The first major
data on interferon-free hepatitis C treatment in people with cirrhosis show
that treatment using BI-201335 – now known as faldaprevir – and BI-207127 with ribavirin can be
safe, and proved effective in up to 69% of patients, according to results from the SOUND-C2 study
presented this week at the 63rd annual meeting of the
American Association for the Study of Liver Diseases (AASLD) in Boston.
Despite their higher risk of
progression to decompensated cirrhosis and liver cancer, most earlier-stage
studies of new hepatitis C drugs exclude people with more severe liver damage
on the grounds of safety and the unpredictable processing of drugs by a more
damaged liver. Moreover, because response rates tend to be poorer in this
population, which would make the drug appear to perform poorly in comparison
with competitor products, companies are unlikely to risk harming early
perceptions of products by recruiting people with cirrhosis into general Phase 2
trials.
Paradoxically, it
is likely to be people with cirrhosis and advanced liver disease who will be
given priority for treatment with new agents as they become available. Data
from earlier stage studies are likely to give people with more advanced disease
an earlier indication of whether the chance of curing hepatitis C infection
will be greatly improved if they defer treatment until new drugs are available.
Glossary
- compensated cirrhosis
The earlier stage of
cirrhosis, during which the liver is damaged but still able to perform most of
its functions. See also ‘cirrhosis’ and ‘decompensated cirrhosis’.
- decompensated cirrhosis
The later stage of
cirrhosis, during which the liver cannot perform some vital functions and
complications occur. See also ‘cirrhosis’ and ‘compensated cirrhosis’.
- IL28B
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.
- sustained virological response (SVR)
Undetectable hepatitis C RNA after treatment has come to an end. Usually SVR refers to RNA remaining undetectable for 24 weeks (six months) after ending treatment and is considered to be a cure. SVR4 and SVR12 refer to RNA remaining undetectable for 4 and 12 weeks respectively.
The SOUND-C2
study was a Phase 2b safety and efficacy study, comparing the performance of
interferon-free combinations containing the hepatitis C protease inhibitor faldaprevir
and the non-nucleoside NS5B polymerase inhibitor BI-207127, with or without
ribavirin. These direct-acting antivirals are being developed by Boehringer
Ingelheim.
Participants
were randomised into 5 study arms:
- Faldaprevir 120mg once daily + BI-207127 600mg 3 times
daily + ribavirin for 16 weeks;
- Faldaprevir 120mg once daily + BI-207127 600mg 3 times
daily + ribavirin for 28 weeks;
- Faldaprevir 120mg once daily + BI-207127 600mg 3 times
daily + ribavirin for 40 weeks;
- Faldaprevir 120mg once daily + BI-207127 600mg twice
daily + ribavirin for 28 weeks;
- Faldaprevir 120mg once daily + BI-207127 600mg 3 times
daily, with no ribavirin.
A total of 362 people, 33 of
them with liver cirrhosis, were recruited to this open-label study.
Participants with cirrhosis were not distributed equally across the study arms,
and the number of patients with cirrhosis was small, limiting the power of the
study to provide evidence regarding the relative performance of different
regimens in people with compensated cirrhosis.
Nevertheless,
noted Vicente Soriano of Hospital Carlos III, Madrid, presenting the results, this is the
first trial to report data on the performance of interferon-free regimens in people with compensated cirrhosis.
In patients with cirrhosis, rates of sustained virologic response 12 weeks
after completing treatment (SVR12) ranged between 43% and 80% for people taking
ribavirin-containing regimens depending on HCV sub-genotype and IL28B host
genotype. Responses were better in people with the IL28B 'CC' host genotype, compared
to those who lacked this gene pattern.
The most common
side-effects in people with cirrhosis were mild rash and gastrointestinal
complaints. Overall, 8% of participants discontinued treatment due to serious
adverse events, most of which were not judged to be drug-related.
The
investigators emphasised the good response rate seen in people with cirrhosis
treated with faldaprevir/BI 207127/ribavirin, as well as the favourable
tolerability profile of this combination in this patient group. The combination
will continue to be investigated in Phase 3 trials involving patients with
cirrhosis.