A 12-week course of the combination of grazoprevir and
elbasvir cured 95% of previously untreated people with gentoypes 1, 4 or 6
hepatitis C infection, according to results of the C-EDGE trial, presented on
Friday at the International Liver Congress in Vienna, Austria.
However, the study also showed that people with higher
baseline hepatitis C virus (HCV) viral load and genotype 1a infection may have a poorer response to
this combination, particularly if they have naturally occurring HCV variants
that are less sensitive to suppression by drugs from the NS5A inhibitor class.
Grazoprevir (an NS3/4 protease inhibitor) and elbasvir (an
NS5A inhibitor) are being developed by Merck. The combination is being studied
as a once-daily, single-tablet regimen, with or without ribavirin. The two
drugs are active against multiple genotypes of hepatitis C.
Glossary
- arthralgia
Pain in the joints.
- 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’.
The study presented at the International Liver Congress by
Dr Stefan Zeuzem of the Goethe University Hospital, Frankfurt, Germany, and
published online today in Annals of
Internal Medicine, is known as C-EDGE, and forms part of a suite of studies
in previously untreated patients, treatment-experienced patients and patients with HIV co-infection.
Results from the treatment-experienced C-EDGE study are reported in a separate
article.
C-EDGE was an international phase III randomised trial, in
which participants were randomly assigned to receive immediate treatment with a
fixed-dose combination of grazoprevir (100mg) and elbasvir (50mg) once daily
for 12 weeks (n = 316), or to receive a placebo for 12 weeks followed by active
open-label treatment for 12 weeks (n = 105). No one received ribavirin in this
study. The study arms were stratified by genotype and by cirrhosis status to
ensure equal distribution.
The study population was predominantly white (63%), 46% were
women and 91% had genotype 1 infection. Twenty-two per cent had cirrhosis. Seventy per cent had HCV RNA
(viral load) above 800,000 IU/ml.
Overall, 95% of the immediate-treatment arm achieved sustained virological response twelve weeks after completing treatment, SVR12
(95% confidence interval 92%-97%). When broken down by genotype, 99% of the
genotype 1b participants achieved SVR12 (n = 131), compared to 92% of genotype 1a
participants (n = 157), 100% of genotype 4 participants (n = 10) and 80% of
genotype 6 participants (n = 70). Virological failure was almost entirely due to
post-treatment relapse (12 cases), with only one case of viral breakthrough
during therapy.
The only baseline factor significantly associated with
achieving a sustained virological response was baseline HCV RNA: participants
with baseline HCV RNA below 800,000 iu/ml were significantly more likely to
achieve SVR12 (100% vs 92.3%).
Analysis of outcomes by baseline resistance-associated
variants (RAVs) showed that presence of NS3 (protease) RAVs made no difference
to response in genotype 1a or genotype 1b participants. In fact, genotype 1a
participants without RAVs showed a non-significant trend towards worse response
than participants with RAVs, when compared to genotype 1b: 89% (1a) vs 100%
(1b) in those without, compared to 97% vs 96% in those with RAVs.
However, when participants were compared according to
baseline RAVs in the NS5A region, genotype 1a participants with baseline RAVs
had significantly poorer responses than those without (58% vs 99%). Where
baseline RAVs conferred a greater than fivefold loss of sensitivity to
elbasvir, SVR was achieved in 22% of participants, compared to an SVR rate of
100% in those with less than fivefold loss of sensitivity.
In ION-3, the phase III study of sofosbuvir/ledipasvir (Harvoni), viral load only became a
factor affecting response when baseline viral load was above 6 million IU/ml,
according to an ad hoc analysis presented at the ID
WEEK 2014 conference in October 2014. Otherwise, virological outcomes were
very similar to those reported in the ION-3 study, across genotypes 1a and 1b
and between people with cirrhosis and without cirrhosis.
The combination was well tolerated, with no significant
difference in reports of the most common adverse events – headache, fatigue,
nausea and arthralgia (joint pain) – between the active treatment and placebo arms. There
was no difference in reports of serious adverse events between the two arms
(2.8% and 2.9%). People with cirrhosis were no more likely to experience
adverse events.
The grazoprevir/elbasvir combination pill is due to be
submitted for regulatory approval in the United States, Europe and other
countries shortly, and may be approved by the end of 2015. It will be the third
all-oral, interferon-free combination to be marketed exclusively by one
company, and will enter a market where AbbVie’s combination treatment (Viekira Pak in the United States, Viekirax and Exviera in the European Union) is trailing badly in competition
with Gilead’s Harvoni
(sofosbuvir/ledipasvir).
Merck is seeking to demonstrate that its combination
addresses unmet needs and provides benefit in specific populations. A number of
studies at the international Liver Congress have reported on the use of the
combination in chronic kidney disease, advanced cirrhosis and highly treatment-experienced
patients, and in people with HIV co-infection. These studies will be reported in
separate articles.
Merck is also seeking to reduce the duration of hepatitis C
treatment and to prove that their combination is active across as many
genotypes as possible, in order to simplify the delivery of treatment and to
make it practical for primary care physicians to treat people with hepatitis C
who do not have major complications such as decompensated cirrhosis, or
post-transplant patients, company spokesman Dr Eliav Barr said at a press
conference on Friday.
Asked about the place of the grazoprevir/elbasvir
combination pill in clinical practice, Dr Stefan Zeuzem said “I love
competition, so we should have as many regimens with excellent virological
response as possible. There is still space for treatment individualisation, and
still only two combinations in a single pill.”
Professor Rajender Reddy of University of Pennsylvania
School of Medicine, speaking at a press conference, agreed that choice of
regimens would be important for physicians and patients, and pointed to the
strong performance of the combination in patients with genotype 4 infection.