Gilead Sciences, Inc. (Nasdaq: GILD) today announced the
presentation of new data from the Phase III ARIES studies evaluating
ambrisentan in patients with pulmonary arterial hypertension (PAH) at
CHEST 2007, the annual meeting of the American College of Chest
Physicians, taking place in Chicago, Illinois, October 20-25.
Ambrisentan is an ETA-selective endothelin receptor antagonist (ERA)
that was recently granted accelerated approval under the tradename
Letairis(TM) (ambrisentan 5 mg and 10 mg tablets) by the U.S. Food and
Drug Administration (FDA). Letairis is indicated as a once-daily
treatment for PAH (WHO Group 1) in patients with WHO Class II or III
symptoms to improve exercise capacity and delay clinical worsening.
"PAH is a progressive, life-threatening disease and fortunately
tremendous research progress has been made over the last two decades,"
said Ronald J. Oudiz, MD, Associate Professor of Medicine, David
Geffen School of Medicine at UCLA and Director, Liu Center for
Pulmonary Hypertension, Los Angeles Biomedical Research Institute at
Harbor-UCLA Medical Center. "It's encouraging that new therapies such
as ambrisentan have become available to treat this serious disease."
In an oral session, Dr. Oudiz presented long-term data (mean
exposure = 71 weeks; maximum exposure = 148 weeks) from an integrated
analysis of 383 patients with idiopathic PAH (IPAH) or PAH associated
with connective tissue disease (PAH-CTD), HIV infection or anorexigen
use who received at least one dose of ambrisentan (2.5, 5 or 10 mg
once-daily) in one of the 12-week Phase III placebo-controlled studies
(ARIES-1 or ARIES-2) or in the long-term extension study for ARIES-1
and ARIES-2 (ARIES-E). Patients who received ambrisentan in ARIES-1 or
ARIES-2 remained on their current dose in ARIES-E. Patients who
received placebo during previous studies were randomized to
ambrisentan (ARIES-1: 5 or 10 mg; ARIES-2: 2.5 or 5 mg) in ARIES-E.
Efficacy and safety assessments were measured from the time of first
dose of ambrisentan. This analysis represents data available as of
November 2006.
At baseline, approximately 89 percent of patients were classified
as having WHO Class II or III symptoms. Baseline six-minute walk
distance (6MWD) for patients in the 2.5, 5 and 10 mg groups were
350+/-87 m, 348+/-87 m and 342+/-81 m, respectively. Patients in the
2.5, 5 and 10 mg groups had baseline Borg dyspnea index (BDI) scores
of 4.1+/-2.7, 3.8+/-2.3 and 2.8+/-2.1, respectively.
Improvements in the non placebo-adjusted 6MWD observed at week 12
for the 2.5, 5 and 10 mg groups (32+/-6.1 m, 36+/-5.7 m and 39+/-6.1
m, respectively) were maintained through week 48 of treatment
(34+/-10.9 m, 41+/-7.9 m and 46+/-7.7 m, respectively). Improvements
in WHO functional class and BDI were also maintained with long-term
ambrisentan treatment. In addition, 95 percent of patients were still
alive at one year of treatment with ambrisentan (95 percent CI: 93-97
percent), based on a Kaplan-Meier analysis.
The one-year risk of liver enzyme (aminotransferase) elevations
greater than three times the upper limit of normal (ULN) for this
Phase III study population was 2.1 percent, which was similar to the
incidence observed for the placebo groups (2.3 percent) in the 12-week
ARIES-1 and ARIES-2 studies. Adverse events in patients receiving
ambrisentan were similar in nature to those reported in the previous
12-week placebo-controlled studies, and included peripheral edema,
headache, upper respiratory tract infection and dizziness. The most
common adverse event was peripheral edema which was reported to be
mild or moderate.
In a second oral presentation, David Badesch, MD, Professor of
Medicine and Clinical Director of the Pulmonary Hypertension Center at
the University of Colorado Health Sciences Center, presented results
from an integrated analysis of the 12-week ARIES-1 and ARIES-2 studies
comparing the safety and efficacy of ambrisentan in patients with IPAH
and PAH-CTD.
