|
Announcement
by Indenix and Novartis on GLOBE Study
Idenix
Pharmaceuticals, Inc. and Novartis Pharma AG announced the results
of the GLOBE study at the 56th Annual Meeting of the American Association
for the Study of Liver Diseases in San Francisco. The GLOBE study,
a Phase III clinical trial, includes 1,367 patients from 20 countries
and is the largest registration trial of chronic hepatitis B patients
ever conducted. The GLOBE study is the first global chronic hepatitis
B registration trial to include patients from China, where the disease
is highly prevalent.
Results from the ongoing GLOBE study demonstrate that the investigational
drug telbivudine
provides significantly greater response on all evaluated
virologic markers compared to lamivudine
after one year, in both HBeAg-positive
and HBeAg-negative
patients with chronic hepatitis B, according to the
announcement.
Patients treated with telbivudine achieved significantly greater
viral suppression than patients treated with lamivudine. Patients
treated with telbivudine also experienced significantly higher rates
of non-detectable viral levels.
"Despite recent advances in the treatment of chronic hepatitis
B, there remains a need for new safe and effective treatment options,"
said Dr. Ching-Lung Lai, Professor of Medicine and Chief
of the Gastroenterology and Hepatology Division at the University
of Hong Kong, and lead investigator of the GLOBE study.
"The
potent viral suppression achieved with telbivudine has the potential
to reduce the serious complications associated with chronic hepatitis
B and telbivudine's favorable safety and convenience profile in
trials to date also may make it a promising treatment option for
patients, including those requiring long-term therapy."
Key Findings from the GLOBE Study
Results from GLOBE indicate that telbivudine produces significantly
greater viral suppression compared to lamivudine after one year.
Telbivudine patients achieved significantly greater HBV DNA reductions
after 52 weeks of treatment in both hepatitis B e-antigen (HBeAg)
positive patients (-6.5 log10 vs. -5.5 log10 with lamivudine; p<0.01)
and HBeAg-negative patients (-5.2 log10, vs. -4.4 log10 with lamivudine;
p<0.01).
Similarly,
after 52 weeks of treatment, significantly more patients receiving
telbivudine achieved clearance of detectable
HBV DNA (PCR negative).
In
HBeAg-positive patients, telbivudine treatment led to loss of detectable
HBV DNA in 60 percent of patients compared to 40 percent with lamivudine
treatment (p<0.01).
In
HBeAg-negative patients, telbivudine treatment reduced HBV DNA to
below detectable levels in 88 percent of patients, compared to 71
percent with lamivudine treatment (p<0.01).
"The positive data from the GLOBE study indicate that telbivudine
may provide a new standard for treating patients with chronic hepatitis
B," said Nathaniel A. Brown, MD, executive vice president,
clinical development and chief medical officer of Idenix.
"We
are pleased with the one-year GLOBE study results that we will include
in the New Drug Application, which we anticipate submitting to the
U.S. Food and Drug Administration in December 2005. Additionally,
we look forward to obtaining the two-year data from GLOBE to evaluate
the longer-term efficacy and safety profile of telbivudine."
Analyses of the one-year GLOBE data demonstrate that, regardless
of treatment, achieving profound viral suppression early in the
course of treatment results in better efficacy outcomes at one year,
including non detectable virus levels (PCR negativity), liver enzyme
(ALT) normalization, HBeAg seroconversion and decreased incidence
of viral resistance.
These
results underscore the importance of early and profound suppression
in patients with chronic hepatitis B. The majority of telbivudine-treated
patients achieved PCR negativity in the first 24 weeks of treatment
and 95 percent of those patients remained PCR negative at one year.
The primary efficacy endpoint of the GLOBE study was therapeutic
response, a composite endpoint coupling viral suppression (serum
HBV DNA suppression below 100,000 copies/mL) with either improved
liver disease markers (ALT normalization) or loss of detectable
hepatitis B e-antigen (HBeAg).
In
HBeAg-positive patients, therapeutic response was significantly
higher among patients treated with telbivudine (75 percent) compared
to patients treated with lamivudine (67 percent) (P<0.05), while
the response after one year was similar for HBeAg-negative patients
taking either treatment (75 percent versus 77 percent, respectively).
Patients receiving telbivudine showed significantly less viral resistance
and less treatment failure compared to patients receiving lamivudine.
Telbivudine was associated with fewer and less severe resistance-associated
elevations ("flares") of serum ALT levels, a cause of
potentially fatal liver failure in chronic hepatitis B patients,
compared to lamivudine.
The diverse nature and rate of occurrence of adverse events were
similar between telbivudine-treated patients and lamivudine-treated
patients. The most common adverse
events for telbivudine and lamivudine were upper respiratory
infection (14 percent versus 13 percent, respectively), headache
(11 percent versus 13 percent, respectively), fatigue (12 percent
versus 10 percent, respectively), and nasopharyngitis (11 percent
versus 10 percent, respectively).
Serum
ALT elevations were more common in lamivudine-treated patients compared
to telbivudine (8 percent vs. 4 percent, respectively). Transient
creatine kinase (CK) elevations, not requiring treatment modification,
were more common with telbivudine compared to lamivudine (9 percent
versus 3 percent, respectively).
About Telbivudine
Telbivudine, an investigational drug, is a specific and selective,
oral, once-daily nucleoside analog
that is being developed for the treatment of chronic hepatitis B
and appears to be unique in its preferential inhibition of 2nd strand
HBV DNA synthesis.
More About GLOBE
Approximately three quarters of telbivudine-treated patients (both
HBeAg-positive and HBeAg-negative) achieved ALT normalization, a
marker of improved liver disease. Similar results were observed
for lamivudine-treated patients.
Additionally, histological analysis revealed that telbivudine, compared
with lamivudine, provided significant improvement
in liver histology after one year in HBeAg-positive
patients (65 percent versus 56 percent, respectively; P<0.02),
which indicates resolution of liver disease associated with HBV
infection.
In HBeAg-negative
patients, histologic responses were similar for telbivudine and
lamivudine (67 percent versus 66 percent, respectively). Histologic
response was defined as a two-point or greater reduction in Knodell
necroinflammatory score, with no worsening in Knodell fibrosis score.
In addition, in HBeAg-positive patients, loss of detectable HBeAg
was similar for both telbivudine- and lamivudine-treated patients
(26 percent versus 23 percent, respectively). Seroconversion (loss
of HBeAg and emergence of the hepatitis B e antibody -- often indicating
sustained clinical improvement) was achieved by 22 percent telbivudine-treated
patients compared to 21 percent of lamivudine-treated patients.
HBeAg loss and seroconversion are not applicable to HBeAg-negative
patients.
GLOBE Study Design
The GLOBE study is a randomized blinded two-year Phase III clinical
trial comparing telbivudine with the standard therapy lamivudine
in 1,367 adults with chronic hepatitis B from 112 clinical centers
internationally.
Key
entry criteria included adults with chronic hepatitis B as evidenced
by a positive confirmation of HBeAg (a marker for HBV infection),
HBV DNA >6 log10 copies/mL by COBAS PCR assay, ALT > or =
1.3-10 times the upper limit of normal (ULN), and compensated liver
disease. Patients were stratified for HBeAg status (+ or -) and
ALT less than or greater than 2.5 times the ULN.
The
trial was designed to perform primary analysis at week 52 with later
analyses at the completion of the trial of the Week 76 and Week
104 results.
11/18/05
Sources
Idenix
Pharmaceuticals
Novartis
Pharma AG
|
