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 called 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).
An inherited gene which all individuals have. There are three genotypes of IL28B; these influence response to hepatitis C and its treatment. People with CC genotype are more likely to spontaneously clear acute infection or (during chronic infection) respond well to interferon-based treatment. The other two genotypes are known as CT and TT.
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
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 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 inteferon 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 in the simeprevir group 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%
per cent 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 people 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, (Q80K) 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%).