Gilead
Sciences is currently testing a portfolio of direct-acting antiviral
agents for the treatment of chronic
hepatitis C virus (HCV) infection. Among these are tegobuvir,
a non-nucleoside HCV NS5B polymerase inhibitor, and GS-9256, a
macrocyclic HCV NS3 protease inhibitor. Both agents have demonstrated
good antiviral activity in preclinical studies.
At
the European Association for the Study of the Liver's International
Liver Congress (EASL 2011) this month
in Berlin, investigators presented posters showing data from
a Phase 2b clinical trial of tegobuvir combined with standard
therapy, as well as earlier data on tegobuvir in regimens that
also include GS-9256.
Tegobuvir
+ Standard Therapy
In
the first study, E. Lawitz and colleagues looked at treatment
with tegobuvir plus pegylated
interferon and ribavirin for either 24 or 48 weeks. This
Phase 2b trial included 252 previously untreated chronic hepatitis
C patients with HCV genotype 1 and without liver cirrhosis.
Participants
were randomly allocated to 3 treatment arms. Arm 1 received
standard therapy consisting of 180 mcg/week pegylated interferon
alfa-2a (Pegasys) plus 1000-1200 mg/day weight-adjusted ribavirin
plus placebo for 48 weeks. Arm 2 received pegylated interferon/ribavirin
plus 40 mg twice-daily tegobuvir for 48 weeks. Arm 3 took the
same triple regimen for 24 weeks then used a response-guided
strategy, either stopping therapy if they experienced extended
rapid virological response (eRVR) or continuing for the standard
duration.
About
60% of participants were men, 85% were white, and the average
age was 47 years; about three-quarters were in the U.S. and
the rest in Europe. About 55% had HCV genotype 1a, the remainder
1b. Proportions with the favorable CC IL28B gene pattern ranged
from 29% to 45%, being higher in the standard therapy arm.
Results
 |
At
week 4, participants who received tegobuvir triple therapy
for either 48 weeks or using response-guided therapy were
significantly more likely to achieve RVR (HCV RNA < 25
IU/mL) compared with standard therapy recipients (53% and
58% vs 20%, respectively). |
|
At
week 12, complete early virological response (cEVR) rates
remained higher in the tegobuvir arms compared with standard
therapy (76%, 81%, and 58%, respectively). |
|
However,
virological response rates were similar across study arms
by week 24 (76%, 69%, and 72%, respectively) and week 48
(65%, 61%, and 66%, respectively). |
|
Sustained
virological response (SVR) rates 24 weeks after completion
of treatment were identical in all 3 arms at 56%. |
|
The
SVR rate was 96% for patients in the response-guided triple
therapy arm who achieved RVR and were treated for 24 weeks. |
|
More
tegobuvir recipients who achieved RVR dropped out prematurely
due to adverse events, however, resulting in a lower positive
predictive value. |
|
Adverse
event profiles were similar overall, though fever, itching,
and muscle aches were more common among tegobuvir recipients. |
Based
on these findings, the researchers concluded, "Similar
SVR rates of 56% were observed with [tegobuvir/pegylated interferon/ribavirin]
and [pegylated interferon/ribavirin], despite a ~30% improvement
in RVR and a ~20% improvement in cEVR."
Tegobuvir
with GS-9256
In
the second poster, G.R. Foster and colleagues presented preliminary
results from a study in which participants received tegobuvir
plus GS-9256 alone, or with ribavirin only, or with pegylated
interferon and ribavirin for 4 weeks prior to continuing on
standard therapy.
This trial included 46 participants. About 80% were men, most
were white, and the median age ranged from 47 to 56 years in
the various treatment arms. Proportions with the favorable CC
IL28B gene pattern ranged from 12% to 40%.
 |
As
previously reported, 100% of patients achieved RVR at week
4 with the quadruple regimen compared to 38% with tegobuvir/GS-9256/ribavirin
and 7% with tegobuvir/GS-9256 alone. |
|
At
week 12, response rates were 100%, 100%, and 80%, respectively. |
|
At
week 24, the corresponding rates were 100%, 100%, and 67%,
respectively. |
|
Tegobuvir
and GS-9256 were generally well-tolerated. |
|
There
were 2 serious adverse events not considered treatment-related
and no grade 4 laboratory abnormalities. |
"We
observed that the addition of ribavirin to GS-9256 + tegobuvir
was associated with greater virologic suppression [and] decreased
resistance emergence," the investigators concluded.
"With
the 3 drugs, (GS-9256 + tegobuvir + ribavirin) 38% achieved
RVR and all subjects then went on to achieve a cEVR and so far
have maintained that response through Week 24 on [pegylated
interferon + ribavirin]," they continued. "With the
4 drugs (GS-9256 + tegobuvir + [pegylated interferon + ribavirin])
all patients achieved RVR, without breakthroughs, and have maintained
this response through Week 24."
Investigator affiliations:
Abstract 252: Alamo Medical Research, San Antonio, TX; Gastroenterology
& Hepatology, Cornell University, New York, NY; Back &
Godofsky, MD, PA, Sarasota, FL; Centre for Gastroenterology,
Barts and London School of Medicine and Dentistry, London, UK;
Wojewódzki Szpital Specjalistyczny, Bialystok, Poland;
Medical Associates Research Group, San Diego, CA; Digestive
and Liver Disease Specialists, Norfolk, VA; Gilead Sciences,
Inc, Foster City, CA.
Abstract 232: Barts and London School of Medicine and Dentistry,
London, UK; Medizinische Kern- und Poliklinik, Hamburg, Germany;
Hospital Beaujon, Paris, France; J.W. Goethe University Hospital,
Frankfurt, Germany; Institute of Liver Studies-King's College
London School of Medicine at King's College Hospital, London,
UK; Medizinische Hochschule Hannover, Hannover, Germany; Hopital
Saint-Louis, Paris, France; Universitatsklinikum Wurzburg, Wurzburg,
Germany; Hospital Erasme, Bruxelles, Belgium; Hopital Michallon-CHU
de Grenoble, La Tronche, France; Universite Catholique de Louvain,
Bruxelles, Belgium; Gilead Sciences, Inc, Foster City, CA.
4/23/11
References
E
Lawitz, I Jacobson, E Godofsky, et al. A phase 2b trial comparing
24 to 48 weeks treatment with tegobuvir (GS-9190)/PEG/RBV to
48 weeks treatment with PEG.RBV for chronic genotype 1 HCV infection.
46th Annual Meeting of the European Association for the Study
of the Liver (EASL 2011). Berlin. March 30-April 3. Abstract
252.
GR
Foster, P Buggisch, P Marcellin, et al. Four-week treatment
with GS-9256 and tegobuvir (GS-9190), ± RBV ±
PEG, results in enhanced viral suppression on follow-up PEG/RBV
therapy, in genotype 1a/1b HCV patients. 46th Annual Meeting
of the European Association for the Study of the Liver (EASL
2011). Berlin. March 30-April 3. Abstract
232.
