Gilead Announces Two-Year Data from Pivotal Phase III Studies Evaluating Viread® for Chronic Hepatitis B
November 01 2008 - 11:00AM
Business Wire
Gilead Sciences, Inc. (Nasdaq:GILD) today announced the
presentation of two-year (96-week) data from two Phase III pivotal
clinical trials, Studies 102 and 103, evaluating the safety and
efficacy of once-daily Viread� (tenofovir disoproxil fumarate)
among adult patients with chronic hepatitis B virus (HBV)
infection. These data will be presented during oral sessions at the
annual meeting of the American Association for the Study of Liver
Diseases (The Liver Meeting 2008) being held this week in San
Francisco (October 31-November 4). Studies 102 and 103 will
evaluate treatment with Viread for up to eight years among patients
with HBeAg-negative and HBeAg-positive chronic hepatitis B,
respectively, with compensated liver disease. Patients in both
studies were originally randomized to receive Viread or Hepsera�
(adefovir dipivoxil). After the completion of 48 weeks of
randomized blinded therapy, all eligible patients were rolled over
to open-label Viread monotherapy. These new data show that patients
who received Viread for up to 96 weeks experienced sustained
suppression of HBV levels in the blood (91 percent and 78 percent
for Studies 102 and 103, respectively). The studies also show that
all Hepsera-treated patients whose HBV levels were suppressed at
week 48 maintained viral suppression after rolling over to Viread,
while Hepsera-treated patients with HBV DNA levels above 400
copies/mL at week 48 experienced significant viral suppression
after rolling over to Viread. Additionally, by week 96 of Study
103, 6 percent of all patients continuing treatment in both groups
experienced �s� antigen (HBsAg) loss, which contributes to
resolution of chronic hepatitis B infection (HBsAg seroconversion
rates were 4 percent among patients originally randomized to
receive Viread and 5 percent for patients who rolled over from
Hepsera). Notably, no mutations associated with resistance to
Viread were reported among patients receiving Viread monotherapy
for up to 96 weeks or in Hepsera-treated patients who rolled over
to Viread. �In this study, Viread produced a significant and
sustained effect over two years of treatment with no evidence of
resistance, which is a substantial clinical finding,� said Patrick
Marcellin, MD of H�pital Beaujon in Clichy, France, the principal
investigator of Study 102. �Additionally, patients in this study
taking Hepsera were rolled over to Viread without new safety
signals and without compromising the efficacy of anti-HBV
treatment.� The U.S. Food and Drug Administration (FDA) approved
Viread for chronic HBV in adults in August 2008 based on earlier
(48-week) results from these studies. Viread and Hepsera are both
manufactured by Gilead. �One of the most important considerations
in treating chronic hepatitis B is resistance. It is reassuring to
see that no patients from either arm of the study demonstrated
resistance to Viread at 96 weeks of treatment,� said Jenny
Heathcote, MD of the University of Toronto, Canada, the principal
investigator for Study 103. �It is also notable that 6 percent of
HBeAg-positive patients experienced �s� antigen loss.� Chronic HBV
affects an estimated 400 million people worldwide, including two
million people in the United States. Many are unaware that they are
infected because the disease may not produce obvious symptoms. One
in four people with chronic hepatitis B die from complications such
as cirrhosis and liver cancer. In the United States, Asian
Americans are disproportionately affected: Foreign-born Asians are
100 times more likely to have the disease compared to non-Asians in
the U.S. population. In September 2008, partly in response to
advances in HBV therapy, the U.S. Centers for Disease Control and
Prevention (CDC) published new HBV screening guidelines
recommending that all individuals from Asian countries be tested
for the disease. In addition to its indication for HBV, Viread is
also indicated in combination with other antiretroviral agents for
the treatment of HIV infection in adults, and is currently the
most-prescribed molecule in antiretroviral therapy in the United
States. About Studies 102 and 103 Studies 102 and 103 were
multi-center, randomized, double-blind Phase III clinical trials
comparing Viread to Hepsera among patients with compensated liver
disease and HBeAg-negative presumed pre-core mutant (n=375) and
HBeAg-positive (n=266) chronic hepatitis B, respectively. The
majority of patients were treatment-na�ve, although some patients
(n=75) were lamivudine-experienced. Patients originally randomized
to Hepsera in both studies rolled over to Viread (n=196) at week
48, while patients originally randomized to Viread continued Viread
treatment in the second 48 weeks (n=389). After 72 weeks, patients
with confirmed viremia (HBV DNA levels at or above 400 copies/mL on
two consecutive visits) had the option of adding emtricitabine
treatment in the form of Truvada�, an investigational product for
the treatment of chronic hepatitis B. Study 102 Results (Oral
Presentation #146) HBeAg-negative patients Using a long-term
evaluation, intent-to-treat analysis algorithm through 96 weeks,
which excluded some patients who discontinued the study for
administrative reasons and had HBV DNA below 400 copies/mL at last
study visit (n=7), 91 percent of those originally randomized to
Viread achieved HBV DNA levels below 400 copies/mL compared to 89
percent of those originally randomized to Hepsera who rolled over
