Second-generation HCV protease inhibitor simeprevir pushes triple therapy cure rate up to 80%

A second-generation hepatitis C protease inhibitor, simeprevir, cured around 80% of previously untreated people with genotype 1 hepatitis C virus (HCV) infection when combined with pegylated interferon and ribavirin, Professor Michael Manns of the University of Hannover Medical School reported on Saturday at the International Liver Congress (EASL 2013) in Amsterdam.

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 people and people with HIV/HCV co-infection are currently underway and should report results later this year.

Speaking at a press conference on the opening day of the International Liver Congress, EASL Secretary-General Prof. Mark Thursz said that he expected simeprevir, another second-generation protease inhibitor faldepravir, and sofosbuvir, a NS5B nucleotide polymerase inhibitor, to “totally cannibalise” the market niche for hepatitis C therapy currently occupied by the first-generation protease inhibitors boceprevir (Victrelis) and telaprevir (Incivo).

Simeprevir is an HCV NS3/NS4 protease inhibitor active against genotypes 1, 2, 4, 5 and 6. It is currently being tested in people with genotype 1 or 4 infection.

Professor Manns presented the results of the QUEST 2 study, which randomised 391 people with genotype 1 HCV infection to receive either simeprevir (also known as TMC435) 150mg once daily or placebo for 12 weeks. All study participants received pegylated interferon and ribavirin. People in the simeprevir arm discontinued pegylated interferon or ribavirin at week 24 if they had satisfactory viral load responses at weeks 4 and 12. People in the placebo arm received pegylated interferon and ribavirin for 48 weeks.

The response-guided 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 the completion of treatment, 81% of people taking simeprevir had achieved a sustained virologic response (SVR12) compared to 50% in the pegylated interferon/ribavirin arm. Responses were even better in those with the favourable 'CC' IL28B genotype, which indicates a greater likelihood of responding successfully to interferon treatment. Ninety-six per cent of those with the 'CC' variant achieved SVR12, compared with 80% of those with the 'CT' variant and 57.5% with the 'TT' variant. In comparison, 81, 40.8 and 19% of people with CC, CT and TT genotypes who received pegylated interferon and ribavirin plus placebo achieved SVR12.

The vast majority of people taking simeprevir (91%) could stop pegylated interferon and ribavirin at week 24 as a result of meeting the response-guided therapy criteria at week 4 and 12. Of those who did not meet these criteria, seven 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 randomised to use either pegylated interferon alfa 2a (Pegasys) or alfa 2b (Peg-Intron). The remainder received pegylated interferon alfa 2a. Whereas 88% of those who received pegylated interferon alfa 2a achieved SVR12, only 77.5% of those who received alfa-2b achieved SVR12. Questioned about the difference, Professor Manns said he could not explain why it had emerged.

Responses to simeprevir hardly differed according to whether participants had HCV genotype 1a or 1b (80 vs 82%), but there was a greater difference in response according to liver disease stage. 66.7% of patients with METAVIR scores of 3 (advanced fibrosis) and 64.7% of those with METAVIR scores of 4, indicating cirrhosis, achieved SVR12, compared to 84.6% with METAVIR scores of 0 to 2.

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 treatment for hepatitis C. Discontinuation rates due to serious adverse events were low: 2.3% in the simeprevir recipients and 1.5% in the control arm, but approximately one quarter of patients in each study arm experienced at least one adverse event classified as severe or potentially life threatening during the first 12 weeks of treatment. The most common adverse events were fatigue, itch, headache, fever and flu-like symptoms. The only side-effect that occurred more frequently in the patients treated with simeprevir was rash (23 vs 11%), and in 97% of cases this was mild or moderate.

The people taking simeprevir had a greater average increase in bilirubin during the first four weeks of treatment, and this took longer to return to normal levels, when compared to the placebo group. Increases in bilirubin were modest and led only to mild jaundice.

In a report on the QUEST 1 study, which had identical design and recruitment criteria, but recruited participants in different regions, investigators reported that a baseline polymorphism, or natural variation, in HCV reduced the likelihood of achieving SVR12.

Unlike in QUEST 2, people in the QUEST 1 study with HCV genotype 1b had a greater likelihood of achieving SVR12 than those with genotype 1a (90 vs 71%).