standard therapy for genotype 1 chronic hepatitis C consists of pegylated
interferon plus ribavirin for 48 weeks. Interferon-based therapy
can cause difficult side effects, however, and only about half of people
with this hard-to-treat genotype achieve a cure.
oral drugs that directly target steps of the viral lifecycle -- such
as HCV protease and polymerase inhibitors -- are in the final stages
of development. Most studies to date have looked at these agents used
alone in regimens with pegylated interferon/ribavirin, but new research
shows that dual or triple combinations may allow selected patients to
achieve sustained response without interferon.
At a late
breaker session, Anna Lok from the University of Michigan at Ann Arbor
and colleagues presented data on Bristol-Myers Squibb's combination
regimen consisting of the HCV NS3 protease inhibitor BMS-650032 and
the NS5A inhibitor BMS-790052.
NS5A is a non-structural protein adjacent to the NS5B polymerase; its
function is not fully understood, but it appears to play a crucial role
in HCV replication.
In the Phase
2a Study AI447011, genotype 1 (mostly 1a) chronic hepatitis C patients
who were null responders to previous interferon-based therapy (<
2 log decline in HCV RNA) were randomly assigned to received 600 mg
twice-daily BMS-650032 plus 60 mg once-daily BMS-790052, either alone
(Group A) or in combination with 180
mcg/week pegylated interferon alfa-2a (Pegasys) and 1000-1200 mg/day
weight-adjusted ribavirin (Group B) for 24 weeks.
weeks of therapy, participants in both the 2-drug and 4-drug groups
saw median HCV RNA viral load decreases of about -5 log. At week 4,
about two-thirds of patients in both groups (64% vs 60%, respectively)
experienced rapid virological response (RVR), or undetectable viral
load (< 10 IU/mL).
point, however, the 4-drug combo with interferon began to show an advantage.
In an intent-to-treat analysis, 45% of patients (5 out of 11) in the
2-drug oral-only group achieved complete early virological response
(EVR) or undetectable HCV RNA at 12 weeks, compared with 90% (9 out
of 10) in the 4-drug group.
half of people (55%) receiving only the oral drugs experienced virological
breakthrough, while everyone taking the 4-drug combo maintained viral
suppression through week 12. Viral breakthrough occurred exclusively
in people with genotype 1a; the 2 participants with genotype 1b in the
2-drug group maintained viral suppression. Breakthrough occurred as
early as week 3 and as late as week 12. Genotyping identified drug-resistance
mutations in the NS3 protease and NS5A regions. Patients who experienced
viral breakthrough in Group A added pegylated interferon/ribavirin,
and most then achieved undetectable viral load.
and BMS-790052 were generally well-tolerated. The most common side effect
was diarrhea, usually mild-to-moderate, affecting about 70% of patients
in both groups. Nausea was more common in the 4-drug group, but otherwise
side effects were statistically similar in the 2 arms. There were no
serious adverse events, treatment discontinuations due to adverse events,
or deaths in either group during the study period.
indicate that these 2 oral drugs alone are not potent enough to maintain
long-term viral suppression for genotype 1a patients, likely due to
development of drug resistance. But the BMS-650032/BMS-790052 combination
increased the likelihood of response to standard therapy at 12 weeks,
and may ultimately allow for shorter interferon-based treatment.
At the same session, Stefan Zeuzem from J.W. Goethe University Hospital
in Frankfurt and colleagues presented data from a study of Gilead Sciences'
NS3 protease inhibitor GS-9256 and NS5B polymerase inhibitor GS-9190,
now named tegobuvir. Study 196-0112 is a Phase 2a trial looking at treatment-naive
genotype 1 patients -- an easier-to-treat population than the null responders
in the Bristol-Myers Squibb study described above.
In this novel study design, 16 patients were randomly assigned to receive
dual therapy with the 2 direct-acting agents alone (75 mg GS-9256 and
40 mg GS-9190, both twice-daily), 15 received triple therapy with these
drugs plus 1000-1200 mg/day weight-adjusted ribavirin, and 15 were to
be treated with quadruple therapy using the same 3 drugs plus 180 mcg/week
pegylated interferon alfa-2a for up to 28 days. Participants with suboptimal
response or viral breakthrough in the 2-drug or 3-drug arms added standard
Median maximum HCV viral load declines at day 28 were -4.1 log in the
2-drug group and -5.1 log in the 3-drug group, indicating that ribavirin
enhanced the antiviral activity of GS-9256 plus GS-9190, even without
interferon. Here too, some participants experienced virological breakthrough.
