Protease Inhibitor Telaprevir (VX-950) Continues to Perform Well in PROVE Trials|
Given the suboptimal efficacy, side effects, and
cost of interferon-based therapy
for chronic hepatitis C virus (HCV) infection,
investigators have explored several novel drugs that directly target various steps
of the viral lifecycle -- an approach dubbed "STAT-C."
the 59th Annual Meeting of the American Association for
the Study of Liver Diseases (AASLD 2008) last week in San Francisco, researchers
presented the latest data on the STAT-C agent furthest along in the development
(VX-950), an HCV protease inhibitor being developed by Vertex Pharmaceuticals
2 Final Results
has been studied in a series of related Phase 2b trials. Data
from the PROVE 1 and PROVE 2 studies were presented earlier this year at the
annual meeting of the European Association for the Study of the Liver (EASL).
Final results from PROVE 2 were presented at AASLD.
In PROVE 2, a total
of 323 treatment-naive patients with genotype
1 chronic hepatitis C were randomized to receive 1 of the following regimens:
750 mg telaprevir
every 8 hours + 180 mcg/week pegylated
interferon alfa-2a (Pegasys) for 12 weeks (T12/P12);
+ Pegasys at the same doses + 1000-1200 mg/day weight-adjusted ribavirin for
12 weeks (T12/PR12);
+ Pegasys + ribavirin for 12 weeks, followed by Pegasys
+ ribavirin without telaprevir for 12 additional weeks (T12/PR24).
Standard therapy with Pegasys
+ ribavirin (+ telaprevir placebo) for 48 weeks (PR48).
majority of participants (about 60%) were men, 94% were white, and the median
age was 45 years. Most (nearly 90%) had HCV RNA > 600,000 IU/mL at baseline
and about 7% had advanced liver
In the final intent-to-treat analysis,
proportions of patients who achieved sustained virological response (SVR) 24 weeks
after completion of therapy were as follows:
69% of patients in the T12/PR24 arm;
60% in the T12/PR12 arm;
46% in the standard therapy PR48 arm;
30% in the T12/P12 (no ribavirin) arm.
14% of patients receiving a 24-week telaprevir
regimen discontinued therapy due to adverse events, compared with 7% in the 48-week
standard therapy arm.
7% of patients across all telaprevir arms
discontinuation due to skin rash.
on these findings, the researches concluded that, "Telaprevir in combination
with [pegylated interferon/ribavirin] demonstrated significantly higher SVR rates
compared with the control group in patients infected with HCV genotype 1, with
the potential to shorten the overall treatment duration by half in most patients."
telaprevir improved response, however, it still appears that ribavirin is needed
to reduce the risk of relapse and increase the likelihood of sustained response.
of Internal Medicine I, JW Goethe University Hospital, Frankfurt a.M., Germany;
AP-HP Henri-Mondor Hospital & University of Paris 12, Créteil, France;
Medical University of Vienna, Vienna, Austria; Royal Free Hospital, London, UK;
Medicines Development Group, Vertex Pharmaceuticals, Inc., Cambridge, MA.
McHutchison and colleagues presented results from a 36-week planned interim analysis
of PROVE 3, which included 453 genotype 1 chronic hepatitis C patients who were
null responders, partial responders, or relapsers following a previous course
of treatment with interferon plus ribavirin.
Two-thirds of study participants
were men, about 90% were white, and the median age was about 50 years. About 60%
had HCV genotype 1a, 30% had 1b, and the rest were undetermined. About 25% had
bridging fibrosis and
about 15% had compensated cirrhosis.
About 60% were prior non-responders (never achieved undetectable HCV RNA), about
30% were relapsers (undetectable HCV RNA at the end of treatment but relapsed
during follow-up and did not achieve SVR), and the remainder experienced virological
breakthrough while still on therapy.
were randomly assigned to receive 1 of the following regimens:
750 mg telaprevir every 8 hours + 180
mcg/week Pegasys + 1000-1200 mg/day ribavirin for 12 weeks, followed by Pegasys
+ ribavirin without telaprevir for 12 additional weeks (T12/PR24);
All 3 drugs at the same doses for 24 weeks,
followed by Pegasys + ribavirin alone for 24 additional weeks (T24/PR48).
Telaprevir + Pegasys without ribavirin
for 24 weeks (T24/P24);
Standard therapy with Pegasys + ribavirin
for 48 weeks (+ telaprevir placebo for the first 24 weeks) (PR48).
