Potency, safety, and pharmacokinetics of the NS3/4A protease inhibitor BI201335 in patients with chronic HCV genotype-1 infection

Manns, Michael P.; Bourlière, Marc; Benhamou, Yves; Pol, Stanislas; Bonacini, Maurizio; Trépo, C.; Wright, David W.; Berg, Thomas; Calleja, José Luís; White, Peter W.; Stern, Jerry O.; Steinmann, Gerhard; Yong, Chan‐Loi; Kukolj, George; Scherer, J.; Boecher, Wulf O.

doi:10.1016/j.jhep.2010.08.040

Cited by 110 publications

(116 citation statements)

References 18 publications

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“…[4][5][6][7] However, combinations of potent direct-acting antiviral agents targeting different stages of the HCV life cycle offer the possibility of interferonfree treatment. The results of phase 1 and 2 studies involving patients with HCV genotype 1 infection have been encouraging and provide support for further development of combination therapies.…”

Section: Resultsmentioning

confidence: 99%

Faldaprevir and Deleobuvir for HCV Genotype 1 Infection

Zeuzem¹,

Soriano²,

Asselah³

et al. 2013

N Engl J Med

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BACKGROUND: Interferon-free regimens would be a major advance in the treatment of patients with chronic hepatitis C virus (HCV) infection. METHODS: In this phase 2b, randomized, openlabel trial of faldaprevir (a protease inhibitor) and deleobuvir (a nonnucleoside polymerase inhibitor), we randomly assigned 362 previously untreated patients with HCV genotype 1 infection to one of five groups: faldaprevir at a dose of 120 mg once daily and deleobuvir at a dose of 600 mg three times daily, plus ribavirin, for 16, 28, or 40 weeks (TID16W, TID28W, or TID40W, respectively); faldaprevir at a dose of 120 mg once daily and deleobuvir at a dose of 600 mg twice daily, plus ribavirin, for 28 weeks (BID28W); or faldaprevir at a dose of 120 mg once daily and deleobuvir at a dose of 600 mg three times daily, without ribavirin, for 28 weeks (TID28W-NR). The primary end point was a sustained virologic response 12 weeks after the completion of therapy. RESULTS: The primary end point was met in 59% of patients in the TID16W group, 59% of patients in the TID28W group, 52% of patients in the TID40W group, 69% of patients in the BID28W group, and 39% of patients in the TID28W-NR group. The sustained virologic response 12 weeks after the completion of therapy did not differ significantly according to treatment duration or dosage among ribavirin-containing regimens. This response was significantly higher with TID28W than with TID28W-NR (P=0.03). Rates of a sustained virologic response 12 weeks after the completion of therapy were 56 to 85% among patients with genotype 1b infection versus 11 to 47% among patients with genotype 1a infection and 58 to 84% among patients with IL28B CC versus 33 to 64% with non-CC genotypes. Rash, photosensitivity, nausea, vomiting, and diarrhea were the most common adverse events. CONCLUSIONS: The rate of a sustained virologic response 12 weeks after the completion of therapy was 52 to 69% among patients who received interferon-free treatment with faldaprevir in combination with deleobuvir plus ribavirin. (Funded by Boehringer Ingelheim; SOUND-C2 ClinicalTrials.gov number, NCT01132313.).

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Section: Resultsmentioning

confidence: 99%

Faldaprevir and Deleobuvir for HCV Genotype 1 Infection

Zeuzem¹,

Soriano²,

Asselah³

et al. 2013

N Engl J Med

Self Cite

211

173

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“…HCV NS3/4A PIs have been shown to rapidly select for the emergence of resistance mutations when administered as monotherapy. 10,12 Therefore, the effect of 3 days of pretreatment of patients with PegIFN and RBV before adding faldaprevir was assessed directly by comparing 240 mg QD dose groups with or without LI. The rationale was that the short delay of the first intake of faldaprevir would prevent the possibility of functional PI monotherapy.…”

Section: Discussionmentioning

confidence: 99%

“…Plasma HCV RNA levels were measured using the Roche COBAS TaqMan HCV/HPS assay (Roche, Pleasanton, CA), at a central laboratory, at the time of screening and during the treatment period at days 1 and 4 and weeks 1,2,4,8,10,12,16,20,24,28,36, and 48. The LLOQ was 25 IU/mL, and the LLOD was 17 IU/mL.…”