In this subgroup analysis, patients with IPAH (n=251) and PAH-CTD
(n=124) received placebo, 2.5, 5 or 10 mg ambrisentan once-daily.
Baseline 6MWD for patients in the IPAH placebo and ambrisentan groups
were 343+/-81 m and 352+/-78 m, respectively. Baseline 6MWD for
patients in the PAH-CTD placebo and ambrisentan groups were 340+/-76 m
and 332+/-84 m, respectively. Patients in the IPAH placebo and
ambrisentan groups had baseline BDI scores of 4.0+/-2.2 and 3.9+/-2.2,
respectively. Patients in the PAH-CTD placebo and ambrisentan groups
had baseline BDI scores of 3.6+/-2.1 and 3.8+/-2.4, respectively.
Improvements in 6MWD at week 12 compared to placebo were observed
for the PAH-CTD subgroup (+19+/-14.8 m; p=0.056) and IPAH subgroup
(+58+/-10.8 m; p less than 0.001), but appeared greater for the IPAH
subgroup. For PAH-CTD patients receiving the FDA-approved doses of 5
or 10 mg (n=62), an improvement of 25+/-14.2 m (p=0.020) in 6MWD was
observed.
Improvements in dyspnea, as measured by the BDI at week 12
compared to placebo, were similar for the IPAH (-0.8+/-0.30; p=0.011)
and PAH-CTD (-1.0+/-0.39; p=0.038) subgroups. WHO functional class
deterioration was similar at week 12 for the IPAH and PAH-CTD
subgroups receiving ambrisentan (3.6 percent and 3.7 percent,
respectively) and was less than that observed in the placebo group
(16.5 percent and 20.9 percent, respectively).
No patients receiving ambrisentan had aminotransferase elevations
greater than three times ULN during this 12-week treatment period
compared to three placebo patients who had IPAH. The incidence of
peripheral edema was greater among patients receiving ambrisentan than
among patients receiving placebo in both the IPAH and PAH-CTD
subgroups, but the placebo-adjusted incidences were similar (6.9
percentage points and 5.8 percentage points, respectively).
"In this study, consistent trends in increased exercise capacity,
decreased dyspnea and less WHO functional class deterioration were
observed with ambrisentan treatment compared to placebo in both the
IPAH and PAH-CTD subgroups," said Dr. Badesch. "These data indicate
that ambrisentan may be a viable treatment for these patient
populations."
WARNING: POTENTIAL LIVER INJURY
Letairis can cause elevation of liver aminotransferases (ALT and
AST) to at least three times the upper limit of normal (ULN). Letairis
treatment was associated with aminotransferase elevations greater than
three times ULN in 0.8 percent of patients in 12-week trials and 2.8
percent of patients including long-term open-label trials out to one
year. One case of aminotransferase elevations greater than three times
ULN has been accompanied by bilirubin elevations greater than two
times ULN. Because these changes are a marker for potentially serious
liver injury, serum aminotransferase levels (and bilirubin if
aminotransferase levels are elevated) must be measured prior to
initiation of treatment and then monthly.
Elevations in aminotransferases require close attention. Letairis
should generally be avoided in patients with elevated
aminotransferases greater than three times ULN at baseline because
monitoring liver injury may be more difficult. If liver
aminotransferase elevations are accompanied by clinical symptoms of
liver injury (such as nausea, vomiting, fever, abdominal pain,
jaundice, or unusual lethargy or fatigue) or increases in bilirubin
greater than two times ULN, treatment should be stopped. There is no
experience with the re-introduction of Letairis in these
circumstances.
CONTRAINDICATION: PREGNANCY
Letairis is very likely to produce serious birth defects if used
by pregnant women, as this effect has been seen consistently when it
is administered to animals. Pregnancy must therefore be excluded
before the initiation of treatment with Letairis and prevented
thereafter by the use of at least two reliable methods of
contraception unless the patient is unable to become pregnant. In
women who can become pregnant, pregnancy tests should be obtained
monthly.
About the Letairis Education and Access Program (LEAP)
Because of the risks of liver injury and birth defects, Letairis
is available only through a special restricted distribution program
called the Letairis Education and Access Program (LEAP) by calling
1-866-664-LEAP (1-866-664-5327). Only prescribers and pharmacies
registered with LEAP are able to prescribe and distribute Letairis. In
addition, Letairis may be dispensed only to patients who are enrolled
in and meet all conditions of LEAP.
