Efficacy, safety and pharmacokinetics of simeprevir and TMC647055/ritonavir with or without ribavirin and JNJ-56914845 in HCV genotype 1 infection

BMC Gastroenterol. 2017 Feb 10;17(1):26. doi: 10.1186/s12876-017-0580-2.

Abstract

Background: A Phase 2a, open-label study (NCT01724086) was conducted to assess the efficacy and safety of a once-daily, 2-direct-acting-antiviral-agent (2-DAA) combination of simeprevir + TMC647055/ritonavir ± ribavirin and of the 3-DAA combination of simeprevir + TMC647055/ritonavir + JNJ-56914845 in chronic hepatitis C virus genotype (GT)1-infected treatment-naïve and prior-relapse patients.

Methods: The study comprised four 12-week treatment panels: Panel 1 (n = 10; GT1a) and Panel 2-Arm 1 (n = 12; GT1b): simeprevir 75 mg once daily + TMC647055 450 mg once daily/ritonavir 30 mg once daily + ribavirin 1000-1200 mg/day; Panel 2-Arm 2 (n = 9; GT1b): simeprevir 75 mg + TMC647055 450 mg/ritonavir 30 mg without ribavirin; Panel 3: simeprevir 75 mg + TMC647055 600 mg/ritonavir 50 mg with (Arm 1: GT1a; n = 7) or without (Arm 2: GT1b; n = 8) ribavirin; Panel 4: simeprevir 75 mg + TMC647055 450 mg/ritonavir 30 mg + JNJ-56914845 30 mg once daily (Arm 1: n = 22; GT1a/GT1b) or 60 mg once daily (Arm 2: n = 22; GT1a/GT1b). Primary endpoint was sustained virologic response 12 weeks after end of treatment (12 weeks of combination treatment; SVR12).

Results: In Panel 1 and Panel 2-Arm 1, 5/10 and 6/12 (50%) GT1a/GT1b + ribavirin patients achieved SVR12, versus 3/9 (33%) GT1b without ribavirin patients in Panel 2-Arm 2. In Panel 3-Arm 1 and Panel 3-Arm 2, 6/7 (86%) GT1a + ribavirin and 4/8 (50%) GT1b without ribavirin patients, respectively, achieved SVR12. In Panel 4, 10/14 (71%) and 14/15 (93%) GT1a patients in Arms 1 and 2 achieved SVR12 compared with 8/8 and 7/7 (100%) GT1b patients in each arm, respectively. No deaths, serious adverse events (AEs), Grade 4 AEs or AEs leading to treatment discontinuation occurred.

Conclusions: The 2- and 3-DAA combinations were well tolerated. High SVR rates of 93% and 100% in GT1a- and GT1b-infected patients, respectively, were achieved in this study by combining simeprevir with JNJ-56914845 60 mg and TMC647055/ritonavir.

Trial registration: NCT01724086 (date of registration: September 26, 2012).

Keywords: Direct-acting antiviral agents; Efficacy; Hepatitis C virus; JNJ-56914845; Ribavirin; Safety; Simeprevir; TMC647055/ritonavir; genotype 1.

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Aged
  • Antiviral Agents / adverse effects
  • Antiviral Agents / pharmacokinetics
  • Antiviral Agents / therapeutic use*
  • Carbamates / adverse effects
  • Carbamates / pharmacokinetics
  • Carbamates / therapeutic use*
  • Drug Therapy, Combination
  • Female
  • Genotype
  • Hepatitis C, Chronic / drug therapy*
  • Hepatitis C, Chronic / genetics
  • Heterocyclic Compounds, 4 or More Rings / adverse effects
  • Heterocyclic Compounds, 4 or More Rings / pharmacokinetics
  • Heterocyclic Compounds, 4 or More Rings / therapeutic use*
  • Humans
  • Male
  • Middle Aged
  • Ribavirin / adverse effects
  • Ribavirin / pharmacokinetics
  • Ribavirin / therapeutic use*
  • Ritonavir / adverse effects
  • Ritonavir / pharmacokinetics
  • Ritonavir / therapeutic use*
  • Simeprevir / adverse effects
  • Simeprevir / pharmacokinetics
  • Simeprevir / therapeutic use*
  • Sulfonamides / adverse effects
  • Sulfonamides / pharmacokinetics
  • Sulfonamides / therapeutic use*
  • Valine / adverse effects
  • Valine / analogs & derivatives*
  • Valine / pharmacokinetics
  • Valine / therapeutic use

Substances

  • 27-cyclohexyl-12,13,16,17-tetrahydro-22-methoxy-11,17-dimethyl-10,10-dioxide-2,19-methano-3,7:4,1-dimetheno-1H,11H-14,10,2,9,11,17-benzoxathiatetraazacyclo docosine-8,18(9H,15H)-dione
  • Antiviral Agents
  • Carbamates
  • GSK2336805
  • Heterocyclic Compounds, 4 or More Rings
  • Sulfonamides
  • Ribavirin
  • Simeprevir
  • Valine
  • Ritonavir