Gilead Announces 72-Week Data From Two Pivotal Phase III Studies Evaluating Viread® for the Treatment of Chronic Hepatitis B
Gilead Sciences, Inc. (Nasdaq:GILD) today announced the presentation of
detailed 72-week data from two pivotal Phase III 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 Friday, April 25, at the
43rd Annual Meeting of the European Association for the Study of the
Liver (EASL) currently taking place in Milan, Italy (April 23-27).
Studies 102 and 103 were designed to evaluate treatment with Viread over
240 weeks among patients with HBeAg-negative (presumed pre-core mutant)
and HBeAg-positive chronic hepatitis B, respectively. Patients in both
studies were originally randomized to receive Viread or Gilead´s
Hepsera® (adefovir
dipivoxil). The studies´ primary efficacy
endpoints were reached at 48 weeks, at which time Viread demonstrated
superior efficacy over Hepsera. After the completion of 48 weeks of
randomized blinded therapy, all eligible patients were offered
open-label Viread monotherapy.
The 72-week data demonstrate that the majority of patients in each study
who were originally randomized to receive Viread had a virologic
response below 400 copies/mL through week 72 (91 percent and 79 percent
respectively). The studies also show that all 88 Hepsera-treated
patients who achieved HBV DNA levels below 400 copies/mL at week 48
maintained viral suppression after switching to Viread. Additionally
Hepsera-treated patients with HBV DNA levels above 400 copies/mL at week
48 experienced rapid viral suppression after switching to Viread in each
study (94 percent and 78 percent, respectively). Viread was generally
well tolerated through week 72.
"These 72-week data indicate that Viread has
the potential to produce a significant and sustained effect on HBV DNA
suppression," said Patrick Marcellin, MD, PhD
Hôpital Beaujon University of Paris and the
principal investigator for Study 102. "When
considered alongside its well-established safety profile, including more
than one million patient years of experience in HIV, I believe Viread
will be an important new treatment option for patients living with
chronic hepatitis B."
Study 102
Study 102 is a multi-center, randomized, double-blind Phase III clinical
trial evaluating the efficacy, safety and tolerability of Viread among
patients with HBeAg-negative presumed pre-core mutant chronic hepatitis
B. Study participants were either new to HBV therapy (treatment-naive)
or had previous experience with lamivudine (treatment-experienced).
Three hundred seventy-five patients were originally randomized in a 2:1
ratio to receive either Viread (300 mg once daily; n=250) or Hepsera (10
mg once daily; n=125) for 48 weeks. Baseline characteristics were
similar between patients in both study arms. After the completion of 48
weeks of randomized blinded therapy, all eligible patients were offered
open-label Viread monotherapy.
At week 72, 91 percent of patients who were originally randomized to
receive Viread had a virologic response below 400 copies/mL. For
Hepsera-treated patients who switched to Viread after week 48, 88
percent achieved HBV DNA levels below 400 copies/mL by week 72. Notably
through week 72, viral suppression was maintained among all patients who
switched to Viread and who were previously virologically controlled with
Hepsera (n=76). Additionally, rapid viral suppression to less than 400
copies/mL was achieved by week 72 in 94 percent of viremic
Hepsera-treated patients who switched to Viread.
At week 72, normal alanine aminotransferases (ALT, a measure of liver
damage) was observed in 79 percent of patients who were originally
randomized to receive Viread and in 77 percent of Hepsera-treated
patients who switched to Viread after Week 48.
Viread was generally well tolerated through week 72. In Study 102
treatment-related serious adverse events occurred in less than 1 percent
of patients who were originally randomized to receive Viread and less
than 1 percent of patients originally randomized to receive Hepsera. The
incidence of Grade 3/4 laboratory abnormalities was comparable in each
arm (14 percent versus 13 percent for Grade 3 abnormalities and 5
percent versus 2 percent for Grade 4 abnormalities). No patient had a
confirmed creatinine clearance of less than 50 mL/minute.
Resistance surveillance through week 72 did not detect any
tenofovir-associated mutations. Two patients exhibited loss of viral
response as defined by study investigators with documented non-adherence
and were evaluated via genotypic analysis. Neither developed mutations
associated with Viread resistance.
