Gilead Sciences, Inc. (Nasdaq:GILD) today announced results of a
post-hoc analysis of data collected during the ARIES-1, ARIES-2 and
ARIES-E studies for Letairis® in pulmonary arterial hypertension (PAH) (WHO Group 1) patients with
primarily WHO functional class II or III symptoms. This analysis
compared one-year clinical outcomes for PAH (WHO Group 1) patients who
initially received placebo during the 12-week, placebo-controlled
ARIES-1 and ARIES-2 studies before receiving ambrisentan during a
long-term, open-label extension study (ARIES-E) to patients receiving
continuous ambrisentan treatment throughout the ARIES studies. Data from
this analysis were presented by Vallerie McLaughlin, MD, Associate
Professor of Medicine, Director, Pulmonary Hypertension Program at the
University of Michigan Health System, at ATS 2008 - Toronto, the International Conference of the American Thoracic Society
taking place May 16-21. 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. ARIES-1 and ARIES-2 were concurrent, double-blind, placebo-controlled
studies evaluating ambrisentan in PAH patients. The studies primarily
enrolled PAH patients with WHO functional class II or III symptoms.
These studies were identical in design except for the investigative
sites and doses of ambrisentan evaluated (ARIES-1: 5 or 10 mg; ARIES-2:
2.5 or 5 mg). In each study, patients were randomized to receive placebo
or ambrisentan orally once daily for 12 weeks. The primary endpoint for
each study was change in six-minute walk distance (6MWD) from baseline
to week 12. Following 12 weeks of treatment, patients continued
treatment with ambrisentan (ABS/ABS group, n=261) or crossed over from
treatment with placebo to ambrisentan (PLB/ABS group, n=132) in ARIES-E. In this analysis, one-year (48 weeks) clinical outcomes were examined
for patients in the ABS/ABS and the PLB/ABS groups. Baseline for all patients was defined as the time of randomization in
ARIES-1 or ARIES-2. Clinical efficacy measures assessed in this analysis
included 6MWD and time to clinical worsening. Clinical worsening was
defined as the time from randomization to the first occurrence of death
lung transplantation, hospitalization for PAH, arterial septostomy
study withdrawal due to the addition of other PAH therapeutics, or study
withdrawal due to two or more early escape criteria. A Kaplan-Meier
analysis was used to evaluate time to clinical worsening and includes
all patients from the time of randomization. Study Results Baseline characteristics were comparable between the ABS/ABS and PLB/ABS
groups. As previously reported, the change from baseline 6MWD at week 12
in the ambrisentan group was +42 meters (95 percent CI: 34 to 51)
compared to +3 meters in the placebo group (95 percent CI: -10 to 16).
At week 12 of treatment, 96 percent of patients in the ambrisentan group
(95 percent CI: 93 percent to 98 percent) were event-free, compared to
86 percent of patients in the placebo group (95 percent CI: 80 percent
to 92 percent). At week 48, 6MWD in the ABS/ABS group was +47 meters (95 percent CI: 35
to 59) compared to 33 meters in the PLB/ABS group (95 percent CI: 16 to
50). Following the addition of ambrisentan to the placebo group after
week 12, the rate of clinical worsening decreased for the PLB/ABS group.
At one year of treatment, the probability of no clinical worsening was
84 percent in the ABS/ABS group (95 percent CI: 80 percent to 89
percent) compared to 76 percent in the PLB/ABS group (95 percent CI: 68
percent to 83 percent). "Despite the availability of multiple
therapies, PAH is often not diagnosed in a timely manner, largely
because classic PAH symptoms such as shortness of breath and chest pain
can be attributed to more common medical conditions," said Dr. McLaughlin. "This data analysis
suggests that delay of initiation of an effective therapy like
ambrisentan may result in a decreased long-term improvement in exercise
capacity and an increased risk of disease progression for patients with
PAH, highlighting the importance of early diagnosis and treatment." During the first 12 weeks of treatment, three (2.3 percent) placebo
patients had liver aminotransferases (ALT or AST) elevations greater
than three times the upper limit of normal (ULN) compared to zero
patients in the ambrisentan group. After one year of treatment, a total
of four (3.0 percent) PLB/ABS patients and four (1.5 percent) ABS/ABS
patients had aminotransferase abnormalities greater than three times
ULN. Peripheral edema and headache occurred in greater than or equal to
10 percent of patients in both the ambrisentan and placebo groups during
the first 12 weeks. By week 48, the adverse events occurring in greater
than or equal to 10 percent of patients in both the ABS/ABS and PLB/ABS
groups were peripheral edema, headache, dizziness, dyspnea exacerbated
upper respiratory tract infection and arthralgia. In addition, cough
nasal congestion and palpitations occurred in greater than or equal to
10 percent of patients in the ABS/ABS group. Nausea was observed in
greater than or equal to 10 percent of patients in the PLB/ABS group.
Right ventricular failure was observed in greater than or equal to 10
percent of patients at week 12 in the placebo group and at week 48 in
the PLB/ABS group. Data from this analysis comparing the PLB/ABS and ABS/ABS groups during
open-label follow-up treatment at 48 weeks have not been reviewed by the
U.S. Food and Drug Administration. Full prescribing information for Letairis is available at www.gilead.com and at 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. GlaxoSmithKline (GSK) holds rights to commercialize ambrisentan for PAH
in territories outside of the United States. On April 25, 2008, GSK
announced that the European Commission issued a marketing authorisation
for ambrisentan, under the tradename Volibris®
for the treatment of PAH in patients classified as WHO functional class
II and III, to improve exercise capacity. GSK has stated that its first
European launches of Volibris are planned in the summer of 2008. 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. Letairis is a registered trademark of Gilead Sciences, Inc. Volibris 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.
