Increases Sustained Response Rates and Shortens Treatment Duration for
Newly Treated Hepatitis C Patients
Vertex Pharmaceuticals' hepatitis C virus (HCV) NS34A protease
added to pegylated interferon plus ribavirin improved sustained
virological response rates for previously untreated patients
with hard-to-treat HCV genotype 1, and enabled many to reduce
treatment duration to 24 weeks, according to 2 Phase 3 studies
presented this week at the American Association for the Study
of Liver Diseases "Liver Meeting" (AASLD
2010) in Boston.
standard therapy for chronic hepatitis C consists of pegylated
interferon plus ribavirin for 24 weeks (HCV
genotypes 2 and 3) or 48 weeks (genotypes
1 or 4). Interferon-based therapy can cause difficult side effects,
however, and only about half of people with hard-to-treat HCV genotype
1 achieve a cure.
The first novel 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
in combination with pegylated interferon plus ribavirin, but some have
started testing all-oral combinations without interferon.
A pair of HCV protease inhibitors, Vertex's telaprevir and Merck's boceprevir,
and, are furthest along in the development pipeline, and many experts
expect that they will be approved next year.
3 ADVANCE trial assessed the safety and efficacy of 2 telaprevir-based
response-guided therapy regimens compared with standard pegylated interferon/ribavirin
for treatment-naive genotype 1 hepatitis C patients.
included 1088 participants. About 60% were men, 9% were black (a group
that responds more poorly to interferon), 77% had high HCV RNA viral
load (>800,000 IU/mL), and just over 20% had bridging fibrosis
started therapy with 180 mcg/week pegylated
interferon alfa-2a (Pegasys) plus 1000-1200 mg/day weight-adjusted ribavirin.
Patients were evenly allocated to 3 arms. People in one arm received
only standard therapy, while those randomly assigned to the other 2
arms also took 750 mg 3-times-daily telaprevir for either 8 or 12 weeks.
who achieved extended rapid virological response (RVR) -- defined as
undetectable HCV RNA viral load at both 4 and 12 weeks -- were treated
for a total of 24 weeks, while those without extended RVR were treated
for a total of 48 weeks.
of patients in the 8-week telaprevir arm and 68% in the 12-week
telaprevir arm achieved RVR at week 4, compared with 9% in the standard
58%, and 8%, respectively, achieved extended RVR at weeks 4 and
an intent-to-treat analysis, significantly more patients in the
telaprevir arms achieved sustained virological response (SVR), or
continued undetectable HCV RNA at 24 weeks after completion of treatment:
telaprevir combination: 69%;
telaprevir combination: 75%;
patients who achieved extended RVR, most achieved SVR in all arms
(83%, 89%, and 97%, respectively).
rates after finishing therapy were 9% in both telaprevir arms and
28% in the standard therapy arm.
black patients, 58% and 62% in the 8-week and 12-week telapravir
arms achieved SVR, compared with 25% in the standard therapy arm.
people with advanced fibrosis or cirrhosis, SVR rates were 53%,
62%, and 33%, respectively.
most common adverse events in the telaprevir arms (reported by >
25% of patients) were fatigue, pruritus (itching), nausea, headache,
anemia, rash, flu-like symptoms, insomnia, fever, and diarrhea.
of patients in the 8-week telaprevir arm, 7% in the 12-week telaprevir
arm, and 4% in the standard therapy arm discontinued treatment due
to adverse events:
1.4%, and 0.0%, respectively, discontinued due to skin rash;
0.8%, and 0.6%, respectively, did so due to anemia.
significantly greater proportion of patients achieved SVR with 12-week
and 8-week telaprevir-based combination regimens...compared with [standard
therapy] control arm," the investigators concluded. "The safety
and tolerability profile of telaprevir in the ADVANCE trial was consistent
with the profile previously reported, with an improvement in treatment
discontinuation rates due to adverse events, including rash and anemia."
