Rapid and strong antiviral activity of the non-nucleosidic NS5B polymerase inhibitor BI 207127 in combination with peginterferon alfa 2a and ribavirin

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• 作者：Dominique Larrey¹ ; ^&dagger ; ; ^{dom-larrey@chu-montpellier.fr} ; Ansgar W. Lohse² ; ^&dagger ; ; Victor de Ledinghen³ ; ^&dagger ; ; Christian Trepo⁴ ; ^&dagger ; ; Tilman Gerlach⁵ ; ^&dagger ; ; Jean-Pierre Zarski⁶ ; ^&dagger ; ; Albert Tran⁷ ; ^&dagger ; ; Philippe Mathurin⁸ ; ^&dagger ; ; Robert Thimme⁹ ; ^&dagger ; ; Keikawus Arasté ; h¹⁰ ; ^&dagger ; ; Christian Trautwein¹¹ ; ^&dagger ; ; Andreas Cerny¹² ; ^&dagger ; ; Nektarios Dikopoulos¹³ ; ^&dagger ; ; Marcus Schuchmann¹⁴ ; ^&dagger ; ; Markus H. Heim¹⁵ ; ^&dagger ; ; Guido Gerken¹⁶ ; ^&dagger ; ; Jerry O. Stern¹⁷ ; ^&dagger ; ; Katherine Wu¹⁷ ; ^&dagger ; ; Nasri Abdallah¹⁸ ; ^&dagger ; ; Birgit Girlich¹⁹ ; ^&dagger ; ; Joseph Scherer¹⁷ ; ^&dagger ; ; Frank Berger²⁰ ; ^&dagger ; ; Martin Marquis²¹ ; ^&dagger ; ; George Kukolj²¹ ; ^&dagger ; ; Wulf Bö ; cher²² ; ^&dagger ; ; Jü ; rgen Steffgen²² ; ^&dagger ;
• 关键词：HCV ; hepatitis C virus ; GT ; genotype ; TN ; treatment-naï ; ve ; TE ; treatment-experienced ; TID ; three times daily ; PegIFN/RBV ; peginterferon alfa and ribavirin ; AEs ; adverse events ; DAAs ; direct-acting antivirals ; PIs ; protease inhibitors ; PK ; pharmacokin
• 刊名：Journal of Hepatology
• 出版年：2012
• 出版时间：July, 2012
• 年：2012
• 卷：57
• 期：1
• 页码：39-46
• 全文大小：857 K

文摘

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Background & Aims

BI 207127 is a potent non-nucleoside hepatitis C virus (HCV) NS5B polymerase inhibitor in vitro.

Methods

In this double-blind, placebo-controlled study, 57 HCV genotype (GT)-1 patients (n = 27 treatment-na?ve [TN]; n = 30 treatment-experienced [TE]) with compensated liver disease were randomised for 28-day treatment with 400, 600, or 800 mg BI 207127 three times daily (TID) or placebo (only TN) in combination with peginterferon alfa 2a and ribavirin (PegIFN/RBV). Plasma HCV RNA was measured by Roche COBAS TaqMan assay.

Results

HCV RNA decreased in a dose-dependent manner with little difference between 600 mg (TN 5.6 log₁₀, TE 4.2 log₁₀) and 800 mg (TN 5.4 log₁₀, TE 4.5 log₁₀). Rapid virological response (RVR; HCV RNA <15 IU/ml) at day 28 occurred in 11/19 TN and 4/30 TE patients treated with BI 207127. GT-1b patients had stronger reductions in HCV RNA than GT-1a (RVR: TN 64 % vs. 43 % ; TE 33 % vs. 5 % ). There were no breakthroughs (HCV RNA rebound >1 log₁₀ from nadir) in the TN groups, whereas 3/30 TE patients experienced breakthrough due to P495-mutations. Gastrointestinal adverse events (AEs) and rash were the major AEs and most frequent at higher doses. One and four patients discontinued due to AEs in the 600 and 800 mg groups, respectively. Overall, tolerability was good and better at 600 mg than 800 mg.

Conclusions

BI 207127 in combination with PegIFN/RBV demonstrated strong antiviral activity with a favourable safety and tolerability profile. The best benefit/risk ratio was observed at 600 mg.