- Category: HCV Treatment
- Published on Friday, 03 May 2013 00:00
- Written by Keith Alcorn
A second-generation HCV protease inhibitor, simeprevir (formerly TMC435), cured around 80% of previously untreated people with genotype 1 hepatitis C infection when combined with pegylated interferon and ribavirin, Michael Manns of the University of Hannover Medical School reported last week at the EASL International Liver Congress (EASL 2013) in Amsterdam. Overall, 91% of simeprevir-treated patients able to stop all treatment after 24 weeks.
Simeprevir is a HCV NS3/NS4 protease inhibitor active against HCV genotypes 1, 2, 4, 5, and 6. It is currently being tested in patients with genotype 1 or 4 infection.
On the basis of these results, simeprevir -- developed by Janssen -- has been submitted for approval to licensing authorities in the United States and European Union, and may receive marketing approval by the end of 2013 for previously untreated patients. Studies in treatment-experienced and HIV/HCV coinfected people are currently underway and should report results later this year.
Manns presented the results of the QUEST 2 study, which randomized 391 patients with genotype 1 HCV infection to receive either simeprevir 150 mg once-daily or placebo for 12 weeks. All patients also received pegylated interferon and ribavirin. Patients in the simeprevir arm discontinued pegylated interferon/ribavirin at week 24 if they had satisfactory viral load responses at weeks 4 and 12. Patients in the placebo arm received pegylated interferon and ribavirin for 48 weeks.
The response-guided therapy criteria for stopping the course of pegylated interferon and ribavirin at week 24 were:
- HCV viral load (RNA) < 25 IU/mL at week 4, even if detectable;
- HCV viral load undetectable (< 25 IU/mL) at week 12.
At 12 weeks after completion of treatment, 81% of simeprevir recipients achieved a sustained virologic response (SVR12) compared to 50% in the pegylated interferon/ribavirin control arm.
Responses were even better in those with the favorable IL28B CC gene pattern, which indicates a greater likelihood of responding successfully to interferon treatment. 96% of those with the CC variant achieved SVR12, compared with 80% of those with the CT variant and 58% with the TT variant. In comparison, 81%, 41%, and 19% of CC, CT, and TT patients who received pegylated interferon/ribavirin plus placebo achieved SVR12.
The vast majority of patients receiving simeprevir (91%) were able to stop pegylated interferon and ribavirin at week 24 as a result of meeting the response-guided therapy criteria at weeks 4 and 12. Of those who failed to meet these criteria, 7 out of 22 nevertheless went on to achieve SVR12.
The study found an intriguing difference in outcomes according to the type of pegylated interferon used. Two-thirds of participants were randomized to use either pegylated interferon alfa-2a (Pegasys) or alfa-2b (PegIntron). The remainder received pegylated interferon alfa 2a. Whereas 88% of those who received pegylated interferon alfa-2a achieved SVR12, only 78% of those who received alfa-2b achieved SVR12. Questioned about the difference, Manns said he could not explain why it had emerged.
Responses to simeprevir hardly differed according to whether participants were infected with HCV genotype 1a or 1b (80% vs 82%), but there was a greater difference in response according to liver disease stage. 67% of patients with METAVIR scores of F3 (advanced fibrosis) and 65% of those with METAVIR scores of F4, indicating cirrhosis, achieved SVR12, compared to 85% with METAVIR scores of 0 to 2 (absent to moderate fibrosis).
In QUEST 2 there was no substantial difference in the incidence of adverse events between treatment arms, suggesting that simeprevir does not worsen the tolerability of interferon-based therapy for hepatitis C. Discontinuation rates due to serious adverse events were low, 2.3% in the simeprevir arm and 1.5% in the control arm. However, approximately one-quarter of patients in each study arm experienced at least 1 adverse event classified as severe or potentially life-threatening during the first 12 weeks of treatment.
The most common adverse events were fatigue, itching, headache, fever, and flu-like symptoms. The only side effect that occurred more frequently in patients treated with simeprevir was rash (23% vs 11%), and in 97% of cases this was mild or moderate.
The simeprevir-treated patients had a greater average increase in bilirubin during the first 4 weeks of treatment, and this took longer to return to normal levels, when compared to the placebo group. Increases in bilirubin were modest, however, and led only to mild jaundice.
In a poster on the QUEST 1 study, which had identical design and recruitment criteria, but enrolled patients in different regions (primarily U.S. for QUEST 1, mainly Europe for QUEST 2), investigators reported that a baseline polymorphism, or natural variation, in HCV reduced the likelihood of achieving SVR12.
Unlike in QUEST 2, patients in the QUEST 1 study with HCV genotype 1b had a greater likelihood of achieving SVR12 than those with genotype 1a (90% vs 71%).
Speaking at a press conference on the opening day of the International Liver Congress, EASL Secretary-General Mark Thursz said that he expected simeprevir, another second-generation protease inhibitor faldepravir, and sofosbuvir, a NS5B nucleotide polymerase inhibitor, to "totally cannibalize" the market niche for hepatitis C therapy currently occupied by the first-generation protease inhibitors boceprevir (Victrelis) and telaprevir (Incivek or Incivo).
M Manns, P Marcellin, F Poordad et al. Simeprevir (TMC435) with peginterferon/ribavirin for treatment of chronic HCV genotype 1 infection in treatment-naive patients: results from QUEST-2 a phase III trial. 48th Annual Meeting of the European Association for the Study of the Liver (EASL 2013). Amsterdam. April 24-28, 2013. Abstract 1413.
I Jacobson, GJ Dore, GR Foster, et al. Simeprevir (TMC435) with peginterferon/ribavirin for treatment of chronic HCV genotype 1 infection in treatment-naïve patients: results from QUEST-1 a phase III trial.48th Annual Meeting of the European Association for the Study of the Liver (EASL 2013). Amsterdam. April 24-28, 2013. Abstract 1425.
Janssen. Findings from Two Phase 3 Studies of Janssen’s Simeprevir Administered Once Daily Demonstrate Sustained Virologic Response in Genotype 1 Chronic Hepatitis C Patients. Press release. April 23, 2013.