Gilead Sciences (Nasdaq:GILD) today announced Phase 3b clinical trial
results from STaR (Single Tablet
Regimen), the first head-to-head study
comparing the single tablet regimens Complera®
(emtricitabine/rilpivirine/tenofovir disoproxil fumarate) and Atripla®
(efavirenz/emtricitabine/tenofovir disoproxil fumarate) in
treatment-naïve adults with HIV infection. Data demonstrated that
Complera, which is marketed as Eviplera® in the European
Union, is non-inferior to Atripla based on the proportion of patients
with HIV RNA levels (viral load) < 50 copies/mL at 48 weeks.
Complera demonstrated a statistically significant difference in efficacy
compared to Atripla among patients with low baseline viral load (?
100,000 copies/mL), and was non-inferior to Atripla among patients with
high baseline viral load (> 100,000 copies/mL). Notably, the virologic
failure rate was low and comparable between Complera and Atripla,
including among patients with baseline viral load up to 500,000
copies/mL. In addition, Complera was well-tolerated with fewer adverse
events across all grades and fewer discontinuations due to adverse
events (3 percent versus 9 percent; p<0.001) in the Complera and Atripla
arms, respectively. These results were presented today in an oral
session at the 11th International Congress on Drug Therapy in HIV
Infection (HIV11) in Glasgow, United Kingdom.
"Since its U.S. approval in 2006, Atripla has become a standard of HIV
care, so the rate of viral suppression demonstrated by Complera in this
study is impressive," said Calvin J. Cohen, MD, M.Sc., Director of
Research, Community Research Initiative of New England and principal
investigator of the STaR study. "Further, these data reinforce the
tolerability profile of Complera and support its role as an important
single tablet treatment option for many HIV patients new to therapy."
At week 48, 86 percent of patients taking Complera (n=338/394) compared
to 82 percent of patients taking Atripla (n=320/392) achieved HIV RNA
levels < 50 copies/mL based on the U.S. Food and Drug Administration
(FDA) snapshot algorithm (95 percent CI for the difference: -1.1 percent
to +9.2 percent; predefined criterion for non-inferiority was the lower
bound of a two-sided 95 percent CI of -12 percent). Among patients with
baseline viral load ? 100,000 copies/mL, 89 percent of Complera patients
(n=231/260) compared to 82 percent of Atripla patients (n=204/250)
achieved viral suppression to < 50 copies/mL (95 percent CI for the
difference: 1.1 percent to 13.4 percent). Among patients with baseline
viral load > 100,000 copies/mL, 80 percent of Complera patients
(n=107/134) and 82 percent of Atripla patients (n=116/142) achieved
viral suppression to < 50 copies/mL (95 percent CI for the difference:
-11.1 percent to 7.5 percent).
Virologic failure per snapshot algorithm was defined as patients failing
to achieve viral load < 50 copies/mL at week 48, or discontinuing study
drug prior to this time point due to lack of efficacy, or discontinuing
study drug for other reasons and with last available viral load showing
? 50 copies/mL. Virologic failure rates for Complera and Atripla were,
respectively, 5 percent and 3 percent for patients with viral load ?
100,000 copies/mL; 10 percent and 9 percent for patients with viral load
> 100,000 to 500,000 copies/mL; and 25 percent and 16 percent for
patients with viral load > 500,000 copies/mL.
Complera was approved in the United States in August 2011 and is
indicated for use as a complete regimen for treatment-naïve adults with
HIV-1 infection. Complera combines Gilead's Truvada®
(emtricitabine and tenofovir disoproxil fumarate) with Janssen R&D
Ireland's rilpivirine (marketed as Edurant®). In previous
studies, more rilpivirine-treated patients with viral load > 100,000
copies/mL at the start of therapy experienced virologic failure compared
to those with viral load < 100,000 copies/mL. Complera has
Boxed Warnings of lactic acidosis/severe hepatomegaly with steatosis and
post treatment acute exacerbation of hepatitis B; see below for
important safety information.
