Gilead Announces Two-Year Clinical Data for Letairis® (ambrisentan) for the Treatment of Pulmonary Arterial Hypertension (WH...
October 28 2008 - 12:00PM
Business Wire
Gilead Sciences, Inc. (Nasdaq:GILD) today announced results of a
two-year (104-week), open-label, uncontrolled, extension study
(ARIES-E) of Letairis� in patients with pulmonary arterial
hypertension (PAH) (WHO Group 1). Data from this study were
presented today at CHEST 2008, the annual meeting of the American
College of Chest Physicians, taking place in Philadelphia, October
25-30. Letairis (ambrisentan 5 mg and 10 mg tablets) is indicated
as a once-daily treatment for PAH (WHO Group 1) in patients with
WHO functional class II or III symptoms to improve exercise
capacity and delay clinical worsening. This pre-specified analysis
was designed to evaluate long-term safety and efficacy in patients
with PAH who received 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 during the subsequent open-label extension study
(ARIES-E). In an oral session, safety and efficacy data were
presented for patients taking ambrisentan for up to two years,
including results describing improvements from baseline in
six-minute walk distance (6MWD) at two years. �As a chronic,
progressive disease, it is important that PAH therapies are
evaluated over the long term to better characterize safety and
efficacy,� 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 and a principal
investigator in the ARIES studies. �This is the first time
prospectively collected two-year clinical trial safety and efficacy
data have been presented evaluating an endothelin receptor
antagonist (ERA) therapy in PAH.� The ARIES-E study included 383
patients with idiopathic PAH (IPAH) or PAH associated with
connective tissue disease (PAH-CTD), HIV infection or anorexigen
use. Long-term safety was the primary endpoint of ARIES-E and
safety and efficacy assessments were analyzed from the time of
first dose of ambrisentan. Patients who received ambrisentan in
ARIES-1 or ARIES-2 were enrolled into ARIES-E at their originally
randomized dose. 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. Patients entered into ARIES-E and
at two years, 261 randomized patients remained on ambrisentan, 22
had transitioned to commercial Letairis therapy (ambrisentan
exposure prior to transition ranged from 75-102 weeks), and 100
discontinued due to death, adverse events or other reasons. At two
years, 82 percent (n=215) of the 261 patients were on ambrisentan
monotherapy. At baseline, approximately 89 percent of patients were
classified as having WHO functional class II or III symptoms and
the mean baseline 6MWD for patients was 347�85 m. The mean baseline
Borg dyspnea index score (BDI), a measure of breathing ability, was
3.9�2.4. Patients receiving the FDA-approved 5 and 10 mg
ambrisentan doses experienced mean improvements from baseline in
6MWD of 34.6 m (95 percent CI: 23.6 m to 45.7 m) and 37.5 m (95
percent CI: 25.4 m to 49.6 m), respectively, at 12 weeks and mean
improvements of 23.2�m (95 percent CI: 8.7 m to 37.8 m) and 28.0 m
(95 percent CI: 10.9 m to 45.1 m), respectively, at two years. The
95 percent confidence intervals for mean change from baseline in
6MWD remained above zero for both the 5 and 10 mg doses at all
points during the study period, indicating that a mean improvement
from baseline in 6MWD was observed through two years of treatment.
The probability of no clinical worsening at two years was 72
percent (95 percent CI: 67-76 percent). Clinical worsening was
defined as death, lung transplantation, PAH hospitalization, atrial
septostomy, addition of prostanoid therapy or study withdrawal due
to addition of other PAH drugs. In addition, 88 percent of patients
receiving ambrisentan were still alive at two years, as assessed by
Kaplan-Meier estimates (95 percent CI: 83-91 percent). As study
ARIES-E is uncontrolled, these findings do not allow for comparison
with a group not given ambrisentan and cannot be used to
definitively determine the long-term effect of ambrisentan on
survival. During the initial 12-week ARIES-1 and ARIES-2 studies,
none of the 261 patients on ambrisentan experienced liver enzyme
(aminotransferase) elevations greater than three times the upper
limit of normal (ULN) compared to 2.3 percent of patients on
placebo. In the Letairis full prescribing information, for all
Letairis-treated patients (n=483), the 12-week incidence of
aminotransferases greater than three times ULN was 0.8 percent. At
two years in ARIES-E, Kaplan-Meier analyses estimated the
probability of experiencing aminotransferase elevations greater
than three times ULN to be 4.2 percent. A total of three patients
taking ambrisentan had aminotransferase elevations greater than
five times ULN during the two-year treatment period, two of whom
discontinued treatment. One patient discontinued ambrisentan due to
aminotransferase elevations greater than three times ULN. The
two-year safety profile of ambrisentan was similar in nature to
that reported in the previous 12-week placebo-controlled studies.
The most frequent adverse events in patients receiving ambrisentan
were peripheral edema, headache, upper respiratory tract infection
and dizziness. Most reports of peripheral edema were reported to be
mild or moderate, with one case leading to study discontinuation.
Additional Data Presented at CHEST Three additional ambrisentan
data sets are being presented for the first time at CHEST. These
include data presented during an oral session today from a post-hoc
analysis evaluating clinical outcomes of patients who experienced
edema during the ARIES-1 and ARIES-2 studies. On Wednesday, October
29, two additional abstracts will be presented during a poster
session, including an analysis from the ARIES-3 study evaluating
ambrisentan use in a subpopulation of patients with pulmonary
hypertension who had previously discontinued bosentan or
sitaxsentan due to liver function abnormalities. A study evaluating
pharmacokinetic interactions between ambrisentan and tadalafil also
will be presented. Full prescribing information for Letairis is
available at www.gilead.com and at
http://www.letairis.com/downloads/LETAIRIS_prescribing_information.pdf
. 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. Obtain monthly pregnancy tests. 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 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. In
addition, there have been post-marketing reports of fluid retention
in patients with pulmonary hypertension, occurring within weeks
after starting Letairis. Patients required intervention with a
diuretic, fluid management, or, in some cases, hospitalization for
decompensating heart failure. Because the post-marketing experience
was reported voluntarily from a population of uncertain size, it is
not possible to reliably estimate the relative frequency or
establish a causal relationship to Letairis drug exposure. 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). 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). No clinically
relevant interactions of Letairis with warfarin or sildenafil have
been observed. Letairis is not recommended in patients with
moderate to severe hepatic impairment. About Letairis Letairis
(ambrisentan) is an endothelin receptor antagonist that has a high
affinity for the endothelin type-A (ETA) receptor. Activation of
the ETA receptor by endothelin-1 (ET-1), 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. Endothelin concentrations are higher in the lung tissue
of PAH patients, thus suggesting that ET-1 may play a critical role
in the pathogenesis or progression of PAH. About Pulmonary Arterial
Hypertension (WHO Group 1) 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 risks that
the safety and efficacy data obtained through 104 weeks of the
ARIES-E study will 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 second quarter 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. Letairis
is a registered 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.
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