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-- AMBITION Study of Ambrisentan/Tadalafil Combination Therapy
Versus Monotherapy Achieves Primary Endpoint of Time to First Clinical
Failure Event --
-- Data Presented at the ERS International Congress 2014 --
MUNICH--(BUSINESS WIRE)--Sep. 8, 2014--
Gilead Sciences, Inc. (Nasdaq:GILD) today announced results from the
AMBITION study (a randomized, double-blind, multicenter study of
first-line combination therapy with AMBrIsentan and Tadalafil
in patients with pulmonary arterial hypertensION), which was
conducted in collaboration with GlaxoSmithKline (GSK). In AMBITION,
first-line treatment of pulmonary arterial hypertension (PAH) with the
combination of ambrisentan 10 mg and tadalafil 40 mg reduced the risk of
clinical failure by 50 percent compared to the pooled ambrisentan and
tadalafil monotherapy arm (hazard ratio = 0.502; 95 percent CI: 0.348,
0.724; p=0.0002). The combination was also statistically significant
versus the individual ambrisentan and tadalafil monotherapy groups for
the primary endpoint (p<0.01). Rates of serious adverse events and
events leading to discontinuation were similar across treatment arms.
Detailed results from the study (Abstract #2916) will be presented today
during an oral session at ERS International Congress 2014, the annual
meeting of the European Respiratory Society.
Gilead plans to submit the AMBITION data in a supplemental new drug
application (sNDA) to the U.S. Food and Drug Administration by the end
of this year. Combination use with ambrisentan and tadalafil is
currently not approved.
Ambrisentan, a selective endothelin type-A receptor antagonist, and
tadalafil, a PDE5 inhibitor, are each approved in the United States, the
European Union (EU) and other countries as once-daily treatments for PAH
(WHO Group 1), in patients with WHO/NYHA functional class II and III
symptoms. Ambrisentan is indicated in the U.S. to improve exercise
ability and delay clinical worsening and in the EU to improve exercise
capacity. Tadalafil 40 mg is indicated in the U.S. and the EU to improve
exercise ability and capacity, respectively. Preclinical data have
suggested these therapies may have synergistic effects.
“The pulmonary hypertension medical community has long been interested
in determining whether newly diagnosed PAH patients would have improved
outcomes with upfront combination therapy versus monotherapy,” said
Lewis J. Rubin, MD, Emeritus Professor, University of California, San
Diego and Co-Chair of the AMBITION Steering Committee. “The majority of
combination studies to date have evaluated add-on combination treatment
approaches with mixed results. Thus, having demonstrated a 50 percent
reduction in risk of clinical failure, the AMBITION results using
ambrisentan and tadalafil together as upfront combination therapy
potentially establish a new treatment paradigm in PAH.”
AMBITION was a randomized, double-blind study designed to compare the
safety and efficacy of investigational first-line combination therapy
(ambrisentan and tadalafil) to first-line monotherapy (ambrisentan or
tadalafil) in patients with WHO/NYHA functional class II and III PAH. In
the study, 500 patients were randomized (2:1:1) to receive ambrisentan
and tadalafil (n=253) or monotherapy with ambrisentan (n=126) or
tadalafil (n=121) (titrated from 5 mg to 10 mg once-daily and from 20 mg
to 40 mg once-daily for ambrisentan and tadalafil, respectively). The
primary endpoint was time to first clinical failure event, defined as
time from randomization to the first occurrence of death (all-cause),
hospitalization for worsening PAH, disease progression or unsatisfactory
long-term clinical response (events adjudicated by an independent,
The treatment effect observed with the primary endpoint was mainly
driven by a reduction in hospitalizations. Time to first hospitalization
was delayed by 63 percent (hazard ratio = 0.372; 95 percent CI: 0.217,
Statistically significant improvements were also observed with the
following secondary endpoints versus the pooled monotherapy arm: change
from baseline at week 24 in N-terminal pro-B-type natriuretic peptide
(NT-proBNP) (-67.4 percent vs. -49.7 percent; p<0.0001), percentage of
patients with satisfactory clinical response at week 24 (39 percent vs.