Complera received marketing authorization from the European Commission
as Eviplera in November 2011, becoming the first single tablet regimen
approved for patients new to HIV therapy in Europe. In November 2012,
Eviplera was added to European AIDS Clinical Society (EACS) treatment
guidelines as a recommended regimen for treatment-naïve HIV patients.
STaR (Study 110) is an ongoing, randomized (1:1), open-label Phase 3b
study evaluating the efficacy and safety of Complera (n=394 treated)
compared to Atripla (n=392 treated) among treatment-naïve HIV-positive
adults with baseline HIV RNA levels ? 2,500 copies/mL. The primary
objective of the study is to evaluate the non-inferiority, at a 12
percent margin, of Complera compared to Atripla in achieving HIV RNA
levels < 50 copies/mL through 48 weeks of therapy, based on the FDA
snapshot algorithm. Secondary endpoints include safety and efficacy of
change from baseline in CD4 cell count at weeks 48 and 96 of therapy,
and development of genotypic and phenotypic resistance at the time of
virologic failure. Randomization was stratified by baseline HIV RNA
levels (? or > 100,000 copies/mL).
Baseline mean CD4 cell counts were 396 cells/mm3 for Complera
patients and 385 cells/mm3 for Atripla patients, and baseline
HIV RNA levels were 4.8 log10 copies/mL in both treatment
arms. In the Complera and Atripla arms, respectively, at baseline, 66
and 64 percent of patients had HIV RNA levels of ? 100,000 copies/mL, 25
percent and 30 percent had HIV-1 RNA levels between 300,000 and 500,000
copies/mL, and 9 percent and 6 percent had HIV-1 RNA levels > than
At week 48, changes in CD4 cell counts were +200 cells/mm3
for patients taking Complera and +191 cells/mm3 for patients
taking Atripla (p=0.34). The overall virologic failure rate per snapshot
algorithm was similar in both treatment arms (8 percent for Complera and
6 percent for Atripla).
Seven percent (n=29) and 14 percent (n=54) of patients in the Complera
and Atripla arms, respectively, experienced a Grade 3 or 4 adverse
event. The most common treatment-related adverse events occurring in
more than 5 percent of Complera patients were headache, insomnia,
dizziness, depression, abnormal dreams, anxiety and somnolence.
Laboratory abnormalities (Grade 3-4) occurring in at least one percent
of patients in either treatment arm included neutrophils, ALT, AST, GGT,
amylase, creatine kinase, hyperglycemia, total cholesterol, glycosuria
and hematuria. Only creatine kinase occurred in more than 5 percent of
patients (5.1 percent in both arms).
Complera patients experienced lower mean increases compared to Atripla
patients in fasting total cholesterol (1 vs. 22 mg/dL) and LDL (1 vs. 14
mg/dL) (p<0.001 for both tests). HDL increased by an average of 2 mg/dL
in the Complera arm vs. 8 mg/dL in the Atripla arm (p<0.001).
Triglycerides decreased by an average of 8 mg/dL among Complera patients
and increased by 8 mg/dL among Atripla patients at 48 weeks (p<0.001).
The ratio of total cholesterol to HDL declined by an average of 0.2 in
both treatment arms.
The mean change in estimated glomerular filtration rate (GFR) by
Cockcroft-Gault at week 48 was -5.4 mL/min for the Complera arm and +4.6
mL/min for the Atripla arm (p<0.001). Resistance mutations were observed
in 4 percent of patients taking Complera and 1 percent of patients
Complera Important Product Safety Information
WARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST
TREATMENT ACUTE EXACERBATION OF HEPATITIS B
Lactic acidosis and severe hepatomegaly with steatosis, including
fatal cases, have been reported with the use of nucleoside analogs,
including tenofovir disoproxil fumarate, a component of Complera, in
combination with other antiretrovirals.
