Protease Inhibitor Telaprevir Demonstrates Good Efficacy
in Both Treatment-experienced and Treatment-naive Patients
Vertex's experimental hepatitis C virus (HCV)
protease inhibitor telaprevir
(formerly known as VX-950) -- which, along
with Schering-Plough's boceprevir
is the most advanced of the directly targeted
oral anti-HCV drugs in development -- continues
to demonstrate good efficacy with acceptable tolerability,
according to data presented last week at the 60th
Annual Meeting of the American Association for
the Study of Liver Diseases (AASLD
2009) in Boston. Final results from the PROVE3
trial showed that patients with prior treatment
failure can be successfully treated with a telaprevir-based
regimen, while Study C208 indicated that twice-telaprevir
works as well as 3-times-daily dosing.
McHutchison and colleagues presented final data from the
Phase 2 PROVE3 trial; the researchers previously presented
interim 36-week data at last year's AASLD meeting.
study included 453 genotype
1 chronic hepatitis C patients who were non-responders,
partial responders, or relapsers following a prior course
plus ribavirin. Two-thirds were men, about 90% were
white, 9% were black, and the median age was about 50 years.
Most (92%) had baseline HCV RNA > 800,000 IU/mL.
About 40% had bridging fibrosis
or compensated cirrhosis.
About 60% were prior non-responders (never achieved undetectable
HCV RNA) and about 30% were relapsers (undetectable HCV
RNA during treatment, but viral load recurred after completing
were randomly allocated to 4 arms, receiving 750 mg 3-times-daily
telaprevir plus 180 mcg/week pegylated
interferon alfa-2a (Pegasys), with or without 1000-1200
mg/day weight-adjusted ribavirin. One group received
all 3 drugs for 12 weeks followed by Pegasys plus ribavirin
without telaprevir for 12 additional weeks (T12/PR24). A
second group received all 3 drugs for 24 weeks, followed
by Pegasys plus ribavirin for 24 additional weeks (T24/PR48).
A third group took telaprevir plus Pegasys without ribavirin
for 24 weeks (T24/P24). Finally, a control arm received
standard therapy using Pegasys plus ribavirin for 48 weeks
RNA was measured at week 4 (rapid virological response,
or RVR), week 12 (early virological response, or EVR), end
of treatment (EOT), and 24 weeks after completion of therapy
(sustained virological response, or SVR); telaprevir recipients
who achieved SVR were tested again 48 weeks after completing
treatment. The study protocol included a stopping rule that
required patients to discontinue treatment if they did not
achieve a response by week 4 or 12, or if they experienced
on these findings, the researchers stated, "SVR rates
in all treatment groups receiving [telaprevir plus pegylated
interferon plus ribavirin] regimens were significantly higher
than with [pegylated interferon plus ribavirin]. Other than
1 patient lost to follow-up, all patients who completed [a
telaprevir] regimen and achieved SVR maintained virologic
response 48 weeks after the end of treatment."
half the participants completed their assigned treatment.
discontinuing treatment due to meeting the defined stopping
rule were 15% in the T12/PR24 arm, 23% in the T24/PR48
arm, and 37% in the T12/P24 arm, compared with 59% in
the standard therapy arm.
discontinuing therapy due to adverse events were 10%,
25%, 9%, and 4%, respectively.
SVR rates were 51% in the T12/PR24 arm, 53% in the T24/PR48
arm, 24% in the T12/P24 arm, and 14% in the standard
therapy arm, but varied according to type of prior failure:
non-responders: 39%, 38%, 11%, and 9%, respectively.
relapsers: 69%, 76%, 42%, and 20%, respectively.
viral breakthough while on treatment: 57%, 63%,
36%, and 40%, respectively.
of viral breakthrough during treatment were 13% in the
T12/PR24 arm, 12% in the T24/PR48 arm, 32% in the T12/P24
arm, and 3% in the standard therapy arm
relapse rates during the 24-week post-treatment follow-up
period were 30%, 13%, 53%, and 53%, respectively.
patients who completed their assigned regimen, relapse
rates were 28%, 4%, 53%, and 52%, respectively.
late relapses were observed during the longer 48-week
post-treatment follow-up period for telaprevir recipients.
events occurring with greater frequency in the telaprevir
compared with standard therapy arms included fatigue,
nausea, diarrhea, headache, skin rash, pruritus (itching),
anemia, insomnia, fever, chills, and hair loss.
leading to treatment discontinuation occurred in 4%,
6%, 5%, and 0% of patients in the T12/PR24, T24/PR48,
T24/P24, and standard therapy arms, respectively.
leading to discontinuation occurred in 0%, 2%, 1%, and
who did not include ribavirin in their regimen were about
half as likely to achieve SVR as those who used all 3 drugs,
demonstrating the importance of ribavirin in preventing
relapse. Overall, prior relapsers and those who previously
experienced viral breakthrough during treatment had better
sustained response rates than prior non-responders. For
prior non-responders, SVR rates were similar in the 24-week
and 48-week treatment arms, although prior relapsers and
breakthroughs tended to respond better with longer treatment.
who failed prior [pegylated interferon plus ribavirin] therapy
can successfully be treated with a telaprevir-based regimen
and maintain SVR 1 year after the end of treatment,"
the investigators concluded.
addition, Gregory Everson and colleagues presented a poster
describing findings from a sub-analysis of "difficult-to-cure"
patients in the Phase 2b PROVE1 and PROVE2 trials. These
trials included treatment-naive genotype 1 chronic hepatitis
C patients. Final PROVE1 results were reported
at the 2008 EASL meeting and final PROVE2 findings presented
last year at AASLD.
present analysis pooled data from PROVE1 and PROVE2 participants
who received the T12/PR24 regimen or standard therapy. Overall
SVR rates were 65% and 44%, respectively, in these arms.