Further analysis showed that most patients who did so had HCV isolates
with NS3 plus NS5B resistance mutations.
At the time of analysis, all 14 participants who had taken the 4-drug
regimen of GS-9256/GS-9190 plus standard therapy for 28 days achieved
RVR (HCV RNA < 25 IU/mL) without viral breakthrough. With 4-drug
therapy the median maximum viral load decline was -5.7 log.
Again, treatment was generally well-tolerated. Most adverse events were
mild-to-moderate and resolved with ongoing therapy. The most common
side effects in each of the 3 arms were headache, diarrhea, and nausea.
Some patients taking the 3-drug combination also experienced fatigue
and insomnia, and some taking the 4-drug regimen experienced flu-like
symptoms. Nearly one-third of patients in all arms saw an increase in
indirect bilirubin levels, which typically resolved with continued dosing
and did not lead to treatment discontinuation.
This study also showed that the combination of direct-acting agents
had potent antiviral activity, but worked better with the addition of
ribavirin and even more so with interferon. These findings suggest some
patients may be able to use HCV protease and polymerase inhibitors with
ribavirin in interferon-sparing regimens.
201335 + BI 207127
Finally, Zeuzem also presented the latest data on Boehringer Ingelheim's
direct-acting dual combination, the NS3/4A protease inhibitor BI
201335 plus the NS5B polymerase inhibitor BI
207127, also used with ribavirin.
In this Phase 1b trial, 32 treatment-naive patients with genotype 1
chronic hepatitis C were randomly assigned to receive either 400 or
600 mg 3-times-daily BI 207127, plus 120 mg once-daily BI 201335, plus
1000-1200 mg/day weight-adjusted ribavirin for 28 days. At that point
all switched to BI 201335 plus pegylated interferon/ribavirin.
All participants experienced a "rapid and sharp" decline in
HCV viral load during the first 2 days of treatment, followed by a slower
second-phase decline in all but 2 patients. At 28 days, 11 of 15 patients
(73%) in the 400 mg BI 201335 dose arm and all 17 (100%) in the 600
mg arm achieved HCV RNA suppression < 25 IU/mL.
Two hard-to-treat patients with genotype 1a and high baseline viral
load in the lower BI 201335 dose arm experienced virological breakthrough
(0.7 and > 1 log increase). At the higher BI 201335 dose level, there
was no difference in response between patients with genotype 1a and
1b, but in the 400 mg dose arm genotype 1a patients had a lower response
Once again, BI 201335/BI 207127 plus ribavirin was generally well-tolerated.
The most common adverse events were mild-to-moderate gastrointestinal
symptoms including diarrhea and nausea, as well as skin rash, and photosensitivity.
There were no severe adverse events or treatment discontinuations during
the 28-day study period. Unconjugated bilirubin levels also increased
in this study.
Investigators concluded that interferon-sparing treatment with BI 201335,
BI 207127, and ribavirin demonstrated strong early antiviral activity
against HCV genotype 1 with good safety and tolerability.
Taken together, these studies indicate that combinations of direct-acting
agents have potent activity against HCV, but require additional drugs
to maintain viral suppression long enough to achieve sustained virological
response, or continued undetectable HCV viral load 24 weeks after completion
Addition of ribavirin alone -- creating an all-oral, interferon-sparing
regimen -- may be a viable option for some patients. Harder-to-treat
individuals, including those with genotype 1a, may also require pegylated
interferon, but the direct-acting drugs will shorten total treatment
In addition to the combinations described here, Vertex Pharmaceuticals
recently announced that it will modify an ongoing Phase 2 trial evaluating
the HCV protease inhibitor
telaprevir plus the polymerase inhibitor
VX-222 so that some participants will also receive ribavirin (without
Abstract LB-8: Research & Development, Bristol-Myers Squibb, Hopewell,
NJ, Princeton, NJ, and Wallingford, CT; University of Michigan, Ann
Arbor, MI; Alamo Medical Research, San Antonio, TX; The Research Institute,
Springfield, MA; University of Colorado-Denver, Aurora, CO; Liver Institute
at Methodist, Dallas, TX; Carolinas Center for Liver Disease, Statesville,
NC; Metropolitan Research, Fairfax, VA
Abstract LB-1: J.W. Goethe University Hospital, Frankfurt, Germany;
ifi-Studien und Projekte GmbH an der Asklepios Klinik St, Georg Haus
K, Hamburg, Germany; Institute of Liver Studies, London, UK; Medizinische
Hochschule Hannover, Hannover, Germany; Hospital Beaujon, Clichy, France;
Barts and London NHS Trust, London, UK; Hôspital Saint-Louis,
Paris, France; Universitatsklinikum Würzburg, Würzburg, Germany;
Hôspital Erasme, Bruxelles, Belgium; CHU de Grenoble - Hospital
Michallon, La Tronche, France; Gilead Sciences, Foster City, CA.
