HCV Protease
Inhibitor Telaprevir plus Pegylated Interferon and Ribavirin Is
Effective in Genotype 1 Prior Non-responders
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| SUMMARY:
The investigational hepatitis C virus (HCV) protease
inhibitor telaprevir combined with pegylated
interferon and ribavirin significantly improved
sustained response rates compared to standard therapy
in genotype 1 chronic hepatitis C patients who did not
achieve a cure with prior interferon-based treatment,
according to findings from the PROVE 3 study reported
in the April
8, 2010 New England Journal of Medicine.
Further telaprevir data will be presented next week
at the European Association for the Study of the Liver
annual meeting (EASL 2010) next week in Vienna. |
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By
Liz Highleyman
About half of people with hard-to-treat HCV genotype 1 do not
achieve sustained virological response (SVR), or undetectable
HCV viral load 6 months after completion of treatment, using a
standard-of-care regimen of pegylated
interferon alfa-2a (Pegasys) or pegylated interferon alfa-2b (PegIntron)
plus weight-adjusted ribavirin for 48 weeks.
While
interferon works by strengthening the immune system's response
against HCV, novel agents that directly target various steps of
the viral lifecycle (known as specifically targeted antiviral
therapy for hepatitis C, or STAT-C) are currently in development.
Telaprevir (formerly known as VX-950), an HCV NS3/4A protease
inhibitor, is furthest along in the pipeline.
In
the latest report, John McHutchison and fellow investigators described
final results from the Phase 2 PROVE 3 trial. Some of the findings
were previously reported at the American Association for the Study
of Liver Diseases meeting (AASLD 2009) this past fall.
PROVE 3 included 453 genotype 1 chronic hepatitis C patients enrolled
at 53 international sites (41 in U.S., 6 in Canada, 3 in the Netherlands,
3 in Germany) who were non-responders, partial responders, or
relapsers following a prior course of at least 12 weeks of pegylated
interferon plus ribavirin.
About two-thirds of participants were men, 89% were white, 9%
were black, and the median age was 51 years. Most (92%) had high
baseline HCV viral load (800,000 IU/mL or higher). Individuals
with hepatitis B, HIV, liver cancer, and decompensated liver disease
were excluded.
A majority (58%) had HCV genotype 1a, the rest had 1b; 16% had
compensated cirrhosis. About 60% were prior non-responders (never
achieved undetectable HCV RNA), 36% were relapsers (undetectable
HCV RNA during treatment with viral load rebound during the post-treatment
follow-up period), and 7% experienced viral breakthrough during
treatment.
Participants were randomly assigned to 4 treatment arms, receiving
a single 1125 mg "loading dose" of telaprevir followed
by 750 mg telaprevir 3-times-daily plus 180 mcg/week pegylated
interferon alfa-2a, with or without 1000-1200 mg/day ribavirin:
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T12PR24
arm: received all 3 drugs for 12 weeks followed by pegylated
interferon plus ribavirin without telaprevir for 12 additional
weeks; |
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T24PR48
arm: received all 3 drugs for 24 weeks, followed by pegylated
interferon plus ribavirin for 24 additional weeks. |
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T24P24
arm: received telaprevir plus pegylated interferon without
ribavirin for 24 weeks. |
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PR48
(control) arm: standard therapy using pegylated interferon
plus ribavirin for 48 weeks. |
Results
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Sustained
response rates in the 3 telaprevir arms were significantly
higher than in the standard therapy arm. |
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SVR
rates were 51% in the T12PR24 arm, 53% in the T24PR48 arm,
and 24% in the T24P24 arm, compared with 14% in the standard
therapy (PR48) arm. |
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Response
rates were higher for prior relapsers than for prior non-responders: |
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Overall
relapse rates were 30% in the T12PR24 arm, 13% in the T24PR48
arm, 53% in the T24P24 arm, and 53% in the PR48 arm. |
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Overall
viral breakthrough rates at week 24 were 13%, 12%, 32%, and
3%, respectively. |
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Viral
breakthrough mostly occurred during the first 12 weeks of
treatment, was more common in people with genotype 1a, and
was associated with known telaprevir resistance mutations. |
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Treatment
discontinuation due to adverse events was more frequent in
the telaprevir arms than in the standard therapy control group
(15% vs 4%). |
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Skin
rash was a common side effect in the telaprevir arms (51%
overall, 5% severe). |
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Rashes
were typically maculopapular and occurred soon after telaprevir
initiation (median 7-28 days) |
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18
patients (5%) in the telaprevir arms discontinued treatment
due to rash, compared with none in the standard therapy arm.
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Decreased
hemoglobin (an indicator of anemia) was more common in the
telaprevir arms and resolved after telaprevir discontinuation
(erythropoietin and related agents were not allowed). |
Based
on these findings, the study authors concluded, "In HCV-infected
patients in whom initial peginterferon alfa and ribavirin treatment
failed, retreatment with telaprevir in combination with peginterferon
alfa-2a and ribavirin was more effective than retreatment with
peginterferon alfa-2a and ribavirin alone."
"The results of this study show a benefit of telaprevir in
patients who had not had a sustained virologic response to an
initial, full course of peginterferon alfa and ribavirin,"
they continued in their discussion. "As in previous studies
in untreated patients, a higher breakthrough rate (32%), higher
relapse rate (53%), and lower sustained virologic response rate
(24%) were observed in the T24P24 group as compared with the T12PR24
group and the T24PR48 group, again demonstrating the necessity
for inclusion of ribavirin in combination with telaprevir and
peginterferon alfa."
"More than half our patients with genotype 1 infection don't
respond to pegylated-interferon and ribavirin, and they have a
very limited chance of achieving permanent viral eradication when
re-treated using currently approved therapies," McHutchison
said in a press release issued by Vertex Pharmaceuticals. "There
is, therefore, a clear need for more effective treatment options
in these patients. The significantly higher SVR rates observed
in the PROVE 3 trial with telaprevir-based regimens represent
an important step forward in the potential future treatment of
patients who have failed current therapies."
Vertex has indicated that Phase 3 SVR data for treatment-naive
patients is expected in the second quarter of this year and for
prior non-responders in the third quarter. The company expects
to request U.S. Food and Drug Association approval[http://www.hivandhepatitis.com/hep_c/news/2010/012209_a.html]
in the second half of 2010.
Duke Clinical Research Institute and Duke University Medical
Center, Durham, NC; Medical School of Hannover, Hannover, Germany;
University of California at San Francisco, San Francisco, CA;
Weill Cornell Medical College, New York, NY; Beth Israel Deaconess
Medical Center, Boston, MA; University of Toronto, Toronto, Canada;
Johann Wolfgang Goethe University Medical Center, Frankfurt am
Main, Germany; Academic Medical Center, Amsterdam, Netherlands;
Vertex Pharmaceuticals, Cambridge, MA; Saint Louis University
School of Medicine, St. Louis, MO.
4/13/10
Reference
JG McHutchison, MP Manns, AJ Muir, and others (PROVE3 Study Team).
Telaprevir for Previously Treated Chronic HCV Infection. New
England Journal of Medicine 362(14): 1292-1303 (Abstract).
April 8, 2010.
Other Source
Vertex
Pharmaceuticals. New England Journal of Medicine Publishes PROVE
3 Trial Showing Telaprevir-Based Regimens Significantly Increased
Sustained Viral Response (SVR) Rates in Patients Who Did Not Achieve
SVR with Prior HCV Therapy. Press release. April 7, 2010.
