The cyclophilin inhibitor SCY-635 suppresses viral replication and induces endogenous interferons in patients with chronic HCV genotype 1 infection

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• 作者：Sam Hopkins¹ ; ^{S.Hopkins@autoimmune.com} ; Betty DiMassimo¹ ; Pamela Rusnak¹ ; Douglas Heuman² ; Jacob Lalezari³ ; Ann Sluder¹ ; Bernard Scorneaux¹ ; Sarah Mosier¹ ; Paul Kowalczyk¹ ; Yves Ribeill¹ ; James Baugh⁴ ; Philippe Gallay⁴
• 关键词：HCV ; hepatitis C virus ; CsA ; cyclosporin A ; EC50 ; 50%effective concentration ; HIV-1 ; Human Immunodeficiency Virus Type-1 ; PPIase ; peptidyl prolyl isomerase ; TEAE ; treatment-emergent adverse event ; CTCAE ; Common Terminology Criteria for Adverse Events ; IF
• 刊名：Journal of Hepatology
• 出版年：2012
• 期刊代码：162_01688278
• 类别：med
• 出版时间：July, 2012
• 卷：57
• 期：1
• 页码：47-54
• 文件大小：971 K

摘要

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Background & Aims

SCY-635 is a non-immunosuppressive analog of cyclosporin A that inhibits cyclophilins A and B and hepatitis C virus (HCV) replication in vitro. In a phase 1b multi-dose escalation study, we evaluated the safety, plasma pharmacokinetics, and antiviral activity of 15 days of monotherapy with SCY-635 in adults with chronic genotype 1 HCV infection.

Methods

Twenty adults with chronic HCV genotype 1 were randomized to SCY-635 oral doses of 100, 200, or 300 mg three times daily for 15 days.

Results

No dose-limiting clinical or laboratory toxicities were identified. On day 15, the mean decline in plasma viremia was 2.24 卤 1.74 log₁₀ IU/ml with SCY-635 900 mg/d. Individual antiviral responses correlated with host IL28B genotype. Post hoc analyses indicated treatment with SCY-635 increased plasma protein concentrations of interferon 伪 (IFN伪), IFNs 位₁ and 位₃, and 2鈥?鈥?oligoadenylate synthetase 1 (2鈥?鈥睴AS-1), with the greatest increases in IL28B CC and CT subjects. Changes in plasma concentrations for all markers were coincident with changes in the plasma concentration of SCY-635. Peaks of IFNs 伪, 位₁, and 位₃ and 2鈥?鈥睴AS-1 were observed within 2 h after drug administration. In replicon cells, SCY-635 enhanced secretion of type I and type III IFNs and increased the expression of IFN-stimulated genes (ISG).

Conclusions

These studies establish clinical proof of concept for SCY-635 as a novel antiviral agent and suggest that restoration of the host innate immune response to chronic hepatitis C infection may represent a major mechanism through which cyclophilin inhibitors exert clinical antiviral activity.