1.4 µM and 3.2 nM, respectively.  Combining NVR 3-778 with each of the three nucleoside analogs resulted in additive antiviral effects.  We also observed an additive antiviral effect from the combination of two HBV core inhibitors, NVR 3-778 and NVR 3-7484.  Cell viability remained above 90% in all samples treated with the highest compound concentrations, either alone or in combination.
Conclusions:
The combination of the HBV core inhibitor NVR 3-778 with nucleoside analogs lamivudine, tenofovir or entecavir showed additive antiviral effects against HBV replication without reductions in cell viabilty.  In addition, the combination of two different HBV core inhibitors showed additive antiviral activity.  These results support further exploration of the benefit of such combinations in intensifying the overall suppression of HBV replication and production of HBV from infected cells.


Disclosure of Interest: A. Lam:  Employee: Novira Therapeutics, C. Espiritu:  Employee: Novira Therapeutics, O. Flores:  Employee: Novira Therapeutics, G. Hartman:  Employee: Novira Therapeutics, K. Klumpp:  Employee: Novira Therapeutics

StephenW

RS-2217

病毒性肝炎

乙肝＆D - 临床（治疗，新的化合物，电阻）





影响HBV核心抑制剂NVR 3-778用核苷类似物或其他HBV CORE抑制剂对HBV DNA复制的HepG2.2.15细胞的抑制作用相结合

安吉拉林* 1，恭Espiritu1，奥斯瓦尔多Flores1，乔治Hartman1，克劳斯Klumpp1

1Novira Therapeutics公司，Doylestown的，美国



通讯作者的邮箱：[email protected]



背景和目的：NVR 3-778代表了一类新HBV核心抑制剂，是临床开发用于治疗慢性乙型肝炎的治疗NVR 3-778的与行动的新机制的HBV复制抑制剂的可用性允许评估的，可以在组合治疗来实现与其它抗病毒剂的潜在增加的抗病毒效力。不同类别的HBV核心抑制剂也可能显示益处结合。

方法：HepG2.2.15细胞含有稳定整合的HBV DNA和产生感染性HBV颗粒。这些细胞被用来研究NVR 3-778和核苷类似物拉米夫定（LMV），替诺福韦（TFV）和恩替卡韦（ETV）之间的相互作用。 NVR 3-778的与另一芯抑制剂的组合，NVR 3-7484还评估。测定的HBV DNA在细胞培养上清液中的减少细胞与不同浓度的NVR 3-778的和为棋盘格式的核苷类似物或其他核心抑制剂6天之后。细胞存活率通过细胞内ATP浓度的测定评估。 MacSynergy II是用来评价化合物的组合的效果。

结果：HBV DNA复制是通过测定在HepG2.2.15细胞的细胞上清液分泌，包被HBV DNA水平监测。 NVR 3-778，NVR 3-7484，LMV，TFV和ETV抑制HBV DNA复制与0.47μM平均EC50值，0.52微米，0.11微米，1.4微米和3.2纳米，分别。结合NVR 3-778与每个导致添加剂抗病毒作用三个核苷类似物。我们还观察到从两个HBV核心抑制剂，NVR 3-778和NVR 3-7484的组合的添加剂的抗病毒效果。细胞生存力具有最高化合物浓度，无论是单独或组合治疗的所有样品中保持在90％以上。

结论：HBV核心抑制剂NVR 3-778的联合核苷类似物拉米夫定，替诺福韦或恩替卡韦对显示HBV的复制添加剂，抗病毒效果，而减少细胞viabilty。此外，两个不同的HBV核心抑制剂的组合显示添加剂的抗病毒活性。这些结果支持进一步探索这种组合的优点在从感染细胞激化HBV复制的总体抑制乙肝病毒的生产。



股权变动：A.林：员工：Novira治疗，圣埃斯皮里图C.：员工：Novira治疗，O.弗洛雷斯：员工：Novira治疗，G.哈特曼：员工：Novira治疗，K. Klumpp的：员工：Novira治疗

newchinabok

November 2015   (final data collection date for primary outcome measure)

newchinabok

2015年11月（最终数据收集日期为主要测量指标）

咬牙硬挺

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