Complera is not approved for the treatment of chronic hepatitis B
virus (HBV) infection and the safety and efficacy of Complera have not
been established in patients coinfected with HBV and HIV-1. Severe acute
exacerbations of hepatitis B have been reported in patients who are
coinfected with HBV and HIV-1 and have discontinued Emtriva or Viread,
which are components of Complera. Hepatic function should be monitored
closely with both clinical and laboratory follow-up for at least several
months in patients who are coinfected with HIV-1 and HBV and discontinue
Complera. If appropriate, initiation of anti-hepatitis B therapy may be
Complera should not be co-administered with the following drugs, as
significant decreases in rilpivirine plasma concentrations may occur due
to CYP3A enzyme induction or gastric pH increase, which may result in
loss of virologic response and possible resistance to Complera or to the
class of NNRTIs:
the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital,
the antimycobacterials rifabutin, rifampin, rifapentine
proton pump inhibitors, such as esomeprazole, lansoprazole,
omeprazole, pantoprazole, rabeprazole
the glucocorticoid systemic dexamethasone (more than a single dose)
St John's wort (Hypericum perforatum)
WARNINGS AND PRECAUTIONS
New onset or worsening renal impairment
including cases of acute renal failure and Fanconi syndrome (renal
tubular injury with severe hypophosphatemia), has been reported with
the use of tenofovir disoproxil fumarate. Assess creatinine clearance
(CrCl) before initiating treatment with Complera. Monitor CrCl and
serum phosphorus in patients at risk for renal impairment, including
patients who have previously experienced renal events while receiving
Hepsera® (adefovir dipivoxil). Avoid administering Complera with
concurrent or recent use of nephrotoxic drugs. Patients with CrCl
below 50 mL per minute should not receive Complera.
Complera should be used with caution
when given with drugs that may reduce the exposure of rilpivirine.
should be used with caution when co-administered with a drug with a
known risk of Torsade de Pointes.
The adverse reaction depressive
disorders (depressed mood, depression, dysphoria, major depression,
mood altered, negative thoughts, suicide attempt, suicidal ideation)
has been reported with rilpivirine. During the Phase 3 trials (N =
1,368), the incidence of depressive disorders (regardless of
causality, severity) reported among rilpivirine (N = 686) or efavirenz
(N = 682) was 8% and 6%, respectively. Most events were mild or
moderate in severity. The incidence of Grade 3 and 4 depressive
disorders (regardless of causality) was 1% for both rilpivirine and
efavirenz. The incidence of discontinuation due to depressive
disorders among rilpivirine or efavirenz was 1% in each arm. Suicide
attempt was reported in 2 subjects in the rilpivirine arm while
suicide ideation was reported in 1 subject in the rilpivirine arm and
in 3 subjects in the efavirenz arm. Patients with severe depressive
symptoms should seek immediate medical evaluation to assess the
possibility that the symptoms are related to Complera, and if so, to
determine whether the risks of continued therapy outweigh the benefits.
Decreases in bone mineral density
Bone mineral density
(BMD) monitoring should be considered for patients who have a history
of pathologic bone fracture or other risk factors for osteoporosis or
bone loss. Cases of osteomalacia (associated with proximal renal
tubulopathy and which may contribute to fractures) have been reported
in association with the use of tenofovir disoproxil fumarate.
Co-administration with other products
Complera should not
be administered concurrently with other medicinal products containing
any of the same active components, emtricitabine, rilpivirine, or
tenofovir disoproxil fumarate (Emtriva, Edurant, Viread, Truvada,
Atripla), with medicinal products containing lamivudine (Epivir,
Epivir-HBV, Epzicom, Combivir, Trizivir), or with adefovir dipivoxil
Redistribution/accumulation of body fat
has been observed in patients receiving antiretroviral therapy.
Immune reconstitution syndrome
syndrome has been reported in patients treated with combination
antiretroviral therapy, including the components of Complera. Further
evaluation and treatment may be necessary. Autoimmune disorders may
occur in the setting of immune reconstitution.
The most common adverse drug reactions to rilpivirine (incidence greater
than or equal to 2%, Grades 2-4) were insomnia and headache.
The most common adverse drug reactions to emtricitabine and tenofovir
disoproxil fumarate (incidence ? 10%) were diarrhea, nausea, fatigue,
headache, dizziness, depression, insomnia, abnormal dreams, and rash.
Complera should not be used with drugs where significant decreases in
rilpivirine plasma concentrations may occur (See CONTRAINDICATIONS).