Important Safety Information
The most common adverse events that occurred at a higher frequency
among Letairis-treated patients compared to placebo included
(placebo-adjusted frequency): peripheral edema (6 percent), nasal
congestion (4 percent), sinusitis (3 percent), flushing (3 percent),
palpitations (3 percent), nasal pharyngitis (2 percent), abdominal
pain (2 percent), constipation (2 percent), dyspnea (1 percent) and
headache (1 percent).
Elevations of liver aminotransferases have been reported with
Letairis and serious liver injury has been reported with related
drugs. Patients should be monitored monthly for liver
aminotransferases and treatment with Letairis should be discontinued
if greater than five times the upper limit of normal or if signs or
symptoms of liver dysfunction are observed.
Letairis is not recommended in patients with moderate to severe
hepatic impairment. For women of childbearing potential, Letairis
treatment should only be initiated after a negative pregnancy test and
only in those using at least two reliable methods of contraception.
Decreases in hemoglobin concentration and hematocrit have followed
administration of other endothelin receptor antagonists and were
observed in clinical studies with Letairis. These decreases were
observed within the first few weeks of treatment with Letairis, and
stabilized thereafter.
Peripheral edema is a known class effect of endothelin receptor
antagonists and is also a clinical consequence of PAH and worsening
PAH. In the placebo-controlled studies, there was an increased
incidence of peripheral edema in patients treated with doses of 5 or
10 mg of Letairis compared to placebo. Most edema was mild to moderate
in severity. Peripheral edema was similar in younger patients (age
less than 65 years) receiving Letairis (14 percent; 29/205) or placebo
(13 percent; 13/104), and was greater in elderly patients (age greater
than or equal to 65 years) receiving Letairis (29 percent; 16/56)
compared to placebo (4 percent, 1/28). The results of such subgroup
analyses must be interpreted cautiously.
Caution should be used when Letairis is co-administered with
cyclosporine A, as it may cause increased exposure to Letairis.
Caution should be used when Letairis is co-administered with
strong CYP3A-inhibitors (e.g., ketoconazole) or CYP2C19-inhibitors
(e.g., omeprazole).
No clinically relevant interactions of Letairis with warfarin or
sildenafil have been observed.
About Letairis
Letairis (ambrisentan) is an endothelin receptor antagonist that
is selective for the endothelin type-A (ETA) receptor. Activation of
the ETA receptor by endothelin, a small peptide hormone, leads to
vasoconstriction (narrowing of blood vessels) and cell proliferation.
The clinical impact of high selectivity for ETA is not known. PAH is
associated with elevated endothelin blood levels.
GlaxoSmithKline holds rights to commercialize ambrisentan for PAH
in territories outside of the United States. A Marketing Authorisation
Application (MAA) for ambrisentan was filed with the European
Medicines Agency (EMEA) earlier this year.
About Pulmonary Arterial Hypertension
PAH is a debilitating disease characterized by constriction of the
blood vessels in the lungs leading to high pulmonary arterial
pressures. These high pressures make it difficult for the heart to
pump blood through the lungs to be oxygenated. Patients with PAH
suffer from shortness of breath as the heart struggles to pump against
these high pressures, causing such patients to ultimately die of heart
failure. PAH can occur with no known underlying cause, or it can occur
secondary to diseases such as connective tissue disease, congenital
heart defects, cirrhosis of the liver and HIV infection. PAH afflicts
approximately 200,000 patients worldwide.
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
risk that further data from additional clinical studies may indicate
that ambrisentan is not a viable treatment for patients in both the
IPAH and PAH-CTD subgroups. 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, 2006 and its Quarterly Reports on Form 10-Q
for the first and second quarters of 2007, 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.
Full prescribing information for Letairis is available at
www.gilead.com and at
http://www.letairis.com/downloads/LETAIRIS_prescribing_information.pdf
Letairis is a trademark of Gilead Sciences, Inc.
For more information on Gilead Sciences, please visit the
company's website at www.gilead.com or call Gilead Public Affairs at
1-800-GILEAD-5 or 1-650-574-3000.