In another analysis from the ADVANCE trial, researchers measured HCV
RNA (using a test with a limit of quantification of 25 IU/mL) and performed
population sequencing of the HCV NS34A protease in blood samples from
patients who did not achieve SVR.
proportions of patients in the 8-week and 12-week telaprevir arms experienced
virological failure at both week 4 and week 12 while taking telaprevir
(2.7% vs 3.3%). But the rate of virological failure after week 12, while
taking only pegylated interferon/ribavirin, was somewhat higher in the
8-week telaprevir arm compared with the 12-week arm (10.2% vs 5.0%).
failure during the pegylated interferon/ribavirin continuation period
was associated with wild-type HCV and lower-level telaprevir-resistant
variants, the researchers noted, suggesting that 4 additional weeks
of telaprevir may further reduce the chances of virological failure.
Among 91 patients with available sequencing data who had telaprevir-resistant
variants after failing to achieve SVR, 60% no longer had evidence of
resistant variants at the end of the study.
results suggest that telaprevir continued to exert antiviral pressure
on wild-type and lower-level [resistant] variants between weeks 8 and
12, thus reducing subsequent virologic failure during the pegylated
interferon/ribavirin treatment phase in the [12-week telaprevir] T12
arm," they concluded.
3 ILLUMINATE trial was designed to confirm both the use of response-guided
therapy and to evaluate whether there was any benefit to extending total
treatment duration from 24 to 48 weeks.
included 540 treatment-naive genotype 1 chronic hepatitis C patients.
About 60% were men, nearly 14% were black, and 11% had liver cirrhosis.
All participants started triple combination therapy using 750 mg 3-times-daily
telaprevir, 180 mcg/week pegylated interferon alfa-2a, and 1000-1200
mg/day weight-adjusted ribavirin. (This study did not include a standard
therapy control arm.)
who achieved extended RVR at weeks 4 and 12 were randomly assigned at
week 20 to continue on pegylated interferon/ribavirin (without telaprevir
from week 12 onward) for a total of either 48 or 24 weeks. Everyone
who did not achieve extended RVR was treated for 48 weeks. Patients
who did not experience at least a 2 log drop in viral load at week 12
or who had detectable HCV RNA at week 24 were considered to have virological
failure and discontinued treatment.
an intent-to-treat analysis, the overall SVR rate was 72% (including
60% of blacks and 63% of patients with advanced fibrosis or cirrhosis).
of study participants achieved RVR at week 4 and 65% achieved extended
RVR at weeks 4 and 12; 322 extended RVR patients were randomized
to the 24-week or 48-week arms.
of patients in the 24-week arm and 88% in the 48-week arm achieved
difference fell within the pre-set 10.5% margin, allowing the researchers
to conclude that 24-week treatment was non-inferior to 48 weeks
for these early responders.
of blacks who experienced extended RVR went on to achieve SVR in
both the 24-week and 48-week arms.
and 88%, respectively, of people with advanced fibrosis/cirrhosis
who achieved extended RVR went on to achieve SVR.
of patients overall stopped treatment early due to virological failure.
of participants overall discontinued study drugs due to adverse
events, most often fatigue (22 people) or anemia (12 people).
patients discontinued due to anemia and 3 people due to skin rash
during the telaprevir treatment phase.
patients who achieved extended RVR, a 24-week telaprevir-based regimen
was non-inferior to 48-week telaprevir-based regimen," the ILLUMINATE
extended RVR randomized patients, there were more adverse events and
adverse event-related treatment discontinuations in the 48-week versus
24-week arm," they continued. "These results support response-guided
therapy for telaprevir-based regimens in treatment-naive patients."
"Many patients today are not motivated to begin hepatitis C therapy
given the year-long treatment time and low cure rates with approved
therapies," said Kenneth Sherman from the University of Cincinnati
College of Medicine in a press release issued by Vertex. "Data
from the ILLUMINATE study are extremely promising and showed that high
viral cure rates and shorter treatment duration may be possible for
the majority of people who have not been treated previously."
