Treatment of chronic hepatitis C patients with the NS3/4A protease inhibitor danoprevir (ITMN-191/RG7227) leads to robust reductions in viral RNA: A phase 1b multiple ascending dose study

Background & Aims Danoprevir is a potent and selective inhibitor of the hepatitis C virus (HCV) NS3/4A serine protease. The present study assessed the safety, pharmacokinetics, and antiviral activity of danoprevir in a randomized, placebo-controlled, 14-day multiple ascending dose study in patients with chronic HCV genotype 1 infection. Methods Four cohorts of treatment-naive (TN) patients (100mgq12h, 100mgq8h, 200mgq12h, 200mgq8h) and one cohort of non-responders (NR) to prior pegylated interferon alfa-ribavirin treatment (300mgq12h) were investigated. Results Danoprevir was safe and well tolerated; adverse events were generally mild, transient and were not associated with treatment group or dose level. Danoprevir displayed a slightly more than proportional increase in exposure with increasing daily dose and was rapidly eliminated from the plasma compartment. Maximal decreases in HCV RNA were: −3.9log 10 IU/ml and −3.2log 10 IU/ml in TN receiving 200mg q8h and 200mg q12h, respectively. End of treatment viral decline in these two cohorts was within 0.1log 10 IU/ml of the viral load nadir. HCV RNA reduction in NR was more modest than that observed in upper dose TN cohorts. The overall incidence of viral rebound was low (10/37) and was associated with the R155K substitution in NS3 regardless of the HCV subtype. Conclusions Danoprevir was safe and well tolerated when administered for 14days in patients with chronic HCV genotype 1 infection. Treatment resulted in sustained, multi-log 10 IU/ml reductions in HCV RNA in upper dose cohorts. These results support further clinical evaluation of danoprevir in patients with chronic HCV.