29 percent; p=0.026) and median change from baseline to week 24 in
six-minute walk distance (6MWD) (49.0 meters vs. 23.8 meters; p<0.0001).
There was no difference between treatment groups in the change from
baseline to week 24 for WHO Functional Class.
No new safety signals were detected with the combination of ambrisentan
and tadalafil. Adverse events occurring more frequently in the
combination arm than in each monotherapy arm were peripheral edema
(Combination: 45 percent; ambrisentan: 33 percent; tadalafil: 28
percent), headache (Combination: 42 percent; ambrisentan: 33 percent;
tadalafil: 35 percent), nasal congestion (Combination: 21 percent;
ambrisentan: 15 percent; tadalafil: 12 percent) and anemia (Combination:
15 percent; ambrisentan: 6 percent; tadalafil: 12 percent).
The AMBITION study was cosponsored by Gilead and GSK. Eli Lilly and
Company also provided funding and tadalafil drug supply for the trial.
Gilead commercializes ambrisentan under the tradename Letairis®
in the U.S. and GSK commercializes ambrisentan under the tradename
Volibris® in territories outside of the United States.
“The AMBITION study is a reflection of Gilead’s ongoing commitment to
PAH,” said Norbert Bischofberger, PhD, Gilead’s Executive Vice President
of Research and Development and Chief Scientific Officer. “We are
pleased that the combination of ambrisentan and tadalafil has resulted
in a clinically meaningful benefit for PAH patients, and we extend our
thanks to the patients, investigators and other research collaborators
who participated in the study.”
In the U.S., Letairis has a labeled BOXED WARNING and an
associated Risk Evaluation and Mitigation Strategy (REMS) program
regarding the risk of embryo-fetal toxicity; see below for Letairis
Important Safety Information.
About Pulmonary Arterial Hypertension (WHO
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
Important U.S. Safety Information for Letairis
BOXED WARNING: EMBRYO-FETAL TOXICITY
Do not administer Letairis to a pregnant female because it may cause
fetal harm. Letairis is very likely to produce serious birth
defects if used by pregnant females, as this effect has been seen
consistently when it is administered to animals.
Exclude pregnancy before the initiation of treatment with Letairis.
Females of reproductive potential must use acceptable methods of
contraception during treatment with Letairis and for one month after
treatment. Obtain monthly pregnancy tests during treatment and 1 month
after discontinuation of treatment.
Because of the risk of embryo-fetal toxicity birth defects, females
can only receive Letairis through a restricted program called the
Letairis REMS program.
Warnings and precautions
Further information is available at www.letairisrems.com
Dosage and administration
Adult Dosage: Initiate treatment at 5 mg once daily, and
consider increasing the dose to 10 mg once daily if 5 mg is tolerated.
Tablets may be taken with or without food. Tablets should not be split,
crushed, or chewed. Doses higher than 10 mg once daily have not been
studied in patients with pulmonary arterial hypertension (PAH).
Pregnancy Testing in Females of Reproductive Potential: Initiate
treatment with, Letairis in females of reproductive potential only after
a negative pregnancy test. Obtain monthly pregnancy tests during
Not recommended in patients with moderate or severe hepatic impairment.
There is no information on the use of Letairis in patients with mild
hepatic impairment; however, exposure to Letairis may be increased in
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 and South America, Europe and
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
Gilead’s ability to submit its sNDA in the currently anticipated
timeline. In addition, regulatory authorities may not approve the sNDA
and any marketing approvals may have significant limitations on use.
Further, even if approved, physicians may not see the benefit of
combining Letairis with tadalafil. 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 June 30, 2014, 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 including BOXED WARNING for
Letairis is available at www.gilead.com.
Letairis and Volibris are registered trademarks of Gilead Sciences,
Inc. or one of its related companies.
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.
Source: Gilead Sciences, Inc.
Gilead Sciences, Inc.Investors:Patrick O’Brien, 650-522-1936Media:Nathan