to Viread at week 48 (p=0.672). Among patients who received Viread
for the entire 96 weeks, 99 percent achieved HBV DNA levels below
400 copies/mL. In addition, all patients who rolled over from
Hepsera to Viread at week 48, regardless of whether they were well
controlled on Hepsera or viremic, achieved viral load suppression
below 400 copies/mL with Viread by week 96. Two patients in Study
102 added emtricitabine treatment in the form of Truvada between
week 72 and week 96 due to confirmed viremia. One of these patients
achieved viral suppression by week 96 and is counted among the 91
percent of patients who experienced sustained suppression with
Viread throughout the 96-week period. Levels of alanine
aminotransferase (ALT, an enzyme that serves as a measure of liver
damage), which had been high at baseline, remained at near-normal
levels between 48 and 96 weeks of treatment in both Viread and
Hepsera-to-Viread groups (mean of 35 and 34 U/L, respectively, at
week 96; p=0.827). Viread was generally well tolerated by study
subjects. The incidence of drug-related serious adverse events was
low, with one event reported in the Viread group and none reported
in the Hepsera-to-Viread group. There was one death in the study,
in the Viread group, due to metastatic liver carcinoma, a known
complication of chronic hepatitis B infection. The incidence of
grade 3-4 laboratory abnormalities was 10 percent for both Viread
and Hepsera-to-Viread groups. No patients experienced a confirmed
0.5 mg/dL increase in serum creatinine or creatinine clearance of
less than 50 ml/min. No resistance to Viread was detected among
patients who received Viread monotherapy over two years. Study 103
Results (Oral Presentation #158) HBeAg-positive patients Using a
long-term evaluation, intent-to-treat analysis algorithm through 96
weeks, which excluded some patients who discontinued the study for
administrative reasons and had HBV DNA below 400 copies/mL at last
study visit (n=8), 78 percent of those originally randomized to
Viread achieved HBV DNA levels below 400 copies/mL compared to 78
percent of those originally randomized to Hepsera who rolled over
to Viread at week 48 (p=0.801). Among patients who received Viread
for the entire 96 weeks, 89 percent achieved HBV DNA levels below
400 copies/mL compared to 85 percent of patients who remained on
Viread at week 96 after switching from Hepsera at week 48
(p=0.374). As in Study 102, all patients who were well controlled
at week 48 on Hepsera (n=12) maintained viral suppression after
switching to Viread. Viremic Hepsera patients responded rapidly
after rolling over to Viread, with 82 percent achieving HBV
suppression below 400 copies/mL by week 96. Twenty-eight patients
in Study 103 added emtricitabine treatment in the form of Truvada
between 72 and 96 weeks due to confirmed viremia. Five of these
patients achieved viral suppression by week 96, two of whom were
counted among the 78 percent of patients who experienced sustained
suppression with Viread over 96 weeks and three of whom were
counted among the 78 percent who achieved suppression after rolling
over from Hepsera. As with Study 102, ALT levels, which had been
elevated at baseline in both patient groups, remained stable at
near-normal levels by week 96 in both Viread and Hepsera-to-Viread
groups (mean of 35 and 39 U/L, respectively; p=0.765). Among
patients who continued treatment to week 96, a similar proportion
of patients in the Viread and Hepsera-to-Viread groups experienced
HBeAg seroconversion (26 percent versus 24 percent, respectively;
p=NS). Seroconversion is defined as both the disappearance of the
hepatitis B �e� antigen, a marker of HBV replication (rendering the
patient �HBe-antigen negative�), and the appearance of antibodies
specific for this antigen (making the patient �HBe-antibody
positive�). In addition, 6 percent of patients in both treatment
groups experienced �s� antigen (HBsAg) loss, which contributes to
resolution of chronic hepatitis B infection (HBsAg seroconversion
rates were 4 percent among patients originally randomized to
receive Viread and 5 percent for patients who rolled over from
Hepsera). As in Study 102, the incidence of drug-related serious
adverse events was similar between the Viread group (one patient)
and the Hepsera-to-Viread group (two patients). The incidence of
grade 3-4 laboratory abnormalities was also similar: 7 percent for
the Viread-only patients and 10 percent for the Hepsera-to-Viread
patients. No patients experienced creatinine clearance of less than
50 ml/min. Two patients in the Hepsera-to-Viread group had a
confirmed 0.5 mg/dL increase in serum creatinine, compared to none
in the Viread group. As with Study 102, no resistance was detected
among patients who received Viread monotherapy over two years.
Continued treatment with Viread for 96 weeks did not reveal any new
adverse reactions and no change in the tolerability profile
observed during the first 48 weeks of treatment. Treatment-related
adverse events observed in greater than 5 percent of patients
during the first 48 weeks of studies 102 and 103 included: nausea,
abdominal pain, diarrhea, headache, dizziness, fatigue,
nasopharyngitis, back pain and skin rash. Important Information
about Viread Viread (tenofovir disoproxil fumarate) is indicated
for the treatment of chronic hepatitis B in adults. This indication
is based on data from one year of treatment in primarily
nucleoside-treatment-na�ve adult patients with HBeAg-positive and
HBeAg-negative chronic hepatitis B with compensated liver disease.
