HCVerso1 and 2: faldaprevir with deleobuvir (BI 207127) and ribavirin for treatment-naïve patients with chronic hepatitis C virus genotype-1b infection

Abstract

The interferon-free combination of once-daily faldaprevir 120 mg, twice-daily deleobuvir 600 mg, and weight-based ribavirin was evaluated in two Phase III studies (HCVerso1, HCVerso2) in hepatitis C virus genotype-1b-infected, treatment-naïve patients, including those ineligible for peginterferon (HCVerso2). Patients without cirrhosis were randomized to 16 weeks (Arm 1; n=208 HCVerso1, n=213 HCVerso2) or 24 weeks (Arm 2; n=211 in both studies) of faldaprevir + deleobuvir + ribavirin. Patients with compensated cirrhosis received open-label faldaprevir + deleobuvir + ribavirin for 24 weeks (Arm 3; n=51, n=72). Primary endpoints were comparisons of adjusted sustained virologic response (SVR) rates with historical rates: 71% (HCVerso1) and 68% (HCVerso2). Adjusted SVR12 rates were significantly greater than historical controls for Arms 1 and 2 in HCVerso2 (76%, 95% confidence interval [CI] 71-81, P=0.002; 81%, 95% CI 76-86, P<0.0001) and Arm 2 in HCVerso1 (81%, 95% CI 77-86, P<0.0001), but not for Arm 1 of HCVerso1 (72%, 95% CI 66-77, P=0.3989). Unadjusted SVR12 rates in Arms 1, 2, and 3 were 71.6%, 82.5%, and 72.5%, respectively, in HCVerso1 and 75.6%, 82.0%, and 73.6%, respectively, in HCVerso2. Virologic breakthrough and relapse occurred in 24-week arms in 8%-9% and 1% of patients, respectively, and in 16-week arms in 7%-8% and 9%-11% of patients, respectively. The most common adverse events were nausea (46%-61%) and vomiting (29%-35%). Adverse events resulted in discontinuation of all medications in 6%-8% of patients. In treatment-naïve patients with hepatitis C virus genotype-1b infection, with or without cirrhosis, faldaprevir + deleobuvir + ribavirin treatment for 24 weeks resulted in adjusted SVR12 rates significantly higher than historical controls. Both studies were registered in ClinicalTrials.gov (NCT01732796, NCT01728324).

Keywords: NS3 protease inhibitor; antiviral; chronic hepatitis C; cirrhosis; nonnucleoside polymerase inhibitor.

Conflict of interest statement

CS has served on the advisory boards for Abbott, AbbVie, Achillion, BI, BMS, Janssen, Gilead, Merck/MSD, Novartis, Roche, and Vertex; the speaker bureaus for Abbott, AbbVie, BI, BMS, Falk, Gilead, Janssen, Merck/MSD, Novartis, Roche, and Siemens; and has received research support from Abbott, Gilead, Janssen, Merck/MSD, Roche, and Siemens. FCastelli has received research support from Abbott, Astellas, BMS, Boehringer Ingelheim, ViiV Healthcare, Schering, Roche, Janssen, Novartis, and Pfizer. PA has served on the advisory boards for AbbVie, Boehringer Ingelheim, Gilead, Janssen, Merck, and Roche; has acted as a consultant for BMS and Merck; and has received research support from Gilead Sciences, Merck, and Roche. MB has acted as a consultant for Boehringer Ingelheim and as a speaker for BMS, Gilead, Janssen, Merck, and Novartis. MC has received research support from BMS and Gilead Science; has served on the advisory boards for AbbVie, Achillion, Alfa Wasserman, Bayer, BMS, GenSpera, Gilead Science, GSK, Janssen, Jennerex, Lundbeck, Merck, Novartis, Roche, Tibotec, and Vertex; and has acted as a speaker for Bayer, BMS, Gilead Science, Janssen, Merck, Novartis, Roche, Sanofi, Tibotec, and Vertex. SP has acted as a consultant and speaker for Abbott, BMS, Boehringer Ingelheim, Gilead Sciences, GSK, Merck, Novartis, Roche, Sanofi, Tibotec, and Vertex; and has received research support from BMS, Gilead, Merck, and Roche. FCalinas has served on the advisory boards for AbbVie, BMS, Gilead Sciences, Janssen, Merck, and Roche; the speaker bureaus for BMS, Gilead Sciences, Janssen, Merck, and Roche; and has acted as a consultant for Boehringer Ingelheim and Intercept. MP has served on the advisory boards, speaker bureaus, or as a consultant for Boehringer Ingelheim, Gilead Sciences, GSK, Janssen, Merck, Vertex, and ViiV Healthcare; received medicines, equipment, or administrative support from Merck; and has received research support from BMS, Gilead Sciences, Novartis, and Roche. AO and MS report no conflicts of interest. JOS, MR, SA, QD, and RV are employees of Boehringer Ingelheim. GK was employed by Boehringer Ingelheim and is currently employed by Gilead Sciences. FJM was employed by Boehringer Ingelheim and is currently employed by AbbVie. DN has received research support from AbbVie, BI, BMS, Genentech, Gilead, Janssen, Kadmon, Merck, and Vertex.

