Researchers are studying a number of oral drug candidates that
directly interfere with hepatitis C virus (HCV) replication.
To date, most clinical trials have combined these drugs with
pegylated interferon (Pegasys
or PegIntron), with or without ribavirin, which stimulates
immune system activity against the virus. Adding direct-acting
agents to standard therapy may improve response rates and shorten
the total length of treatment.
these experimental compounds, telaprevir
-- which interferes with the HCV protease enzyme -- is furthest
along in the drug development pipeline. Vertex has indicated
that it expects to complete its application for Food and Drug
Administration (FDA) approval by the end of the year.
is an edited excerpt from a Vertex press release describing
the REALIZE trial and its most recent findings.
of People Whose Prior Treatment for Hepatitis C Was Unsuccessful
Achieved SVR (Viral Cure) with Telaprevir-Based Therapy in Phase
3 REALIZE Study
of people achieved SVR with pegylated-interferon and ribavirin
alone in the control arm
and tolerability results were consistent with prior Phase
of rolling New Drug Application submission on track for
the fourth quarter 2010
Mass. -- September 7, 2010 -- Vertex Pharmaceuticals Incorporated
(Nasdaq: VRTX) today announced that 65% of people overall achieved
a sustained viral response (SVR or viral cure) with a telaprevir-based
regimen in the pivotal Phase 3 REALIZE study, as compared to
17% of people in the control arm who received pegylated-interferon
and ribavirin alone. REALIZE enrolled three groups of patients
with genotype 1 hepatitis C who had undergone at least one prior
treatment course with pegylated interferon and ribavirin but
did not achieve SVR: (1) those who relapsed, (2) those who achieved
a partial response and (3) those who had almost no response,
known as a null response. REALIZE is the only Phase 3 hepatitis
C study to date of an investigational direct-acting antiviral
therapy that was designed to evaluate all major subgroups of
people whose prior treatment was unsuccessful, including those
who had a null response. The safety and tolerability results
were consistent with results from the other two Phase 3 studies
of telaprevir. The REALIZE study was conducted by Vertex's collaborator,
"The REALIZE data represent a major milestone in the development
of new treatments for hepatitis C, as patients who received
telaprevir-based therapy had a viral cure rate almost four times
greater than the cure rate in those treated with available medicines,"
said Stefan Zeuzem, MD, Professor of Medicine and Chief of the
Department of Medicine at the JW Goethe University Hospital,
Frankfurt, Germany and Principal Investigator of the trial.
"These results may provide hope to people who have not
been cured and who are in need of new treatment options, including
those with advanced liver disease."
"Along with results from ADVANCE and ILLUMINATE, the REALIZE
data provide us with a strong understanding of telaprevir's
potential role in helping many people with hepatitis C achieve
a cure, regardless of their treatment history," said Robert
Kauffman, MD, PhD, Senior Vice President and Chief Medical Officer
for Vertex. "With these data, we look forward to completing
our rolling New Drug Application submission for telaprevir later
Overview of SVR Results
The primary endpoint of the study was SVR in each of the two
telaprevir arms compared to the control arm, as well as across
the three subgroups of people included in the study. One of
the telaprevir treatment arms was designed to evaluate, for
the first time, whether there was any further improvement in
viral cure rates when delaying the start of telaprevir by four
weeks, during which time patients received four weeks of pegylated
interferon and ribavirin alone, compared to a simultaneous start.
The SVR rates between these two arms were similar and there
was no clinical benefit to the telaprevir delayed start treatment
arm in any of the subgroups of patients. The table below combines
the two telaprevir arms compared to the control.
Analysis: 78% (n=300/383)**
Analysis: 21% (n = 20/95)**
endpoint analysis: The SVR rates observed in the overall
combined telaprevir-based arms were statistically significant
when compared with the control arm (p < 0.0001). Additionally,
the SVR rates observed in each of the three groups of
patients evaluated were statistically significant when
compared with the control arm (relapsers and partial responders
(p<0.0001) and null responders (p<0.001)).
SVR rates from the combined telaprevir-based treatment
groups. There were two telaprevir-based treatment groups:
12 weeks of telaprevir (750 mg, q8h), pegylated-interferon
(Peg-IFN) & ribavirin (RBV), followed by 36 weeks
of Peg-IFN & RBV alone or
4 weeks of Peg-IFN & RBV alone followed by 12 weeks
of telaprevir (750 mg, q8h), Peg-IFN & RBV, followed
by 32 weeks of Peg-IFN & RBV alone
weeks of placebo, Peg-IFN & RBV, followed by 36 weeks
of Peg-IFN and RBV alone
|Null Responder: Defined as a person
who achieved a less than 2 log10 reduction in
HCV RNA at week 12 of a prior course of therapy.
|Relapser: Defined as a person
whose hepatitis C virus was undetectable at the completion
of at least 42 weeks of a prior course of therapy but whose
virus became detectable during the follow-up period.
|Partial Responder: Defined as
a person who achieved at least a 2 log10 reduction
at week 12, but whose hepatitis C virus never became undetectable
by week 24 of a prior course of therapy.
on hepatitis C treatment response and the REALIZE study
(including trial design diagram) can be found at http://investors.vrtx.com/press.cfm.
rates for the telaprevir simultaneous start arm and the delayed
start arm were 64% and 66%, respectively, overall, based on
an intent-to-treat (ITT) analysis. For the primary analysis,
the SVR rates for the telaprevir simultaneous start arm, delayed
start arm and control arm, respectively, were 83%, 88% and 24%
in relapsers (p<0.0001); 59%, 54% and 15% in partial responders,
(p<0.0001); and 29%, 33% and 5% in null responders, (p<0.001).