Study 103
Study 103 is a multi-center, randomized, double-blind Phase III clinical
trial evaluating the efficacy, safety and tolerability of Viread among
treatment-naive patients with HBeAg-positive chronic hepatitis B. Two
hundred sixty-six patients were originally randomized in a 2:1 ratio to
receive either Viread (300 mg once daily; n=176) or Hepsera (10 mg once
daily; n=90). Baseline characteristics were similar between patients in
both study arms. As with Study 102, after the completion of 48 weeks of
randomized blinded therapy, all eligible patients were offered
open-label Viread monotherapy.
At week 72, 79 percent of patients who were originally randomized to
receive Viread had a virologic response below 400 copies/mL. Among
Hepsera-treated patients who switched to Viread after Week 48, 76
percent achieved HBV DNA below 400 copies/mL by week 72. Through week
72, viral suppression was maintained among all patients who switched to
Viread and who were previously virologically controlled with Hepsera
(n=12). Additionally, rapid viral suppression to less than 400 copies/mL
was achieved by week 72 in 78 percent of viremic Hepsera-treated
patients who switched to Viread after week 48.
At week 72, normal ALT levels were observed in 77 percent of patients
who were originally randomized to receive Viread and 61 percent of
Hepsera-treated patients who switched to Viread.
Among patients for whom seroconversion data was available through week
64, 26 percent of patients who were originally randomized to receive
Viread "e" antigen
seroconverted, compared to 21 percent of Hepsera-treated patients who
switched to Viread. Seroconversion is defined as both the disappearance
of the hepatitis B "e" antigen (HBe-antigen negative), a marker of HBV replication, and the
appearance of antibodies specific for this antigen (HBe-antibody
positive). In addition, 5 percent of patients who were originally
randomized to receive Viread compared to zero percent of Hepsera-treated
patients who switched to Viread after week 48 experienced "s" antigen (HBsAg) loss (p=0.004), which can indicate that a patient has
cleared chronic hepatitis B infection.
As with Study 102, Viread was generally well tolerated. At week 72
treatment-related serious adverse events occurred in 4 percent of
patients who were originally randomized to receive Viread and 7 percent
of Hepsera-treated patients. The incidence of Grade 4 laboratory
abnormalities was comparable in each arm (12 percent versus 11 percent).
Grade 3 laboratory abnormalities, excluding ALT elevations, were 18 and
10 percent, respectively. Grade 3 ALT elevations were 15 and 10 percent
respectively, in the Viread and Hepsera arms. No patient had a confirmed
creatinine clearance of less than 50 mL/minute.
The most common adverse reactions among patients receiving Viread for
chronic hepatitis B in Studies 102 and 103 were headache, diarrhea
vomiting, abdominal pain, nausea, abdominal distension, flatulence, ALT
increase and fatigue.
In terms of resistance surveillance, between weeks 48 and 72 no patients
experienced a loss of virologic response.
Additional Oral Presentations at EASL
Three additional oral presentations, one of which features the first
data to be presented from Study 106, will be highlighted at EASL. Study
106 is an ongoing, randomized, double-blind Phase II study of
individuals with chronic hepatitis B infection randomized in a 1:1 ratio
to receive monotherapy with Viread (n=53) or combination therapy with
Truvada® (emtricitabine
and tenofovir disoproxil fumarate), a fixed-dose combination of Viread
and Emtriva® (emtricitabine) (n=52). At study entry, participants were experiencing
suboptimal virological response (HBV DNA levels greater than or equal to
1,000 copies/mL) with Hepsera therapy (for greater than 24 weeks
but less than 96 weeks). The majority of study participants (58 percent)
had previously been treated with lamivudine and 22 percent (n=23) had
developed resistance mutations to lamivudine or Hepsera.
Through week 48, there were no statistically significant differences
between the Viread and Truvada arms, with 81 percent of patients in both
groups achieving HBV DNA suppression below 400 c/mL. Virologic response
was independent of pre-existing lamivudine or adefovir-associated
mutations. The study is ongoing and will continue to assess the best
long-term treatment strategy for these difficult-to-treat patients.
