The
Liver Meeting also heard results of new studies of interferon-free regimens for
the treatment of hepatitis C virus (HCV). It is possible that the first interferon-free
drug combinations for the treatment of hepatitis C genotypes 2 and 3 could be
approved by the end of 2013 in the United States, and shortly afterwards in the
European Union. Interferon-free drug combinations for genotype 1 could be
approved by the end of 2014 or in early 2015.
Several
companies are competing to develop interferon-free regimens. Each has different
strengths and weaknesses, based on the data presented so far. Larger phase III
licensing studies will further illuminate the differences, but it may take a
number of years before any studies take place which compare interferon-free
regimens directly, if at all.
These
combinations are briefly described below, in alphabetical order by name of the
company developing each combination.
AbbVie
Eric Lawitz of the Texas Liver Institute, presents results of the AbbVie interferon-free phase II study at The Liver Meeting 2013. Photo by Liz Highleyman, hivandhepatitis.com.
AbbVie is testing ABT-450,
an HCV protease inhibitor boosted by ritonavir, and ABT-267, an NS5A inhibitor,
in several phase III studies in combination with a third drug, the
non-nucleoside polymerase inhibitor ABT-333. These trials will begin to report
results by the end of 2013, and it is likely that AbbVie will submit a
licensing application in early 2014 for this three-drug, interferon-free
combination in order to achieve marketing approval in the second half of 2014.
AbbVie presented results of a
study testing two drugs – ABT-450 and ABT-267 – in people with genotype. In this study, 90% of
previous null responders and 95% of previously untreated patients achieved
sustained virologic response (SVR12).
A potential drawback of these combinations is the use of ritonavir to
boost blood levels of ABT-450. Ritonavir causes increases in the levels of a
wide range of other medicines. Use of ritonavir 100mg alongside at least 18
drugs from 10 different classes is contraindicated; these include commonly
prescribed medications such as anti-arrhthymics, ergot alkaloids used in
migraine treatment, and the statins simvastatin and lovastatin. The extent to
which these potential interactions might pose a problem may become clearer when
results of phase III studies are reported in April 2014 at the International Liver Congress, the annual meeting of the European Association for the Study of the Liver (EASL).
Boehringer-Ingelheim
Boehringer-Ingelheim
previously presented phase II results of its study of an interferon-free
combination containing the protease inhibitor faldaprevir, the non-nucleoside
NS5B polymerase inhibitor deleobuvir (BI-207127) and ribavirin at The Liver Meeting 2012. This combination was most potent in patients with
genotype 1b infection, and is being tested in phase III studies in this patient
group only. Results of these studies are expected in the second quarter of
2014.
At The Liver Meeting 2013,
Boehringer Ingelheim presented
early results from a small phase II study of faldaprevir and deleobuvir
combined with an NS5A inhibitor PPI-668, developed by its partner Presidio. The
combination was tested with or without ribavirin in harder-to-treat patients
with genotype 1a infection. Seventeen patients had completed a 12-week course of
treatment by the time of The Liver Meeting, all had undetectable HCV at this
point, and no viral relapse had occurred in 13 patients who had reached the
4-week post-treatment stage. Further results reporting the development of this
combination can be expected in 2014.
Bristol-Myers
Squibb
Gregory Everson of the University of Colorado presents results of the BMS interferon-free phase II study at The Liver Meeting 2013. Photo by Liz Highleyman, hivandhepatitis.com.
Bristol-Myers
Squibb presented results of a 12-week study of a three-drug combination which does not include
ribavirin. This combination of daclatasvir, asunaprevir and BMS-791325 achieved
cure rates of over 90% in this study of previously untreated patients. There
was no difference in response between genotype 1a and 1b patients and the
combination was well tolerated.
Gilead
Edward Gane, of Auckland Clinical Studies, presenting new data on sofosbuvir at The Liver Meeting. Photo by Liz Highleyman, hivandhepatitis.com.
Gilead
presented results from two studies of a three-drug
combination of sofosbuvir, ledipasvir
and either ribavirin or GS-9669. In people with genotype 1 hepatitis C, with advanced
liver disease (F3 or F4) and no previous response to interferon-based treatment,
both combinations cured 100% of patients. People taking ribavirin experienced
declines in haemoglobin levels but people taking GS-9669 did not. Up to 40% of
people who received ribavirin developed anaemia. When a six-week course of
sofosbuvir, ledipasvir and ribavirin was tested in previously untreated people
with less advanced liver disease, one quarter experienced viral relapse after
completing treatment.
Merck
Merck
presented
results of an early-stage study of its two-drug combination. The
study compared a combination of two drugs with and without ribavirin in
previously untreated patients with genotype 1a and 1b hepatitis C infection.
Merck is slightly behind several other pharmaceutical companies in progress
towards the development of interferon-free drug combinations for treatment of
hepatitis C.
Ribavirin
made little or no difference to the chances of cure in this study, unlike some
of the other interferon-free combinations being tested. All 11 patients in the
ribavirin-free arm of this study were cured.
A two-company combination
Ira Jacobson of Weill Cornell Medical College presents results of the COSMOS study at The Liver Meeting 2013. Photo by Liz Highleyman, hivandhepatitis.com.
The
most potent, the best tolerated or the most affordable combinations of
hepatitis C drugs might come from mixing the products of different companies.
Some drugs will only be available as part of fixed-dose, single-company
combinations, but other agents will be available for combination.
Janssen
has tested the combination of its protease inhibitor simeprevir with Gilead’s
nucleotide polymerase inhibitor sofosbuvir in the COSMOS study. Results of this study show that in previous null responders with mild or
moderate liver fibrosis and genotype 1 infection this combination cured all
patients. In people with advanced liver disease (F3/F4), early results (four weeks
post-treatment) indicate that this combination is also highly effective.
Further research will be needed in a larger number of patients to provide more information
on efficacy and safety.
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