Scynexis' Oral SCY-635 Shows Potential
From the PharmaLive.com News Archive - Nov. 11, 2012
Scynexis announced the results of a Phase 2a study of lead candidate SCY-635 in combination with pegylated interferon and ribavirin (Peg-IFN/RBV) for the treatment of the hepatitis C virus that showed SCY-635 has the potential to play an important role in the reversal of immune exhaustion, restoring the immune systems of difficult to treat patients with HCV.
Scynexis英语口语SCY-635显示了潜在的
从该PharmaLive.com的新闻存档 - 2012年11月11日
Scynexis宣布的结果2A期研究的主角人选SCY-635结合聚乙二醇干扰素和利巴韦林治疗的丙型肝炎病毒(Peg-IFN/RBV)表明SCY-635有可能发挥了重要的作用在逆转的免疫耗竭,恢复难以治疗HCV患者的免疫系统。
关于SCY-635
About SCY-635
SCY-635 is a novel oral Cyclophilin inhibitor in Phase 2 studies for the treatment for Hepatitis C (HCV) and in preclinical studies for the treatment of Hepatitis B (HBV). Studies to date have demonstrated that SCY-635 is unique in that it plays a dual role as a synergistic Direct Acting Antiviral (DAA) and a stimulator of the host immune system (Immune Acting Antiviral or IAA). The addition of SCY-635 to the repertoire of currently approved HCV therapies could breathe new life into the future of the immunotherapeutic options for treating HCV.
SCY-635是一种新型的口服亲环素抑制剂在第二阶段研究用于治疗丙型肝炎病毒(HCV)和乙型肝炎病毒(HBV)治疗的临床前研究。最新研究表明,SCY-635的独特之处在于它扮演着双重角色,作为一个协同的直接作用抗病毒药物(DAA)和刺激宿主的免疫系统(免疫代理抗病毒药物或IAA)。 SCY-635的剧目目前已获得批准的HCV疗法可以用于治疗丙型肝炎的免疫治疗方案的未来注入新的活力。
作者: StephenW 时间: 2012-11-27 23:09
EASL 2012
PROGRAM ABSTACT
ALISPORIVIR-INDUCED INHIBITION OF CELLULAR CYCLOPHILINS DISRUPTS HEPATITIS B VIRUS (HBV) REPLICATION IN VITRO AND IS SYNERGISTIC IN COMBINATION WITH DIRECT ANTIVIRAL TARGETING HBV-DNA POLYMERASE
Speaker: Shilpa Chokshi Author: S. Phillips1, S. Chokshi1*, A. Riva1, N.V. Naoumov2 Affiliation: 1Foundation for Liver Research, Institute of Hepatology, London, UK, 2Novartis Pharma AG, Basel, Switzerland. *[email protected]
Background/aims: Cyclophilins are intracellular proteins with enzymatic activity - peptidyl-prolyl-isomerase that plays a major role in the life cycle of Hepatitis C virus. By targeting host cyclophilins Alisporivir (DEB025) exerts potent anti-HCV activity in vitro and in clinical studies. We have recently shown in vitro that cyclophilin inhibition with Alisporivir or NIM811 also interferes with HBV replication, with Alisporivir having a greater effect than NIM811. To elucidate the underlying mechanisms, in the present study we compared in vitro the effects on HBV replication of Alisporivir alone, Alisporivir in combination with a potent antiviral targeting HBV-DNA polymerase, and in cells after selective knockdown of individual cyclophilins.
Material and methods: Stably(HepG2215) and transiently(HUH-7) transfected cells, producing full HBV virions and HBsAg particles, were treated with a range of Alisporivir concentrations (0.25/1.0/5.0/20 ug/ml) alone, Telbivudine alone, or combinations of Alisporivir and Telbivudine. To determine the involvement of individual cyclophilins, HepG2215 cells were transfected with siRNA-specific for cyclophilin (Cyp) A, C or D and additionally treated with Alisporivir. Cytoplasmic extracts and supernatants were harvested at baseline; 24, 48 and 72 hours post-treatment. The kinetics of antiviral activity was assessed by quantitation of intracellular and secreted HBV-DNA (real-time qPCR) and HBsAg levels (ELISA).
Results: Both in HepG2215 and HUH-7 cells, Alisporivir treatment resulted in dose-dependent reduction of intracellular and secreted HBV-DNA at all time points, by 70% (p=0.004) and 63% (p< 0.001), respectively, compared with untreated controls. The combination of Alisporivir and Telbivudine had greater effects in reducing intracellular (p=0.001) and secreted (p=0.028) HBV-DNA, and >3-fold reduction of HBsAg versus either Alisporivir or Telbivudine alone. CypA, C or D expression was markedly reduced after transfection with corresponding siRNA, which was associated with significant decrease of HBV-DNA and HBsAg levels (p< 0.001). Alisporivir treatment of cells silenced for CypA, C or D further reduced HBV-DNA and HBsAg levels, with greater antiviral effects in CypC or CypD silenced cells, compared with CypA silenced cells (p< 0.001).
Conclusion: These results suggest that Alisporivir interferes with multiple sites of HBV replication and its antiviral activity is synergistic with direct antiviral targeting viral DNA polymerase, such as Telbivudine.