Section: Efficacy Assessmentsmentioning

confidence: 99%

“…9 Phase 1b studies demonstrated that faldaprevir QD combined with PegIFN/RBV was well tolerated and induced strong antiviral responses in treatment-naïve and -experienced HCV GT-1 patients. 10 Here, we report on the results of a phase 2b, multicenter, randomized, double-blind study of faldaprevir or placebo in combination with PegIFN/RBV in treatmentnaïve, HCV GT-1-infected patients (SILEN-C1; Safety, and antIviraL Effect of faldaprevir iN hepatitis C).…”

mentioning

confidence: 99%

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Faldaprevir combined with pegylated interferon alfa-2a and ribavirin in treatment-naïve patients with chronic genotype1 HCV: SILEN-C1 trial

et al. 2013

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Faldaprevir (BI 201335) is a potent, hepatitis C virus (HCV) NS3/4A protease inhibitor with pharmacokinetic properties supportive of once-daily (QD) dosing. Four hundred and twenty-nine HCV genotype (GT)-1 treatment-naïve patients without cirrhosis were randomized 1:1:2:2 to receive 24 weeks of pegylated interferon alfa-2a and ribavirin (PegIFN/RBV) in combination with placebo, faldaprevir 120 mg QD with 3 days of PegIFN/RBV lead-in (LI), 240 mg QD with LI, or 240 mg QD without LI, followed by an additional 24 weeks of PegIFN/RBV. Patients in the 240 mg QD groups achieving maintained rapid virologic response (mRVR; viral load [VL] <25 IU/mL at week 4 and undetectable at weeks 8-20) were rerandomized to cease all treatment at week 24 or continue receiving PegIFN/RBV up to week 48. VL was measured by Roche TaqMan. Sustained virologic response (SVR) rates were 56%, 72%, 72%, and 84% in the placebo, faldaprevir 120 mg QD/LI, 240 mg QD/LI, and 240 mg QD groups. Ninety-two percent of mRVR patients treated with faldaprevir 240 mg QD achieved SVR, irrespective of PegIFN/RBV treatment duration. Eighty-two percent of GT-1a patients who received faldaprevir 240 mg QD achieved SVR versus 47% with placebo. Mild gastrointestinal disorders, jaundice resulting from isolated unconjugated hyperbilirubinemia, and rash or photosensitivity were more common in the active groups than with placebo. Discontinuations resulting from adverse events occurred in 4%, 11%, and 5% of patients treated with 120 mg QD/LI, 240 mg QD/LI, and 240 mg QD of faldaprevir versus 1% with placebo. Conclusion: Faldaprevir QD with PegIFN/RBV achieved consistently high SVR rates with acceptable tolerability and safety at all dose levels. The 120 and 240 mg QD doses are currently undergoing phase 3 evaluation. (HEPATOLOGY 2013;57:2143-2154

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“…Faldaprevir (BI 201335) is a potent HCV NS3/4A PI administered once daily [10][11][12]. Four phase 2 studies evaluated the efficacy and safety of faldaprevir with PegIFN alfa-2a plus RBV [13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

STARTVerso1: A randomized trial of faldaprevir plus pegylated interferon/ribavirin for chronic HCV genotype-1 infection

Ferenci

Asselah

Foster

et al. 2015

Journal of Hepatology

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Background & Aims:The efficacy and tolerability of faldaprevir, a potent hepatitis C virus (HCV) NS3/4A protease inhibitor, plus peginterferon (PegIFN) and ribavirin (RBV) was assessed in a double-blind, placebo-controlled phase 3 study of treatment-naïve patients with HCV genotype-1 infection. Methods: Patients were randomly assigned (1:2:2) to PegIFN/ RBV plus: placebo (arm 1, n = 132) for 24 weeks; faldaprevir (120 mg, once daily) for 12 or 24 weeks (arm 2, n = 259); or faldaprevir (240 mg, once daily) for 12 weeks (arm 3, n = 261). In arms 2 and 3, patients with early treatment success (HCV-RNA <25 IU/ml at week 4 and undetectable at week 8) stopped all treatment at week 24. Other patients received PegIFN/RBV until week 48 unless they met futility criteria. The primary endpoint was sustained virologic response 12 weeks post-treatment (SVR12). Results: SVR12 was achieved by 52%, 79%, and 80% of patients in arms 1, 2, and 3, respectively (estimated difference for arms 2 and 3 vs. arm 1: 27%, 95% confidence interval 17%-36%; and 29%, 95% confidence interval, 19%-38%, respectively; p <0.0001 for both). Early treatment success was achieved by 87% (arm 2) and 89% (arm 3) of patients, of whom 86% and 89% achieved SVR12. Adverse event rates were similar among groups; few adverse events led to discontinuation of all regimen components. Conclusions: Faldaprevir plus PegIFN/RBV significantly increased SVR12, compared with PegIFN/RBV, in treatment-naïve patients with HCV genotype-1 infection. No differences were seen in responses of patients given faldaprevir once daily at 120 or 240 mg. Ó

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Potency, safety, and pharmacokinetics of the NS3/4A protease inhibitor BI201335 in patients with chronic HCV genotype-1 infection

Cited by 110 publications

References 18 publications

Faldaprevir and Deleobuvir for HCV Genotype 1 Infection

Faldaprevir and Deleobuvir for HCV Genotype 1 Infection

Faldaprevir combined with pegylated interferon alfa-2a and ribavirin in treatment-naïve patients with chronic genotype1 HCV: SILEN-C1 trial

STARTVerso1: A randomized trial of faldaprevir plus pegylated interferon/ribavirin for chronic HCV genotype-1 infection

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