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Strong antiviral activity and safety of IFN-sparing treatment with the protease inhibitor BI 201335, the HCV polymerase inhibitor BI 207127, and ribavirin, in patients with chronic hepatitis C: the SOUND-C1 trial
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Reported by Jules Levin
AASLD Nov 2 2010 Boston
Stefan Zeuzem,1 Tarik Asselah,2 Peter Angus,3 Jean-Pierre Zarski,4 Dominique Larrey,5 Beat Müllhaupt,6 Ed Gane,7 Markus Schuchmann,8 Ansgar Lohse,9 Stanislas Pol,10 Yves Benhamou,11 Jean-Pierre Bronowicki,12 Stuart Roberts,13 Keikawus Arasteh,14 Fabien Zoulim,15 Markus Heim,16 Jerry O. Stern,17 George Kukolj,18 Gerhard Nehmiz,19 Carla Haefner,19 Wulf O. Boecher19
1J.W. Goethe University Hospital, Frankfurt, Germany; 2Hopital Beaujon, Paris, France; 3Austin Hospital, Heidelberg, Victoria, Australia; 4Hopital Albert Michallon, Grenoble, France; 5Hopital Saint-Eloi, Montpellier, France; 6University Hospital of Zurich, Zurich, Switzerland; 7Auckland City Hospital, Auckland, New Zealand; 8Johannes Gutenberg University Mainz, Mainz, Germany; 9University Hospital Hamburg-Eppendorf, Hamburg, Germany; 10Hopital Cochin, Paris, France; 11Hopital Pitié-Salpêtrière, Paris, France; 12Hopital de Brabois, Nancy, France; 13Alfred Hospital, Melbourne, Victoria, Australia; 14EPIMED/Vivantes Auguste-Viktoria-Klinikum, Berlin, Germany; 15Hopital Hotel-Dieu, Lyon, France; 16University Hospital Basel, Basel, Switzerland; 17Boehringer Ingelheim, Ridgefield, CT, USA; 18Boehringer Ingelheim (Canada) Ltd, Laval, Quebec, Canada; 19Boehringer-Ingelheim Pharma GmbH, Biberach, Germany
Stefan Zeuzem,1 Tarik Asselah,2 Peter Angus,3 Jean-Pierre Zarski,4 Dominique Larrey,5 Beat Müllhaupt,6 Ed Gane,7 Markus Schuchmann,8 Ansgar Lohse,9 Stanislas Pol,10 Yves Benhamou,11 Jean-Pierre Bronowicki,12 Stuart Roberts,13 Keikawus Arasteh,14 Fabien Zoulim,15 Markus Heim,16 Jerry O. Stern,17 George Kukolj,18 Gerhard Nehmiz,19 Carla Haefner,19 Wulf O. Boecher19
1J.W. Goethe University Hospital, Frankfurt, Germany; 2Hopital Beaujon, Paris, France; 3Austin Hospital, Heidelberg, Victoria, Australia; 4Hopital Albert Michallon, Grenoble, France; 5Hopital Saint-Eloi, Montpellier, France; 6University Hospital of Zurich, Zurich, Switzerland; 7Auckland City Hospital, Auckland, New Zealand; 8Johannes Gutenberg University Mainz, Mainz, Germany; 9University Hospital Hamburg-Eppendorf, Hamburg, Germany; 10Hopital Cochin, Paris, France; 11Hopital Pitié-Salpêtrière, Paris, France; 12Hopital de Brabois, Nancy, France; 13Alfred Hospital, Melbourne, Victoria, Australia; 14EPIMED/Vivantes Auguste-Viktoria-Klinikum, Berlin, Germany; 15Hopital Hotel-Dieu, Lyon, France; 16University Hospital Basel, Basel, Switzerland; 17Boehringer Ingelheim, Ridgefield, CT, USA; 18Boehringer Ingelheim (Canada) Ltd, Laval, Quebec, Canada; 19Boehringer-Ingelheim Pharma GmbH, Biberach, Germany
ABSTRACT
Background: BI 201335 and BI 207127 are potent and specific inhibitors of the hepatitis C virus (HCV) NS3/4A protease and the NS5B RNA-dependent RNA polymerase, respectively. An IFN-free combination of both antivirals with ribavirin (RBV) to eradicate HCV infection would create a major paradigm shift in HCV treatment.
