18 Selumetinib Boceprevir and telaprevir also are associated with a high incidence of adverse events (AEs), including anemia, rash, and renal dysfunction.19, 20, 21 and 22 Recently, the nucleotide analog NS5B polymerase inhibitor sofosbuvir also was approved for the treatment of chronic HCV infection in the United States and Europe, representing an improvement on first-generation DAAs.23 and 24

Simeprevir (TMC435) is administered orally, once daily, as a single pill25; has been approved in Japan, Canada, the United States and Russia; and is under regulatory review in Europe for the treatment of chronic HCV infection. The median simeprevir EC50 and EC90 values against a HCV genotype 1b replicon were 9.4 and 19 nmol/L, respectively.26 Activity of simeprevir against a selection of genotype 1a (N = 78) and 1b (N = 59) chimeric replicons carrying NS3 sequences from HCV NS3/4A protease

inhibitor-naive subjects resulted in median fold change in EC50 of 1.4 (interquartile range [IQR], 0.8–11) and 0.4 (IQR, 0.3–0.7), compared IDH assay with reference genotype 1b replicon. Genotype 1a (N = 33) and 1b (N = 2) isolates with a baseline Q80K polymorphism, a naturally occurring NS3 polymorphism that confers low-level resistance to simeprevir, resulted in a median fold change in simeprevir EC50 of 11 (IQR, 7.4–13) and 8.4, respectively. Simeprevir has antiviral activity in patients infected with HCV genotypes 1, 2, 4, 5, and 6,27, Nitroxoline 28, 29 and 30 and is being evaluated in both PegIFNα/RBV and IFN-free combinations.27, 28, 31, 32, 33 and 34 Simeprevir in combination with PegIFNα/RBV showed SVR rates of approximately 80% in phase 3 trials in treatment-naive patients with HCV genotype 1 infection, with most patients (>84%) able to reduce their treatment duration to 24 weeks.33 and 34 In these studies, no additional AEs were observed with simeprevir compared with those seen with PegIFNα/RBV alone. Results of the PROtease inhibitor TMC435 In patientS who have previously

rElapsed on IFN/RBV (PROMISE) study, a randomized, double-blind, placebo-controlled, phase 3 trial undertaken to assess the efficacy, safety, and tolerability of simeprevir with PegIFNα-2a/RBV (PR) for the treatment of chronic HCV genotype 1 infection in patients who had relapsed after previous IFN-based therapy, are presented. Patients were enrolled at study sites in 14 countries across North America, Europe, and the Asia–Pacific region. Eligible patients were adults (≥18 y) with confirmed genotype 1 HCV infection and screening plasma HCV-RNA levels greater than 10,000 IU/mL, who had relapsed after 24 weeks or more of IFN-based therapy (undetectable HCV-RNA at end of treatment [EOT] or within 2 months after EOT, with documented relapse within 1 year after therapy).