Gilead’s Complera® Non-Inferior to Atripla® Among Treatment-Naïve HIV
-- STaR Study Findings Support Complera as an Important Single Tablet Regimen
GLASGOW, England -- November 15, 2012
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/mm^3 for Complera patients and
385 cells/mm^3 for Atripla patients, and baseline HIV RNA levels were 4.8
log 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 500,000 copies/mL.
At week 48, changes in CD4 cell counts were +200 cells/mm^3 for patients
taking Complera and +191 cells/mm^3 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 taking Atripla.
Complera Important Product Safety Information and Indication
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
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 warranted.
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
*the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin
*the antimycobacterials rifabutin, rifampin, rifapentine
*proton pump inhibitors, such as esomeprazole, lansoprazole, omeprazole,
*the glucocorticoid systemic dexamethasone (more than a single dose)
*St John’s wort (Hypericum perforatum)
WARNINGS AND PRECAUTIONS
*New onset or worsening renal impairment
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.
Complera 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
Immune reconstitution 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 rilpivirine.
*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
*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 de Pointes.
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
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
*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 Pacific.
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
U.S. full prescribing information for Atripla is available at www.Atripla.com
U.S. 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 Sciences,
Atripla is a registered trademark of Bristol-Myers Squibb & Gilead Sciences,
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, follow Gilead on Twitter (@GileadSciences) or call Gilead
Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.
Patrick O’Brien, Investors, +1 650-522-1936
Cara Miller, Media (U.S.), +1 650-522-1616
Stephen Head, Media (Europe), +44 (208) 587-2359
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