Complera is a complete regimen for the treatment of HIV-1 infection;
therefore Complera should not be administered with other
antiretroviral medications for the treatment of HIV-1 infection.
Drugs inducing or inhibiting CYP3A enzymes: Rilpivirine is
primarily metabolized by cytochrome P450 (CYP) 3A, and drugs that
induce or inhibit CYP3A may thus affect the clearance of rilpivirine.
Coadministration of rilpivirine and drugs that induce CYP3A may result
in decreased plasma concentrations of rilpivirine and loss of
virologic response and possible resistance to rilpivirine or to the
class of NNRTIs. Coadministration of rilpivirine and drugs that
inhibit CYP3A may result in increased plasma concentrations of
Drugs increasing gastric PH: Coadministration of rilpivirine
with drugs that increase gastric pH may decrease plasma concentrations
of rilpivirine and loss of virologic response and possible resistance
to rilpivirine or to the class of NNRTIs.
Drugs affecting renal function: Since emtricitabine and
tenofovir are primarily eliminated by the kidneys, coadministration of
Complera with drugs that reduce renal function or compete for active
tubular secretion may increase serum concentrations of emtricitabine,
tenofovir, and/or other renally eliminated drugs. Some examples
include, but are not limited to, acyclovir, adefovir dipivoxil,
cidofovir, ganciclovir, valacyclovir and valganciclovir.
QT prolonging drugs: There is limited information available on
the potential for a pharmacodynamic interaction between rilpivirine
and drugs that prolong the QTc interval of the electrocardiogram. In a
study of healthy subjects, supratherapeutic doses of rilpivirine (75
mg once daily and 300 mg once daily) have been shown to prolong the
QTc interval of the electrocardiogram. Complera should be used with
caution when coadministered with a drug with a known risk of Torsade
DOSAGE AND ADMINISTRATION
Adults: The recommended dose of Complera is one tablet taken
orally once daily with a meal.
Renal Impairment: Because Complera is a fixed-dose combination,
it should not be prescribed for patients requiring dose adjustment such
as those with moderate or severe renal impairment (creatinine clearance
below 50 mL per minute).
Complera is indicated for use as a complete regimen for the treatment of
HIV-1 infection in antiretroviral treatment-naïve adults. This
indication is based on Week 48 safety and efficacy analyses from 2
randomized, double-blind, active controlled, Phase 3 trials in
treatment-naïve subjects comparing rilpivirine to efavirenz.
The following points should be considered when initiating therapy with
More rilpivirine-treated subjects with HIV-1 RNA greater than 100,000
copies/mL at the start of therapy experienced virologic failure
compared to subjects with HIV-1 RNA less than 100,000 copies/mL at the
start of therapy
The observed virologic failure rate in rilpivirine-treated subjects
conferred a higher rate of overall treatment resistance and
cross-resistance to the NNRTI class compared to efavirenz
More subjects treated with rilpivirine developed
lamivudine/emtricitabine associated resistance compared to efavirenz
Complera is not recommended for patients less than 18 years of age.
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 Asia
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 risk
that healthcare providers may not recognize the benefits of starting HIV
patients new to therapy on Complera. In addition, as Complera is used
over longer periods of time by many patients with underlying health
problems taking numerous other medicines, Gilead may find new issues
such as safety, resistance or drug interaction issues, which may require
it to provide additional warnings or contraindications on the label or
narrow Complera's approved indication, each of which could reduce the
market acceptance of Complera. 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 Quarterly Report on Form 10-Q for
the quarter ended September 30, 2012, 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 Complera is available at www.Complera.com
full prescribing information for Atripla is available at www.Atripla.com
full prescribing information for Truvada is available at www.Truvada.com
EU Summary of Product Characteristics for Atripla, Eviplera and
Truvada are available at www.ema.europa.eu
Complera, Eviplera and Truvada are registered trademarks of Gilead
Atripla is a registered trademark of Bristol-Myers Squibb & Gilead
Edurant is a registered trademark of Janssen R&D Ireland.
For more information on Gilead Sciences, please visit the company's
website at www.gilead.com,
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at 1-800-GILEAD-5 or 1-650-574-3000.
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+44 (208) 587-2359