"In our Phase 3 program, starting people with 12 weeks of telaprevir-based
combination therapy resulted in significant improvements in viral cure
rates, regardless of race, extent of liver damage or experience with
prior treatment," Vertex Senior Vice President and Chief Medical
Officer Robert Kauffman said in the company press release. "The
results of the ADVANCE and ILLUMINATE studies represent a major milestone
in the development of telaprevir and offer hope for doctors and the
millions of people living with hepatitis C who need new and more effective
last week that partner Tibotec is starting a new multinational Phase
3 clinical trial for treatment-naive patients, called OPTIMIZE, looking
at a more convenient regimen of telaprevir administered twice rather
Jacobson study (ADVANCE): Weill Cornell Medical College, New York, NY;
Duke University Medical Center, Durham, NC; Royal Free and University
College, London, UK; St Louis University School of Medicine, St Louis,
MO; University of Pennsylvania School of Medicine, Philadelphia, PA;
California Pacific Medical Center, San Francisco, CA; Hopital Beaujon,
Paris, France; Vertex Pharmaceuticals, Cambridge, MA; Johann Wolfgang
Goethe University Medical Center, Frankfurt am Main, Germany.
Kieffer study (ADVANCE): Vertex Pharmaceuticals, Cambridge, MA; Tibotec
BVBA, Mechelen, Belgium; Tibotec Inc, Titusville, NJ. Zeuzem study (EXTEND):
Johann Wolfgang Goethe University Medical Center, Frankfurt am Main,
Germany; Johns Hopkins University School of Medicine, Baltimore, MD;
INSERM Unit 871, Lyon, France; University of Cincinnati College of Medicine,
Cincinnati, OH; University of Padova, Padova, Italy; Harvard School
of Public Health, Boston, MA; Tibotec BVBA, Mechelen, Belgium; Vertex
Pharmaceuticals, Cambridge, MA; Tibotec Inc., Titusville, NJ; Duke University
Medical Center, Durham, NC.
Sherman study (ILLUMINATE): University of Cincinnati College of Medicine,
Cincinnati, OH; Northwestern University, Chicago, IL; Beth Israel Deaconess
Medical Center, Boston, MA; University of Florida, Gainesville, FL;
Johns Hopkins University School of Medicine, Baltimore, MD; University
of Colorado Denver, Aurora, CO; University of North Carolina at Chapel
Hill, Chapel Hill, NC; Vertex Pharmaceuticals Incorporated, Cambridge,
MA; Cedars-Sinai Medical Center, Los Angeles, CA.
JG McHutchison, GM Dusheiko, and others. Telaprevir in Combination with
Peginterferon and Ribavirin in Genotype 1 HCV Treatment-Naïve Patients:
Final Results of Phase 3 ADVANCE Study. 61st Annual Meeting of the American
Association for the Study of Liver Diseases (AASLD 2010). Boston, October
29-November 2, 2010. Abstract
TL Kieffer, DJ Bartels, J Sullivan, and others. Clinical Virology Results
from Telaprevir Phase 3 Study ADVANCE. 61st Annual Meeting of the American
Association for the Study of Liver Diseases (AASLD 2010). Boston, October
29-November 2, 2010. Abstract
KE Sherman. SL Flamm, NH Afdhal, and others. Telaprevir in Combination
with Peginterferon Alfa2a and Ribavirin for 24 or 48 weeks in Treatment-Naive
Genotype 1 HCV Patients who Achieved an Extended Rapid Viral Response:
Final Results of Phase 3 ILLUMINATE Study. 61st Annual Meeting of the
American Association for the Study of Liver Diseases (AASLD 2010). Boston,
October 29-November 2, 2010. Abstract
Vertex Pharmaceuticals. New Data From Phase 3 Studies Showed Superior
SVR (Viral Cure) Rates Achieved with Telaprevir-Based Combination Therapy
in People with Hepatitis C, Regardless of Race or Stage of Liver Disease.
release. October 30, 2010.