A pair of four-drug interferon-based
hepatitis C regimens worked well, but further study has been halted after a few
patients experienced serious adverse events, according to a set of
presentations last week at the 48th International
Liver Congress (EASL 2013) in Amsterdam. While this type of quad regimen
has little if any future, some of the component drugs remain promising.
The first direct-acting antiviral agents
(DAAs) for chronic hepatitis C were approved in 2011, changing the treatment
paradigm. While the future of therapy for most people with hepatitis C is
likely to be all-oral regimens, the first two DAAs were approved for use with,
and most current candidates were first tested with, pegylated interferon and
ribavirin.
The pace of drug development for
hepatitis C has been so rapid that some approaches have become obsolete even
before they finish clinical trials. Such is the case for two quadruple regimens
tested by Gilead Sciences containing dual DAAs in combination with pegylated
interferon and ribavirin. Results from three studies were presented at the
International Liver Congress.
Glossary
- 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.
- pancytopenia
Low
numbers of all blood cells.
- Alexander Thompson from St Vincent's Hospital in
Melbourne reported results from an evaluation of the HCV NS3 protease
inhibitor GS-9451 (200mg once-daily) plus the NS5A inhibitor ledipasvir
(formerly GS-5885; 30mg once-daily) plus pegylated interferon and
ribavirin for six or 12 weeks in 244 treatment-naive people who had
hepatitis C genotype 1 with the favourable IL28B 'CC' gene pattern and no
liver cirrhosis. While a quadruple regimen is quite intensive for this
easy-to-treat patient population, treatment lasting less than two months
would be a breakthrough.
- Gregory Everson from the University of Colorado
presented findings from a study looking at the same regimen for 24 or 48
weeks in 163 treatment-experienced, non-cirrhotic, genotype 1 patients.
- Andrew Muir from Duke University
reported results from a study of GS-9451 (200mg once-daily) plus the
non-nucleoside HCV polymerase inhibitor tegobuvir (formerly GS-9190; 30mg
twice-daily) with pegylated interferon/ribavirin for 16 or 24 weeks in 239
treatment-naive, non-cirrhotic, genotype 1 patients.
Overall, both regimens worked quite well.
GS-9451/ledipasvir/pegylated
interferon/ribavirin for 6 or 12 weeks produced 12-week post-treatment
sustained virological response (SVR12) rates of 79% and 98%, respectively,
among early responders who were eligible for duration randomisation. There was
no significant difference in response between people with HCV subtypes 1a and
1b. These findings, Thompson said, show that shortened treatment is feasible
for patients with favourable response predictors.
The same regimen produced an overall
SVR12 rate of 70% for treatment-experienced patients, rising to 87% for those
who achieved extended rapid virological response and were eligible for the
shorter treatment duration. Here, IL28B 'CC' and HCV subtype 1b both predicted
better response.
GS-9451/tegobuvir/pegylated
interferon/ribavirin also worked well, though full analysis was not possible
because the four-drug regimen was halted prematurely. The reported SVR12 rate
for the quad regimen was 79%, but this rose to 97% among people who completed
16 or 24 weeks on the combination Again, people with IL28B 'CC' or subtype 1b
saw better response rates.
Both regimens were generally safe and
well tolerated, with mostly the usual side-effects associated with interferon
and ribavirin. However, Gilead, in
consultation with the US Food and Drug Administration, halted testing of both
quadruple regimens after three patients developed aplastic anaemia or
pancytopenia, a condition that results in deficiencies of red blood cells,
white blood cells, and platelets.
It is not clear which, if any, of the
experimental drugs – alone or in combination – caused this serious adverse
event, but Gilead elected to stop ongoing
studies of dual DAAs in interferon-based regimens. This appears to be a
reasonable decision: even if safety concerns are resolved, such intensive
regimens are not likely to be popular given the development of simpler
combinations – including some interferon-free – with similar or better efficacy
and tolerability.
Gilead has discontinued all development of
tegobuvir. Dr Muir told infohep that GS-9451 is still being tested (as part of
a non-quad regimen) in at least one ongoing clinical trial, and it remains
listed in the development portfolio on the company's website.
Ledipasvir continues to look very
promising as a component of interferon-free therapy. According to a report
at the recent Conference on Retroviruses and Opportunistic Infections (CROI
2013), a three-drug oral regimen of ledipasvir, the nucleotide HCV
polymerase inhibitor sofosbuvir (formerly GS-7997) and ribavirin cured 100% of
both treatment-naive patients and prior non-responders. Gilead
is now testing a coformulation containing ledipasvir plus sofosbuvir.