The numbers of patients in clinical trials who were
nucleoside-experienced or who had lamivudine-associated mutations
at baseline was too small to reach conclusions of efficacy. Viread
has not been evaluated in patients with decompensated liver
disease. Viread is indicated in combination with other
antiretroviral agents for the treatment of HIV-1 infection. The
following points should be considered when initiating therapy with
Viread for the treatment of HIV-1: Viread should not be used in
combination with Truvada (emtricitabine/tenofovir disoproxil
fumarate) or Atripla� (efavirenz/emtricitabine/tenofovir disoproxil
fumarate). The recommended dose for the treatment of chronic
hepatitis B and HIV is 300 mg once daily taken orally without
regard to food. The dosing interval of Viread should be adjusted in
patients with renal impairment. Lactic acidosis and severe
hepatomegaly with steatosis, including fatal cases, have been
reported with the use of nucleoside analogs alone or in combination
with other antiretrovirals. Severe acute exacerbations of hepatitis
have been reported in HBV-infected patients who have discontinued
anti-hepatitis B therapy, including Viread. Hepatic function should
be monitored closely with both clinical and laboratory follow-up
for at least several months in patients who discontinue
anti-hepatitis B therapy, including Viread. If appropriate,
resumption of anti-hepatitis B therapy may be warranted. New onset
or worsening of renal impairment including cases of acute renal
failure and Fanconi syndrome has been reported with the use of
Viread. It is recommended to assess creatinine clearance (CrCl)
before initiating treatment with Viread and monitor CrCl and serum
phosphorus in patients at risk. Administering Viread with
concurrent or recent use of nephrotoxic drugs should be avoided.
Viread should not be administered in combination with Hepsera. HIV
antibody testing should be offered to all HBV-infected patients
before initiating therapy with Viread. Viread should only be used
as part of an appropriate antiretroviral combination regimen in
HIV-infected patients with or without HBV coinfection. Decreases in
bone mineral density (BMD) have been observed in HIV-infected
patients. It is recommended that BMD monitoring be considered for
patients with a history of pathologic fracture or who are at risk
for osteopenia. The bone effects of Viread have not been studied in
patients with chronic HBV infection. Redistribution/accumulation of
body fat has been observed in HIV-infected patients receiving
antiretroviral combination therapy. Immune reconstitution syndrome
has been observed in HIV-infected patients receiving antiretroviral
combination therapy, including Viread, which may necessitate
further evaluation and treatment. In controlled clinical trials in
patients with chronic hepatitis B, the most common adverse reaction
(all grades) is nausea. In HIV-infected patients, the most common
adverse reactions (incidence ?10 percent, grades 2-4) are rash,
diarrhea, headache, pain, depression, asthenia, and nausea.
Important Information about Hepsera (adefovir dipivoxil) Hepsera is
indicated for the treatment of chronic hepatitis B in patients 12
years of age and older with evidence of active viral replication
and either evidence of persistent elevations in serum
aminotransferases (ALT or AST) or histologically active disease.
This indication is based on histological, virological, biochemical,
and serological responses in adult patients with HBeAg+ and HBeAg�
chronic hepatitis B with compensated liver function, and with
clinical evidence of lamivudine-resistant hepatitis B virus with
either compensated or decompensated liver function. For patients 12
to 10 percent) in compensated disease patients is asthenia and in
pre- and post-transplantation lamivudine resistant liver disease
patients is increased creatinine. About Gilead Sciences Gilead
Sciences is a biopharmaceutical company that discovers, develops
and commercializes innovative therapeutics in areas of unmet
medical need. The company's mission is to advance the care of
patients suffering from life-threatening diseases worldwide.
Headquartered in Foster City, California, Gilead has operations in
North America, Europe and Australia. This press release includes
forward-looking statements, within the meaning of the Private
Securities Litigation Reform Act of 1995, that are subject to
risks, uncertainties and other factors, including the risks that
physicians may not prescribe Viread over existing HBV medications
and that the safety and efficacy data obtained through 96 weeks of
Studies 102 and 103 may not be observed in other studies or in
clinical practice. These risks, uncertainties and other factors
could cause actual results to differ materially from those referred
to in the forward-looking statements. The reader is cautioned not
to rely on these forward-looking statements. These and other risks
are described in detail in Gilead�s Annual Report on Form 10-K for
the year ended December 31, 2007 and its Quarterly Report on Form
10-Q for the first, second and third quarters of 2008, as filed
with the U.S. Securities and Exchange Commission. All
forward-looking statements are based on information currently
available to Gilead, and Gilead assumes no obligation to update any
such forward-looking statements. U.S. full prescribing information
for Viread is available at www.Viread.com U.S. full prescribing
information for Hepsera is available at www.Hepsera.com U.S. full
prescribing information for Truvada is available at www.Truvada.com
Viread, Hepsera and Truvada are registered trademarks of Gilead
Sciences, Inc. For more information on Gilead, please call the
Gilead Public Affairs Department at 1-800-GILEAD-5 (1-800-445-3235)
or visit www.gilead.com.
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