Abstract LB-7: J.W. Goethe University Hospital, Frankfurt, Germany;
Hôpital Beaujon, Paris, France; Austin Hospital, Heidelberg, VIC,
Australia; Hôpital Albert Michallon, Grenoble, France; Hôpital
Saint-Eloi, Montpellier, France; University Hospital of Zurich, Zurich,
Switzerland; Auckland City Hospital, Auckland, New Zealand; Johannes
Gutenberg University Mainz, Mainz, Germany; University Hospital Hamburg-Eppendorf,
Hamburg, Germany; Hôpital Cochin, Paris, France; Hôpital
Pitié-Salpêtrière, Paris, France; Hôpital
de Brabois, Nancy, France; Alfred Hospital, Melbourne, VIC, Australia;
Vivantes Auguste-Viktoria-Klinikum, Berlin, Germany; Hôpital Hotel-Dieu
, Lyon, France; University Hospital Basel, Basel, Switzerland; Boehringer
Ingelheim, Ridgefield, CT; Boehringer Ingelheim (Canada) Ltd, Laval,
QC, Canada; Boehringer-Ingelheim GmbH, Biberach, Germany.
A Lok, D Gardiner, E Lawitz, and others. Combination Therapy With BMS-790052
and BMS-650032 Alone or With PegylatedInterferon and Ribavirin (pegIFN/RBV)
Results in Undetectable HCV RNA Through 12 Weeks of Therapy in HCV Genotype
1 Null Responders. 61st Annual Meeting of the American Association for
the Study of Liver Diseases (AASLD 2010). Boston, October 29-November
2, 2010. Abstract
M Bifano, H Sevinsky, BR Bedford, and others. Co-administration of BMS-790052
and BMS-650032 does not result in a clinically meaningful pharmacokinetic
interaction in healthy subjects. 61st Annual Meeting of the American
Association for the Study of Liver Diseases (AASLD 2010). Boston, October
29-November 2, 2010. Abstract
P Buggisch, K Agarwal, and others. Dual, Triple, and Quadruple Combination
Treatment with a Protease Inhibitor (GS-9256) and a Polymerase Inhibitor
(GS-9190) alone and in Combination with Ribavirin (RBV) or PegIFN/RBV
for up to 28 days in Treatment Naïve, Genotype 1 HCV Subjects.
61st Annual Meeting of the American Association for the Study of Liver
Diseases (AASLD 2010). Boston, October 29-November 2, 2010. Abstract
T Asselah, PW Angus, and others. Strong antiviral activity and safety
of IFN-sparing treatment with the protease inhibitor BI 201335, the
HCV polymerase inhibitor BI 207127 and ribavirin in patients with chronic
hepatitis C. 61st Annual Meeting of the American Association for the
Study of Liver Diseases (AASLD 2010). Boston, October 29-November 2,
Squibb. Bristol-Myers Squibb Posts New Data on Combination of Investigational
Compounds BMS-790052 and BMS-650032 for the Treatment of Chronic Hepatitis
C. Press release. November 1, 2010; Pipeline Asset Update for BMS-790052
(NS5A inhibitor) and BMS-650032 (NS3 inhibitor) (undated).
Gilead's Investigational Hepatitis C Compounds GS 9190 and GS 9256 in
Combination with Standard of Care Therapies Achieve Substantial Viral
Suppression in Phase II Study. Press release. October 30, 2010.
Ingelheim. Boehringer Ingelheim's oral hepatitis C protease inhibitor
and polymerase inhibitor combination shows rapid viral response without
use of pegylated interferon. Press release. October 30, 2010.
Vertex Pharmaceuticals. Vertex Announces Plans to Enroll Additional
Treatment Arm in Ongoing Phase 2 Combination Study of Telaprevir and
VX-222 for the Treatment of People with Hepatitis C. Press release.
November 10, 2010.