Also being presented Friday are two sub-set analyses examining the
efficacy of Viread in cirrhotic patients, as well as in
lamivudine-experienced and treatment-naive patients.
Viread for HBV
Viread is currently indicated in combination with other antiretroviral
agents for the treatment of HIV-1 infection in adults and is the
most-prescribed molecule in HIV combination therapy in the United States
and in several European Union nations. On March 19, 2008, the Committee
for Medicinal Products for Human Use (CHMP) of the European Medicines
Agency (EMEA) issued a positive opinion on Gilead´s
application to extend the indication for Viread to
include chronic hepatitis B in adults. The European Commission generally
issues an updated Marketing Authorisation within a few months of a CHMP
recommendation. The product was recently approved for the treatment of
chronic hepatitis B in Turkey and New Zealand, and marketing
applications are currently pending in the United States, Canada and
Australia.
About Chronic Hepatitis
Chronic hepatitis B is caused by the hepatitis B virus (HBV), which is
up to 100 times more easily transmitted than HIV, the AIDS virus.
Chronic hepatitis B is frequently referred to as a "silent
killer" because it can gradually destroy the
liver over the course of years, often without producing symptoms.
Worldwide, an estimated 400 million people are infected with the disease.
About Viread (tenofovir disoproxil
fumarate) for HIV
In the United States, Viread is indicated in combination with other
antiretroviral agents for the treatment of HIV-1 infection.
Lactic acidosis and severe hepatomegaly with steatosis, including fatal
cases, have been reported with the use of nucleoside analogues alone or
in combination with other antiretrovirals. Viread is not approved for
the treatment of chronic hepatitis B virus (HBV) infection and the
safety and efficacy of Viread have not been established in patients
coinfected with HBV and HIV. Severe acute exacerbations of hepatitis B
have been reported in patients who have discontinued Viread. Hepatic
function should be monitored closely with both clinical and laboratory
follow-up for at least several months in patients who are co-infected
with HIV and HBV and discontinue Viread. If appropriate, initiation of
anti-hepatitis B treatment may be warranted.
It is important for patients to be aware that anti-HIV medicines
including Viread do not cure HIV infection or AIDS, and do not reduce
the risk of transmitting HIV to others.
Renal impairment, including cases of acute renal failure and Fanconi
syndrome (renal tubular injury with severe hypophosphatemia), has been
reported in association with the use of Viread. It is recommended that
creatinine clearance be calculated in all patients prior to initiating
therapy with Viread and as clinically appropriate during therapy.
Routine monitoring of calculated creatinine clearance and serum
phosphorous should be performed in patients at risk for renal
impairment. Dosing interval adjustment and close monitoring of renal
function are recommended in all patients with creatinine clearance less
than 50mL/min. Viread should be avoided with concurrent or recent use of
a nephrotoxic agent.
The U.S. package insert advises that co-administration of Viread and
didanosine should be undertaken with caution. Patients should be
monitored closely for didanosine-associated adverse events and
didanosine should be discontinued if these occur. Patients on atazanavir
and lopinavir/ritonavir plus Viread should be monitored for
Viread-associated adverse events and Viread should be discontinued if
these occur. When co-administered with Viread, it is recommended that
atazanavir be given with ritonavir 100 mg. Atazanavir without ritonavir
should not be co-administered with Viread.
Decreases in bone mineral density (BMD) at the lumbar spine and hip have
been seen with the use of Viread. The effect on long-term bone health
and future fracture risk is unknown. Cases of osteomalacia (associated
with proximal renal tubulopathy) have been reported in association with
the use of Viread.
Changes in body fat have been observed in patients taking anti-HIV
medicines. The mechanism and long-term health effect of these changes
are unknown. Immune Reconstitution Syndrome has been reported in
patients treated with combination therapy, including Viread.