In a logistic regression analysis, lower baseline HCV RNA
(< 800,000 IU/mL), younger age (< 45 years), and white
race were predictors of SVR. The investigators concluded
that, "Telaprevir-based triple therapy improved SVR
rates in patients predicted to have low virologic response
to the current standard treatment."
C208 was an open-label, Phase 2 trial conducted by Tibotec
in Europe. This trial included 161 previously untreated
genotype 1 chronic hepatitis C patients. About half were
men, about 90% were white, the mean age was about 45 years,
and about 20% had fibrosis.
were randomly allocated to 4 treatment arms, received telaprevir
at doses of either 750 mg 3-times-daily (every 8 hours)
or 1125 mg twice-daily (every 12 hours). Each dose was combined
with either Pegasys
interferon alfa-2b (PegIntron) plus ribavirin. Patients
took telaprevir for 12 weeks, followed by pegylated interferon/ribavirin
for at least an additional 12 weeks.
a response-guided design, patients who achieved RVR at week
4 and maintained undetectable viral load (< 25 IU/mL)
through week 20 could stop all treatment at 24 weeks; they
were then followed for 6 months post-treatment to evaluate
SVR. The study protocol required that patients who did not
meet these criteria receive pegylated interferon plus ribavirin
for a total of 48 weeks.
of patients across all treatment arms were required
to continue treatment through week 48.
an intent-to-treat analysis, similar proportions of
patients in the 3-times-daily and twice daily arms --
as well as those receiving Pegasys vs PegIntron -- achieved
SVR, not a statistically significant difference:
taking 3-times-daily telaprevir plus Pegasys;
taking 3-times-daily telaprevir plus PegIntron;
taking twice-daily telaprevir plus Pegasys;
taking twice-daily telaprevir plus PegIntron.
only at patients who achieved RVR, the SVR rates were
91%, 93%, 91%, and 92%, respectively.
patients who completed their assigned regimen, 3% experienced
viral relapse during post-treatment follow-up.
of patients experienced viral breakthrough during telaprevir
and tolerability were similar with 3-times-daily and
most common adverse events were pruritis, nausea, rash,
anemia, flu-like illness, fatigue, and headache, occurring
with similar frequency in the both arms.
of participants permanently discontinued therapy due
to serious adverse events, mostly rash (3%) and anemia
on these findings, the researchers concluded that "treatment
with telaprevir [every 8 hours] or [every 12 hours] in combination
with [pegylated interferon/ribavirin] yielded high and comparable
rates of virological response at week 12, independent of
baseline viral load or viral subtype.
high SVR rates and similar safety outcomes between the twice-daily
and 3-times-daily treatment groups, the results from this
exploratory study support the future evaluation of telaprevir-based
regimens dosed twice daily," Dr Marcellin said in a
press release issued by Vertex. "These results also
highlight the potential future role for response-guided
therapy with the goal of improving treatment outcomes and
potentially shortening the duration of therapy for the majority
McHutchison, MP Manns, A Muir, and others. PROVE 3 Final
Results and 1-Year Durability of SVR with Telaprevir-Based
Regimen in Hepatitis C Genotype 1-Infected Patients with
Prior Non-response, Viral Breakthrough or Relapse to Peginterferon-Alfa-2a/b
and Ribavirin Therapy. 60th Annual Meeting of the American
Association for the Study of Liver Diseases (AASLD 2009).
Boston. October 30-November 1, 2009. Abstract 66.
Everson, GM Dusheiko, P Ferenci, and others. Telaprevir,
Peginterferon Alfa-2a and Ribavirin Improved Rates of Sustained
Virologic Response (SVR) in "Difficult-to-Cure"
Patients With Chronic Hepatitis C (CHC): a Pooled Analysis
From the PROVE 1 and PROVE 2 Trials. 60th Annual Meeting
of the American Association for the Study of Liver Diseases
(AASLD 2009). Boston. October 30-November 1, 2009. Abstract
Marcellin, X Forns, T Goeser, and others. Virological Analysis
of Patients Receiving Telaprevir Administered q8h or q12h
with Peginterferon-Alfa-2a or -Alfa-2b and Ribavirin in
Treatment-Naïve Patients with Genotype 1 Hepatitis
C: Study C208. 60th Annual Meeting of the American Association
for the Study of Liver Diseases (AASLD 2009). Boston. October
30-November 1, 2009. Abstract 194.
than 80% of Hepatitis C Patients Treated in Study C208 Achieved
an SVR with Telaprevir-Based Regimens. Press release.
October 31, 2009.