Figures

Figure 1

Patient disposition in HCVerso1 (A) and HCVerso2 (B) Notes:aAdverse event 11, lack of efficacy 7, lost to follow-up 2, withdrawal 4, other 2. bAdverse event 12, lack of efficacy 8, lost to follow-up 2, withdrawal 4, other 1. cAdverse event 12, lack of efficacy 7, lost to follow-up 2, withdrawal 4, other 2. dAdverse event 5, lack of efficacy 13, withdrawal 1, other 1. eAdverse event 4, lack of efficacy 13, withdrawal 2. fAdverse event 4, lack of efficacy 13, withdrawal 1, other 1. gAdverse event 16, lack of efficacy 17, withdrawal 8, other 1. hAdverse event 16, lack of efficacy 18, withdrawal 8. iAdverse event 17, lack of efficacy 17, withdrawal 8, other 1. jAdverse event 4, lack of efficacy 4, withdrawal 2, other 3. kAdverse event 4, lack of efficacy 5, withdrawal 2, other 2. lAdverse event 5, lack of efficacy 4, withdrawal 2, other 3. mAdverse event 13, lack of efficacy 12, withdrawal 6, other 3. nAdverse event 16, lack of efficacy 11, withdrawal 5, other 3. oAdverse event 1, protocol violation 1. pAdverse event 14, lack of efficacy 14, withdrawal 9, other 1. qAdverse event 15, lack of efficacy 14, withdrawal 9, other 1. rAdverse event 4, lack of efficacy 8, withdrawal 2. sAdverse event 5, lack of efficacy 7, withdrawal 2, other 1. Abbreviations: C, compensated cirrhosis; DBV, deleobuvir; DC, discontinuation; FDV, faldaprevir; NC, no cirrhosis; RBV, ribavirin.

Figure 2

Adjusted SVR12 versus historical control for HCVerso1 (A) and HCVerso2 (C), and SVR12 by treatment group for HCVerso1 (B) and HCVerso2 (D) Notes:aAdjusted for inclusion of patients with cirrhosis (11% in historical trials of approved DAAs and PegIFN). bCombination of the rates for 16 weeks in patients without cirrhosis and 24 weeks in patients with cirrhosis. Error bars indicate 95% CI values. Abbreviations: C, compensated cirrhosis; CI, confidence interval; SVR12, sustained virologic response at 12-week posttreatment; wks, weeks.

Figure 3

SVR12 for 24-week versus 16-week regimen by subgroups in HCVerso1 (A) and HCVerso2 (B) Notes:aNo patient in the 16-week or 24-week non-cirrhotic arms had fibrosis stage F4. Abbreviations: AA, African-American; CI, confidence interval; GGT, gamma-glutamyl transferase; PegIFN, peginterferon-α; VL, viral load; wks, weeks.