The most common adverse events among patients receiving Viread with
other antiretroviral agents in a pivotal clinical study (Study 903) were
mild to moderate gastrointestinal events and dizziness. Moderate to
severe adverse events occurring in more than 5 percent of patients
receiving Viread included rash (rash, pruritis, maculopapular rash
urticaria, vesiculobullous rash and pustular rash), headache, pain
diarrhea, depression, back pain, fever, nausea, abdominal pain, asthenia
(weakness) and anxiety. In another pivotal study (Study 907), less than
1 percent of patients discontinued participation because of
gastrointestinal events.
For full prescribing information outside of the United States
physicians should consult their local product labeling.
About Hepsera (adefovir dipivoxil)
In the United States, 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.
Hepsera is not recommended for use in children less than 12 years of age.
Severe acute exacerbations of hepatitis have been reported in patients
who have discontinued anti-hepatitis B therapy, including Hepsera.
Hepatic function should be closely monitored in both clinical and
laboratory follow-up for at least several months in patients who
discontinue hepatitis B therapy. If appropriate, resumption of therapy
may be warranted. In patients at risk of having underlying renal
dysfunction, chronic administration of Hepsera may result in
nephrotoxicity. These patients should be monitored closely for renal
function and may require dose adjustment. Dose adjustment is recommended
in patients with serum creatinine <50
mL/min. HIV resistance may emerge in chronic hepatitis B patients with
unrecognized or untreated HIV infection treated with anti-hepatitis B
therapies, such as therapy with Hepsera, that may have activity against
HIV. Lactic acidosis and severe hepatomegaly with steatosis, including
fatal cases, have been reported with the use of nucleoside analogs alone
and in combination with other antiretrovirals.
Adverse reactions identified from placebo-controlled and open label
studies include the following: asthenia, headache, abdominal pain
diarrhea, nausea, dyspepsia, flatulence, increased creatinine, and
hypophosphatemia. Additional adverse reactions observed from an
open-label study in pre- and post-transplant patients include abnormal
renal function, renal failure, vomiting, rash and pruritus.
For full prescribing information outside of the United States
physicians should consult their local product labeling.
Viread and Hepsera are the result of a collaborative research effort
between Dr. Antonin Holy, Institute for Organic Chemistry and
Biochemistry, Academy of Sciences of the Czech Republic (IOCB) in Prague
and Dr. Erik DeClercq, Rega Institute for Medical Research, Katholic
University in Leuven, Belgium.
About Truvada (emtricitabine/tenofovir
disoproxil fumarate)
Truvada is a fixed-dose combination tablet containing 200 mg of
emtricitabine (Emtriva) and 300 mg of tenofovir disoproxil fumarate
(Viread). In the United States, Truvada is indicated in combination with
other antiretroviral agents, such as non-nucleoside reverse
transcriptase inhibitors or protease inhibitors, for the treatment of
HIV-1 infection in adults.
Lactic acidosis and severe hepatomegaly with steatosis, including fatal
cases, have been reported with the use of nucleoside analogues alone or
in combination with other antiretrovirals. Truvada is not approved for
the treatment of chronic hepatitis B virus (HBV) infection and the
safety and efficacy of Truvada has not been established in patients
co-infected with HBV. Severe acute exacerbations of hepatitis B have
been reported in patients who have discontinued Emtriva or Viread, the
components of Truvada. Hepatic function should be monitored closely with
both clinical and laboratory follow-up for at least several months in
patients who are co-infected with HBV and discontinue Truvada. If
appropriate, initiation of anti-hepatitis B treatment may be warranted.
It is important for patients to be aware that Truvada does not cure HIV
infection or AIDS and do not reduce the risk of transmitting HIV to
others.
It is not recommended that Truvada be used as a component of a triple
nucleoside regimen. Truvada should not be coadministered with Atripla
Emtriva, Viread or lamivudine-containing products, including Combivir
(lamivudine/zidovudine), Epivir® or Epivir-HBV® (lamivudine), Epzicom? (abacavir sulfate/lamivudine) or Trizivir® (abacavir sulfate/lamivudine/zidovudine). In treatment-experienced
patients, the use of Truvada should be guided by laboratory testing and
treatment history.
For full prescribing information outside of the United States
physicians should consult their local product labeling.
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.
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, Emtriva 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.