RNA was measured at week 4 (rapid
virological response, or RVR), week 12 (early
virological response, or EVR), end of treatment (EOT), and 12 months after
completion of therapy for the 2 groups treated for 24 weeks (SVR12; standard
sustained virological response is ascertained 24 weeks after competing treatment.)
Stopping rules required patients to discontinue treatment if they did not achieve
a response by week 4 or 12, or if they experienced viral breakthrough.
In an intent-to-treat analysis at week
4, no patients in the PR48 arm, 61% in the T12/PR24 arm, 47% in the T24/P24 (no
ribavirin) arm, and 50% in the T24/PR48 arm achieved undetectable HCV RNA.
At week 12, the corresponding percentages
were 8%, 75%, 53%, and 66%.
At week 24, the percentages were 33%,
70%, 48%, and 56%, respectively.
In the 2 groups whose treatment ended
at 24 weeks, SVR12 rates were 52% in the T12/PR24 arm and 21% in the T24/P24 arm:
41% vs 11% for prior non-responders;
73% vs 46% for prior relapsers;
44% vs 20% for those with prior viral
In the longer treatment groups, 30% in
the PR48 arm and 46% in the T24/PR48 arm achieved undetectable HCV RNA at 36 weeks,
but they were still receiving therapy.
In the telaprevir arms, viral breakthrough
occurred more often in patients with genotype 1a compared with 1b.
A total of 224 patients discontinued therapy
prior to week 24:
Due to stopping rules: 72% in the PR48
arm, 28% in the T12/PR24 arm, 50% in the T24/P24 arm, and 49% in the T24/PR48
Due to adverse events (AEs): 4%, 7%, 8%,
and 22%, respectively.
Gastrointestinal symptoms were significantly
more frequent in the telaprevir arms.
on these findings, the investigators stated, "In a population of patients
who have failed previous [pegylated interferon/ribavirin] treatment, response
rates 12 weeks after end of treatment were 52% overall in the T12/PR 24 arm: 73%
in prior relapsers, 41% in prior non-responders."
reported more frequently in the tipranavir arms compared with the standard therapy
arm were gastrointestinal symptoms, headache, anemia, and skin symptoms (rash
and pruritis, or itching).
AEs were similar in type and frequency to those seen with [pegylated interferon/ribavirin],"
they noted. Treatment discontinuation rates at week 36 were 16% in the telaprevir
arms and 4% in the standard therapy arm.
"Data from Phase 2 telaprevir
clinical studies in genotype 1 HCV patients are encouraging as responses were
seen in treatment-naive patients, as well as in those who had previously failed
treatment with the current standard of care regimen," McHutchison stated
in a press release issued by Vertex. "PROVE 3 data showed that a telaprevir
regimen produced a 52% SVR12 in treatment-failure subjects, which is noteworthy
as patients who have failed therapy are very difficult to manage due to limited
available treatment options and are at greater risk for developing progressive
PROVE 3 is ongoing, and will report SVR outcomes
for patients in the 48-week treatment arms at a later date.
Research Institute, Durham, NC; McGuire DVAMC, Fairfax, VA; University of California,
San Francisco, CA; Medizinische Hochschule Hannover, Hannover, Germany; St Louis
University, St Louis, MO; Weill Medical College of Cornell University, New York,
NY; Beth Israel Deaconess Medical Center, Boston, MA; University of Toronto, Toronto,
Ontario, Canada; Saarland University Hospital, Homburg/Saar, Germany; University
of Amsterdam, Amsterdam, Netherlands; Vertex Pharmaceuticals, Inc., Cambridge,
in Black and Latino Patients
studies have shown that African-American and Latino patients have lower SVR rates
than white when using interferon-based therapy, but it remains to be determined
whether this is also the case with STAT-C agents.
In the PROVE 1 trial,
treatment-naive genotype 1 patients were randomized to receive telaprevir for
12 weeks + Pegasys for either 12, 24, or 48 weeks, or else standard therapy with
Pegasys + ribavirin for 48 weeks. Out of 250 total participants, nearly 75% were
white and about 10% each were black and Latino.
Viral decline at 1 week
was significantly different in the white and African-American subgroups receiving
Pegasys/ribavirin standard therapy, but not in the groups that added telaprevir.