Methods: In this randomized open-label trial, 32 treatment-naïve HCV genotype-1 (GT-1) patients were treated over 4 weeks with 400 or 600 mg three times a day (TID) BI 207127, BI 201335 120 mg once daily (QD) and RBV (1,000/1,200 mg daily in two doses). Plasma HCV RNA virus load (VL) was measured by Roche COBAS TaqMan assay with a lower limit of quantification of 25 IU/mL.
Results: At baseline, mean age was 51 ± 11 years, mean body mass index 23.8 ± 3.4 kg/m2, mean VL 6.48 log10. All patients had a rapid and sharp VL decline during the first 2 days, followed by a slower second phase decline in all except 2 patients. One patient experienced VL breakthrough (increase by >1 log10 from nadir during treatment) and 1 other experienced a 0.7 log10 VL increase. Both were in the lower dose group and were GT-1a patients with high baseline VL. On Day 29, all patients were switched per protocol to treatment with BI 201335 and PegIFN/RBV. Virological response rates (VL <25 IU/mL) after 1, 2, 3 and 4 weeks of oral treatment are shown in the table.
At the higher dose level, there was no difference between GT-1a and 1b, while GT-1a patients at 400 mg TID had a lower response rate than those with GT-1b. The PegIFN sparing treatment was well tolerated. The most common adverse events (AEs) were mostly mild gastrointestinal effects (diarrhea, nausea, vomiting), rashes or photosensitivity. There were no severe AEs, serious AEs or treatment discontinuations within the 4-week study period. Laboratory parameters did not indicate any relevant changes from baseline, except for a continuous drop in alanine aminotransferase in all patients, a decrease of hemoglobin (median -1.7 and -2.6 g/dL)a and increase of unconjugated bilirubin (median +9.8 and +11.5 µmol/L).a
Conclusions: PegIFN sparing treatment with the NS3/4A inhibitor BI 201335, NS5B inhibitor BI 207127, and RBV, demonstrated strong early antiviral activity against HCV GT-1 with good safety and tolerability. A phase 2b trial testing different dose regimens of this combination, with longer durations, is planned to evaluate sustained virologic response rates.
aCorrected for final data as presented in Tables 2 and 4.
INTRODUCTION
· Current standard therapy for hepatitis C virus (HCV) genotype (GT) 1 with peginterferon alfa and ribavirin (PegIFN/RBV) for 48 weeks, has limited efficacy and reduced tolerability, with severe adverse events (AEs) causing treatment discontinuations and contraindications
· New HCV treatments, ie direct-acting antivirals (DAAs), targeting the HCV encoded NS3/4A protease or the NS5B polymerase, with PegIFN/RBV increase sustained virological response (SVR) rates and prevent the rapid selection of resistance mutations seen when DAAs are administered as monotherapy. Thus, problems with interferon tolerability, administration convenience and contraindications remain
· BI 201335 is a potent and specific HCV NS3/4A protease inhibitor with once-daily (QD) dosing.1 Phase 1b and 2 clinical investigations show that BI 201335 combined with PegIFN/RBV is well tolerated and induces strong antiviral responses in HCV GT-1-infected patients2,3
· BI 207127 is a specific and reversible non-nucleoside thumb-pocket 1 HCV NS5B polymerase inhibitor with potent and specific antiviral activity in vitro. In clinical phase 1b trials, BI 207127 in combination with PegIFN/ RBV demonstrated robust antiviral activity in treatment-naïve (TN) patients4
· Drug-resistance studies in cell culture demonstrate that BI 201335 and BI 207127 have different resistance profiles and, in pair-wise combination studies, profoundly reduce the emergence of drug-resistant variants
· This multicenter, open label, phase 1b trial 1241.21 (SOUND-C1) investigates safety, antiviral effect and pharmacokinetics of BI 207127 in combination with BI 201335 and RBV for 4 weeks in TN patients with chronic HCV GT-1 infection
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