Gilead Sciences, Inc. (Nasdaq:GILD) today announced that the U.S.
Food and Drug Administration (FDA) has granted approval of
Letairis(TM) (ambrisentan) 5 mg and 10 mg tablets. Letairis is an
endothelin receptor antagonist (ERA) indicated for the once-daily
treatment of pulmonary arterial hypertension (WHO Group 1) in patients
with WHO Functional Class II or III symptoms to improve exercise
capacity and delay clinical worsening. Letairis will be available in
the United States early next week. Because of the risks of liver
injury and birth defects, the product will be available through the
Letairis Education and Access Program (LEAP), a restricted
distribution program designed to help patients learn about the risks
of Letairis.
"PAH is a debilitating and life-threatening disease for which
there remains a significant need for new treatments," said Lewis J.
Rubin, MD, Professor of Medicine, University of California, San Diego.
"The availability of new treatments such as ambrisentan is critical to
our ability to help patients living with this serious disease."
"All of us at Gilead extend our thanks to the investigators and
patients who took part in the Letairis clinical trials, and we
appreciate the hard work of the U.S. FDA to ensure this product
reaches those in need as quickly as possible," said John C. Martin,
PhD, President and CEO of Gilead Sciences. "As a company dedicated to
advancing therapeutics for diseases that represent significant unmet
medical needs, we look forward to partnering with the PAH community to
help patients living with this disease."
In two randomized, double-blind, 12-week, placebo-controlled Phase
III clinical trials (ARIES-1 and ARIES-2) involving a total of 393
patients, treatment with Letairis resulted in a significant
improvement in six-minute walk distance. An increase in walk distance
was observed after four weeks of treatment with each dose regimen of
Letairis, with a dose-response observed after 12 weeks of treatment.
In ARIES-1, placebo-adjusted mean and median changes from baseline of
31 meters and 27 meters (p=0.008), respectively, were observed for the
5 mg dose. Placebo-adjusted mean and median changes from baseline of
51 meters and 39 meters (p less than 0.001), respectively, were
observed for the 10 mg dose. In ARIES-2, placebo-adjusted mean and
median changes from baseline of 59 meters and 45 meters (p less than
0.001), respectively, were observed for the 5 mg dose.
Treatment with Letairis also significantly delayed time to
clinical worsening of PAH. Clinical worsening was defined as the first
occurrence of death, lung transplantation, hospitalization for PAH,
atrial septostomy, study withdrawal due to the addition of other PAH
therapeutic agents, or study withdrawal due to early escape
(progressive disease).
The long-term follow-up of the patients who were treated with
Letairis in the two pivotal studies and the open-label extension
(n=383) shows that 95 percent were still alive at one year and 94
percent were still receiving Letairis monotherapy. These uncontrolled
observations do not allow comparison with a group not given Letairis
and cannot be used to determine the long-term effect of Letairis.
In ARIES-1 and ARIES-2, a total of 261 patients received Letairis
at doses of 2.5, 5 or 10 mg once daily and 132 patients received
placebo. The most common adverse events that occurred at a higher
frequency among Letairis-treated patients compared to placebo in the
ARIES-1 and ARIES-2 studies included (placebo-adjusted frequency):
peripheral edema (6 percent), nasal congestion (4 percent), sinusitis
(3 percent), flushing (3 percent) and palpitations (3 percent). Most
adverse drug reactions were mild to moderate and only nasal congestion
was dose-dependent.
In addition to data from Phase III clinical trials, the Letairis
approval is also supported by data from an uncontrolled, open-label
study of 36 patients who had previously discontinued endothelin
receptor antagonists (bosentan, an investigational drug, or both) due
to aminotransferase elevations greater than three times the upper
limit of normal(ULN). With a median follow-up period of 13 months and
with 50 percent of patients increasing the dose of Letairis to 10 mg,
no patients were discontinued for aminotransferase elevations. The
most common adverse events observed were peripheral edema, headache,
dyspnea and flushing. The study suggests that Letairis may be an
option for patients who have experienced asymptomatic aminotransferase
elevations on other ERAs after aminotransferase levels have returned
to normal.
"Just ten years ago, patients had few options available to combat
their disease, but there is now an emerging sense of hope as awareness
of this important disease grows and new treatments become available,"
said Rino Aldrighetti, President and CEO of the Pulmonary Hypertension
Association (PHA).
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.
About Gilead(TM)Solutions
Gilead also today announced the launch of Gilead(TM)Solutions, a
comprehensive set of programs designed to help patients navigate the
reimbursement process for Letairis and help minimize barriers to
treatment.
"Gilead is committed first and foremost to patients," said Dr.
Martin. "Our hope is that this program will ensure greater access to
care for PAH patients with a variety of circumstances, including the
often overlooked group of patients who have some form of prescription
insurance but have prohibitively high out-of-pocket expenses."
Gilead will assist most eligible privately-insured patients who
have high monthly co-payments with a portion of their out-of-pocket
expenses. Similarly, patients with Medicare prescription drug coverage
or other government-funded insurance may receive assistance with
co-payments and deductibles through two existing independent patient
foundations. Some restrictions will apply. Gilead's reimbursement
support team will guide patients to these resources and explain
program eligibility guidelines and the amount of financial assistance
available.
Similar to programs Gilead has established for patients in other
disease areas, including HIV/AIDS and chronic hepatitis B, uninsured
or underinsured patients will have access to reimbursement counseling
and support in applying for public insurance programs for which they
may qualify.
Gilead has also established a program that addresses the unique
access issues that exist at the launch of a new product before
formulary status and payer coverage levels are finalized. This will
ensure that physicians and patients have immediate access to Letairis
while Gilead's reimbursement support team works to identify
appropriate financial assistance.
Gilead Solutions programs and services will only be available
following enrollment in LEAP.
"Many PAH patients face significant financial barriers, such as
prohibitively high co-payment expenses, while also struggling to
navigate what can be a difficult treatment authorization process as
well as a complicated reimbursement process, all while dealing with
their PAH symptoms," said Joy Beckmann, RN, MSN, Chair, PH Resource
Network, Pulmonary Hypertension Association and Senior Research
Coordinator, Liu Center for Pulmonary Hypertension, Los Angeles
Biomedical Research Institute at Harbor-UCLA Medical Center. "It's
important that adequate programs are in place to ensure that patients
are not denied access to treatment for financial reasons."
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.
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(TM)
Letairis(TM) (ambrisentan) is an endothelin receptor antagonist
that is selective for the endothelin type-A (ET(A)) receptor.
Activation of the ET(A) receptor by endothelin, a small peptide
hormone, leads to vasoconstriction (narrowing of blood vessels) and
cell proliferation. The clinical impact of high selectivity for ET(A)
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. 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.
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 Gilead(TM)Solutions will not provide greater access to care
for PAH patients with a variety of circumstances. 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 Report on Form 10-Q for the first quarter of 2007, 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 www.Letairis.com.
Letairis is a trademark of Gilead Sciences, Inc.
For more information on Gilead Sciences, please visit the
company's web site at www.gilead.com or call Gilead Public Affairs at
1-800-GILEAD-5 or 1-650-574-3000.