Antiviral activity of TMC435 monotherapy in patients infected with HCV genotypes 2–6: TMC435-C202, a phase IIa, open-label study

Department of Gastroenterology and Hepatopancreatology, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.
Journal of Hepatology (Impact Factor: 11.34). 02/2012; 56(6):1247-53. DOI: 10.1016/j.jhep.2011.12.033
Source: PubMed


TMC435 is an investigational, once-daily, oral NS3/4A protease inhibitor currently in phase III development for the treatment of hepatitis C virus (HCV) infection. Phase I and II studies in patients infected with HCV genotype 1 have demonstrated that TMC435 is generally well tolerated, has a pharmacokinetic profile that supports once daily dosing, and demonstrates potent antiviral activity. This phase IIa study (TMC435-C202; NCT00812331) was conducted to investigate the antiviral activity, safety, tolerability, and pharmacokinetics of TMC435 in treatment-naїve patients infected with HCV genotypes 2-6.
The study consisted of 7 days of monotherapy with TMC435 (200mg once daily). Patients could begin treatment with pegylated interferon/ribavirin from day 8 with a follow-up period up to days 37-42.
Thirty-seven patients were enrolled in Germany, Belgium and Thailand. For the primary end point at day 8, the mean (± standard error) change in plasma HCV ribonucleic acid (log(10)IU/ml) from baseline was the greatest for genotypes 6 (-4.35 ± 0.29) and 4 (-3.52 ± 0.43), followed by genotypes 2 (-2.73 ± 0.71) and 5 (-2.19 ± 0.39). No antiviral activity was evident for genotype 3. Viral breakthrough occurred in six patients during the monotherapy phase and in six additional patients during PegIFN/RBV-only period. All adverse events were mild or moderate and there were no discontinuations during the TMC435 monotherapy period.
The results of this phase IIa proof-of-concept trial provide evidence that TMC435 has a spectrum of activity against multiple HCV genotypes, except for genotype 3. In this study, TMC435 was generally safe and well tolerated.

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    • "Simeprevir is a highly specific, potent HCV NS3/4A protease inhibitor, and biochemical assays have shown that HCV NS3/4A proteases of genotypes 1a and 1b, respectively, are inhibited with 0.5 nM and 0.4 nM of simeprevir.13 In genotypes except HCV genotype 3, simeprevir has been shown to be effective in vivo.14,15 This compound has synergistic effects with interferon-α and HCV NS5B inhibitor, and it has additive effects with ribavirin in HCV replicon cells.13 "
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    ABSTRACT: Chronic hepatitis C virus (HCV) infection causes end-stage liver diseases and hepato cellular carcinoma. In the USA, Canada, and Japan, simeprevir - one of the second-generation HCV NS3/4A protease inhibitors - in combination with peginterferon α-2a or 2b plus ribavirin has recently been approved for HCV genotype 1-infected patients and is now used in daily clinical practice. This review summarizes the mechanism of action of simeprevir and the results of clinical trials of simeprevir and peginterferon plus ribavirin for HCV genotype 1 patients. In general, the simeprevir and peginterferon plus ribavirin treatment is highly effective and its adverse events are similar to those of peginterferon plus ribavirin only, the exception being milder, reversible jaundice. In the near future, the development of interferon-free regimens with simeprevir is expected. Careful attention should be paid to new results of clinical trials with simeprevir.
    Therapeutics and Clinical Risk Management 05/2014; 10(1):387-394. DOI:10.2147/TCRM.S50170 · 1.47 Impact Factor
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    • "Simeprevir monotherapy induces a significant mean decrease of viremia of 4.35 log10 IU/mL after 8 days for the GT-6 patients; the mean decrease for GT-5 patients is only 2.19 log10 IU/mL (2.71 log10 IU/mL at day 3).84 "
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    ABSTRACT: The launch of first-generation protease inhibitors (PIs) is a major step forward in HCV treatment. However, the major advance is up to now restricted to genotype 1 (GT-1) patients. The development of second-wave and second-generation PIs yields higher antiviral potency through plurigenotypic activity, more convenient daily administration, fewer side effects and, for the second-generation PIs, potential activity against resistance-associated variants. NS5B inhibitors include nucleoside/nucleotide inhibitors (NIs) and non-nucleotide inhibitors (NNIs). NIs have high efficacy across all genotypes. Sofosbuvir has highly potent antiviral activity across all genotypes in association with pegylated interferon and ribavirin (PR), thus allowing shortened treatment duration. NS5A inhibitors (NS5A.I) have highly potent antiviral activity. It has recently been shown for the first time that NS5A.I in combination with protease inhibitors can cure GT-1b null responders in an interferon-free regimen. Besides, several studies demonstrate that interferon (IFN)-free regimens with direct-acting antiviral agent combinations are able to cure a large number of either naïve or treatment-experienced GT-1 patients. Moreover, quadruple regimen with PR is able to cure almost all GT-1 null responders. The development of pan-genotypic direct-acting antiviral agents (NIs or NS5A.I) allows new combinations with or without PR that increase the rate of sustained virological response for all patients, even for those with cirrhosis and independently of the genotype. Therefore, the near future of HCV treatment looks promising. The purpose of this article is to provide an overview of the clinical results recently reported for HCV treatment.
    Clinical Pharmacology: Advances and Applications 01/2014; 6(1):1-17. DOI:10.2147/CPAA.S30338
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    • "newer generations of protease inhibitors for HCV, e.g., simeprevir (TMC435), with favorable sideeffect profiles have demonstrated activity against HCV genotypes non-3 [32] [33] and are also currently in phase III trials. Considering the relatively poor outcome as well as considerable adverse events and treatment duration in this study as well as previous reports among patients with relapse after prior 24 weeks of therapy, deferring therapy may be preferential . "
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    ABSTRACT: Objectives: Uncertainty remains regarding the efficacy of retreatment with current standard-of-care peg-interferon (peg-IFN) and ribavirin among patients infected with hepatitis C virus (HCV) genotypes 2 or 3 with relapse after prior therapy. Materials and methods: Seventy-one patients with chronic HCV genotype 2/3 with prior relapse were enrolled in a phase III multicenter study. Patients were retreated with peg-IFNα-2a 180 μg per week and ribavirin 1000/1200 mg daily. Patients having received previous therapy for 24 weeks were retreated for 48 weeks (Group A), whereas patients having received at least 12 weeks but less than 24 weeks of treatment were allocated to either 48 (Group B) or 24 weeks (Group C) on the basis of whether they had achieved rapid virological response (RVR). Results: Sustained virological response (SVR) rates of 53%, 81% and 75% were achieved in groups A, B and C, respectively. Patients with favorable baseline characteristics, e.g., less advanced liver fibrosis, age <40 years, duration of infection <20 years, or BMI < 25 kg/m(2), tended to have more favorable outcomes. All patients achieving HCV RNA below 1000 IU/mL day 6 achieved SVR in contrast to none of the patients with detectable HCV RNA at week 12. Conclusions: Retreatment with peg-IFN and ribavirin for 24-48 weeks entails SVR among the majority of HCV genotype 2/3 infected patients with prior relapse. However, in light of the prolonged treatment duration, moderate effect and considerable side effects, deterring therapy until new options are available may be preferential, particularly in patients previously treated for 24 weeks.
    Scandinavian Journal of Gastroenterology 07/2013; 48(7):839-847. DOI:10.3109/00365521.2013.793389 · 2.36 Impact Factor
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