The hepatitis C protease inhibitor simeprevir (formerly TMC435) was
generally safe and well tolerated in people with advanced liver fibrosis or
cirrhosis and improved sustained response rates when added to pegylated
interferon and ribavirin, researchers reported at The Liver Meeting 2012, the 63rd Annual Meeting of the American Association for the Study
of Liver Diseases (AASLD) last week in Boston. Two related reports showed that
simeprevir is not implicated in drug-drug interactions.
The recent approval of the first direct-acting hepatitis C drugs has
ushered in a new era of treatment. Whilst many people with hepatitis C look
forward to interferon-free oral regimens, patients with advanced liver disease
may not have time to wait and will need to use direct-acting agents with pegylated interferon/ribavirin. As this group
does not respond as well to interferon-based therapy and is less able to
tolerate drug side-effects, they need new add-ons that increase the likelihood
of a cure with minimal extra toxicity.
Fred Poordad from Cedars-Sinai
Medical Center in Los Angeles presented results from a subgroup analysis of
participants with advanced liver fibrosis in the PILLAR and ASPIRE
trials, two phase 2b
randomised studies that assessed the safety and efficacy of simeprevir plus pegylated
interferon and ribavirin in people with genotype 1 HCV.
TMC435 is a once-daily HCV NS3/4A protease inhibitor being jointly developed by Janssen Therapeutics
(formerly Tibotec) and Medivir. Early studies showed
that it has potent activity against HCV genotype 1, lesser activity against
genotypes 2, 4, 5 and 6, and a favourable safety profile.
The PILLAR trial enrolled 386
treatment-naive genotype 1 chronic hepatitis C patients including people with
advanced fibrosis (Metavir stage F3). Participants were randomly assigned to
75 or 150mg once-daily simeprevir or placebo in combination with pegylated
interferon alfa-2a (Pegasys) and 1000-1200mg/day weight-adjusted
ribavirin for 12 or 24 weeks. Using
a response-guided therapy algorithm, people who achieved HCV suppression by
week 4 and remained undetectable from weeks 12 to 24 could stop treatment at
that point; otherwise they continued on pegylated interferon/ribavirin alone
through week 48.
enrolled about 462 treatment-experienced
genotype 1 hepatitis C patients - prior relapsers, partial responders and null
responders - including
people with advanced fibrosis or cirrhosis (Metavir stage 4). They were
randomly assigned to receive 100 or 150mg once-daily simeprevir or
placebo with pegylated interferon/ribavirin for 12, 24 or 48 weeks; the 12- and
24-week arms then continued on pegylated interferon/ribavirin alone through
Overall, as previously reported, both studies found
that adding simeprevir to pegylated interferon/ribavirin led to significantly higher sustained virological response
rates after completion of treatment. Simeprevir was generally safe and well
tolerated, with the only notable added side-effect being elevated bilirubin.
(Overall PILLAR and ASPIRE results were presented in a poster at this year's
Poordad's presentation reported findings from a post hoc analysis of the safety and efficacy of triple therapy
amongst participants with advanced liver damage in the two trials who received
150mg simeprevir – the dose selected for further development. The pooled analysis included
26 treatment-naive people with F3 fibrosis from PILLAR as well as 42
treatment-experienced participants with F3 fibrosis and 49 with F4 cirrhosis
A majority of participants (85% from PILLAR and about 65% from ASPIRE)
were men, more than 90% were white and the median age was in the early fifties.
Just over half had hard-to-treat HCV subtype 1a. People with very low platelet
counts or decompensated cirrhosis were excluded.
Amongst the previously untreated participants in PILLAR, 79% of those
who received simeprevir triple therapy achieved sustained virological response
24 weeks after the end of treatment (SVR24), compared with 71% of
those in the placebo arm. Sixteen of the nineteen patients were eligible for
response-guided therapy, and within this subgroup the SVR24 rate
Amongst the PILLAR participants who experienced treatment failure on
simeprevir, one (5%) had viral breakthrough and two (12%) relapsed. Amongst the
ASPIRE participants, the corresponding proportions were 12 and 20%,
respectively; in addition five people (7%) stopped treatment early because they
met futility rules.
Simeprevir triple therapy was generally safe and well tolerated in these
patients with advanced liver damage. Almost all participants in all study arms
reported some side-effects, the most common being fatigue, flu-like symptoms,
itching and rash, but these were mostly mild or moderate in intensity.
Grade 3/4 adverse events occurred in 43% of simeprevir recipients and
27% of those on pegylated interferon/ribavirin alone. Serious adverse event
rates were 8 and 10%, respectively; 9% of patients taking triple therapy, but
none in the control arm, stopped treatment early for this reason.
Turning to laboratory abnormalities, 16% of simeprevir recipients and
27% of those on pegylated interferon/ribavirin alone developed at least
moderate anaemia, but none in either group had severe anaemia.
Grade 3 total bilirubin elevations occurred in 7 and 3%, respectively,
but again none had severe hyperbilirubinemia. The researchers noted that
bilirubin changes were transient, generally mild or moderate, were not associated
with elevated ALT or AST (enzymes signalling liver inflammation) and rarely led
Reassuringly, the frequencies of serious adverse events, laboratory
abnormalities and withdrawals amongst people with advanced fibrosis or
cirrhosis were similar to those seen amongst participants with absent (stage F0),
mild (stage F1) or moderate (stage F2) liver fibrosis receiving the same
treatment assignments in the study populations as a whole.
In conclusion, the investigators reported "promising SVR rates with
simeprevir 150mg in HCV genotype 1-infected treatment-naive and -experienced
patients". In particular, they emphasised the 33% response rate for prior
null responders with advanced fibrosis/cirrhosis – one of the
most difficult groups to treat.