Safety & Tolerability Results
The safety and tolerability results of the telaprevir-based
regimens in the REALIZE study were consistent with results reported
from the Phase 3 ADVANCE and ILLUMINATE studies. The most common
adverse events, reported in any treatment arm during the telaprevir
dosing periods and up to week 16 to account for the telaprevir
delayed start arm in order of frequency, were fatigue, pruritis
[itching], headache, rash, flu-like symptoms, nausea and anemia,
with the majority being mild to moderate. Of these, fatigue,
pruritis, rash, flu-like symptoms, nausea and anemia were more
common in the telaprevir-based treatment arms compared to control.
Adverse events leading to discontinuation of all study drugs
during the telaprevir dosing period and up to week 16 occurred
in 4% of people in the combined telaprevir arms and 3% in the
control arm during the same period. Discontinuation of all drugs
due to anemia and rash during the telaprevir dosing period and
up to week 16 occurred in 0.6% and 0.4% of patients, respectively,
in the combined telaprevir arms, while discontinuation of all
three drugs due to rash and anemia did not occur in the control
arm during the same period. As in ADVANCE and ILLUMINATE, the
use of erythropoiesis-stimulating agents (ESAs) was not allowed
in this study.
Telaprevir is an investigational, oral inhibitor of HCV protease,
an enzyme essential for viral replication, and is being developed
by Vertex Pharmaceuticals in collaboration with Tibotec Pharmaceuticals
and Mitsubishi Tanabe Pharma. With results from the three Phase
3 studies of telaprevir -- ADVANCE, ILLUMINATE and REALIZE --
Vertex is on track to complete its rolling New Drug Application
(NDA) submission to the U.S. Food and Drug Administration (FDA)
in the fourth quarter of 2010.
REALIZE enrolled people with hepatitis C who did not achieve
a viral cure after receiving at least one course of prior treatment
with pegylated-interferon and ribavirin. Patients in the study
were enrolled based on their response to prior treatment: 53%
were prior relapsers, 19% were prior partial responders and
28% were prior null responders. In this study, 26% of patients
overall had cirrhosis and 89% of patients overall had a high
viral load (HCV RNA greater than or equal to 800,000 IU/mL)
when entering the study. Specifically in the null responder
population, there were an even greater number of people with
cirrhosis (33%) and high viral load (95%). Approximately 50%
of patients were genotype 1a and 50% were genotype 1b.
About the Study
REALIZE was a pivotal Phase 3, randomized, double-blind, placebo-controlled
study conducted in 662 people at more than 100 international
clinical trial sites with the majority in Europe and North America.
The study was designed to evaluate the efficacy, safety and
tolerability of telaprevir-based regimens in people infected
with genotype 1 chronic hepatitis C who did not achieve a viral
cure after at least one prior treatment with interferon-based
therapy. There were two telaprevir-based arms (simultaneous
and delayed start) and one control arm. Patients were randomized
2:2:1 to the two telaprevir arms and the control arm, respectively.
The primary endpoint of the REALIZE study was SVR, defined as
the proportion of people who had undetectable HCV RNA (<
25 IU/mL undetectable by Roche COBAS Taqman HCV test) 24 weeks
after the end of all treatment. REALIZE was designed to compare
the SVR rates for each of the telaprevir-based regimens with
the control arm, separately for the prior response subgroups
of relapsers and non-responders (null and partial responders),
and then for the two subgroups of non-responders. The secondary
endpoint was to evaluate the safety and tolerability of telaprevir
in combination with pegylated-interferon and ribavirin.
As in all Phase 3 studies of telaprevir, patients received no
more than 12 weeks of telaprevir given in combination with pegylated
interferon and ribavirin. In REALIZE, the telaprevir arms included
12 weeks of telaprevir in combination with pegylated-interferon
and ribavirin with 36 weeks of pegylated-interferon and ribavirin
alone for a total of 48 weeks of treatment.
About the Telaprevir Development Program
To date, more than 2,500 people with hepatitis C have received
telaprevir-based therapy as part of Phase 2 studies and the
Phase 3 ADVANCE, ILLUMINATE and REALIZE studies. Together, these
studies enrolled people with genotype 1 hepatitis C who had
not been treated for their disease previously as well as people
who had been treated before but did not achieve a viral cure.
Vertex retains commercial rights to telaprevir in North America.
Tibotec has rights to commercialize telaprevir in Europe, South
America, Australia, the Middle East and certain other countries.
Mitsubishi Tanabe Pharma has rights to commercialize telaprevir
in Japan and certain Far East countries.
Vertex Pharmaceuticals Incorporated is a global biotechnology
company committed to the discovery and development of breakthrough
small molecule drugs for serious diseases. The Company's strategy
is to commercialize its products both independently and in collaboration
with major pharmaceutical companies. Vertex's product pipeline
is focused on viral diseases, cystic fibrosis, inflammation,
autoimmune diseases, epilepsy, cancer and pain. Vertex co-discovered
the HIV protease inhibitor, Lexiva, with GlaxoSmithKline. For
more information, see www.vrtx.com.
Vertex Pharmaceuticals. 65% of People Whose Prior Treatment
for Hepatitis C Was Unsuccessful Achieved SVR (Viral Cure) with
Telaprevir-Based Therapy in Phase 3 REALIZE Study. Press release.
September 7, 2010.