SVR rates in patients receiving telaprevir appeared higher compared with standard
therapy across all racial/ethnic groups:
62% vs 41% for whites;
44% vs 11% for African-Americans;
65% vs 33% for Latinos.
sub-analysis suggests that telaprevir-based regimens enhance early viral responses
and subsequently lead to improved viral responses in African-Americans, Latinos,
and Caucasians," the researchers concluded. "Given the burden of disease
among African-Americans and Latinos, it is imperative these results be confirmed
in larger phase 3 clinical trials."
Duke Clinical Research Institute,
Duke University, Durham, NC; Alamo Medical Research, San Antonio, TX; Henry Ford
Hospital, Detroit, MI; Weill Medical College of Cornell University, New York,
NY; Vertex Pharmaceuticals, Boston, MA; Fundacion de Investigacion de Diego, Ponce
School of Medicine, San Juan, Puerto Rico.
the open-label Study C208 is assessing the efficacy and safety of telaprevir at
a dose of 1125 twice-daily (every 12 hours) versus the three-times-daily (every
8 hours) dose used in the PROVE trials. Telaprevir at each dose level was combined
with either Pegasys or pegylated
interferon alfa-2b (Pegintron) + ribavirin
In an interim analysis of data from 161
treatment-naive genotype 1 chronic hepatitis C patients, the following percentages
achieved undetectable HCV RNA:
every 8 hours + Pegasys/ribavirin:
80% at week 4, 93% at week 12;
every 8 hours + PegIntron/ribavirin:
69% and 93%, respectively;
every 12 hours + Pegasys/ribavirin:
83% and 83%, respectively;
every 12 hours + PegIntron/ribavirin:
67% and 85%, respectively.
Treatment discontinuation rates were 10%,
5%, 10%, and 8%, respectively, in the 4 study arms.
3%, 7%, 5%, and 8%, respectively, experienced
the context of the two currently available standard-of-care regimens," the
researchers concluded, "telaprevir 750 mg [every 8 hours] or 1125 mg [every
12 hours] in combination with [pegylated interferon/ribavirin] yielded high rates
of virological response and low viral breakthrough at week 4."
Unit, University of Barcelona, Barcelona, Spain; Hôpital Beaujon, Clichy,
France; Klinikum der Universität zu Köln, Köln, Germany; Medical
University of Vienna, Vienna, Austria; University Hospital Gasthuisberg, Leuven,
Belgium; Clinic of Infectious and Tropical Diseases, University of Brescia, Brescia,
Italy; Radboud University Nijmegen Medical Center, Nijmegen, Netherlands; Tibotec
BVBA, Mechelen, Belgium; Tibotec Inc., Yardley, PA.
Zeuzem, C Hezode, P Ferenci, and others. Telaprevir in Combination with Peginterferon-Alfa-2a
with or without Ribavirin in the Treatment of Chronic Hepatitis C: Final Results
of the PROVE2 Study. 59th Annual Meeting of the American Association for the Study
of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract
JG McHutchison, ML Shiffman, N Terrault, and others. A Phase 2b Study
of Telaprevir with Peginterferon-Alfa-2a and Ribavirin in Hepatitis C Genotype
1 Null and Partial Responders and Relapsers Following a Prior Course of Peginterferon-Alfa-2a/b
and Ribavirin Therapy: PROVE3 Interim Results. 59th Annual Meeting of the American
Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October
31-November 4, 2008. Abstract 269.
AJ Muir, EJ Lawitz, JG McHutchison,
and others. Viral Responses in African-Americans, Latinos and Caucasians in the
US Phase 2 Study (PROVE1) of Telaprevir with Peginterferon Alfa-2a and Ribavirin
in Treatment-Naïve Genotype 1-infected Subjects with Hepatitis C. 59th Annual
Meeting of the American Association for the Study of Liver Diseases (AASLD 2008).
San Francisco. October 31-November 4, 2008. Abstract 1846.
X Forns, P Marcellin,
T Goeser, and others. Phase 2 Study of Telaprevir Administered q8h or q12h with
Peginterferon-Alfa-2a or -Alfa-2b and Ribavirin in Treatment-Naïve Subjects
with Genotype 1 Hepatitis C: Week 4 Interim Results. 59th Annual Meeting of the
American Association for the Study of Liver Diseases (AASLD 2008). San Francisco.
October 31-November 4, 2008. Abstract 1854.
Pharmaceuticals. New Clinical Data Support Broad Profile for Telaprevir in Patients
with Genotype 1 Hepatitis C Virus (HCV) Infection. Press release. November