Gilead Sciences, Inc. (Nasdaq: GILD) today announced detailed
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). In AMBITION, conducted in
collaboration with GlaxoSmithKline (GSK), combination therapy with
Letairis® (ambrisentan) and tadalafil reduced the risk of clinical
failure by 50 percent compared to the pooled Letairis and tadalafil
monotherapy arm (hazard ratio = 0.50; 95 percent CI: 0.35, 0.72;
p<0.001). These data were published in The New England Journal
of Medicine.
Letairis, a selective endothelin type-A receptor antagonist, and
tadalafil, a PDE5 inhibitor, are each approved in the United States
(U.S.), the European Union (EU) and other countries as once-daily
treatments for patients with pulmonary arterial hypertension (PAH)
(WHO Group 1) with WHO/NYHA functional class II and III symptoms.
Letairis is indicated in the U.S. to improve exercise ability and
delay clinical worsening and in the EU under the tradename
Volibris® 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. However, combination use
with Letairis and tadalafil is currently not approved.
“The only other published, large-scale, event-driven study to
date in PAH compared an endothelin receptor antagonist to placebo
in patients who were either treatment-naïve or on background
therapy, however, all patients in AMBITION received an approved
therapy for PAH,” said Lewis J. Rubin, MD, Emeritus Professor,
University of California, San Diego and Co-Chair of the AMBITION
Steering Committee. “Thus, the magnitude of the effect with this
combination in comparison to active monotherapy is impressive,
particularly in WHO functional class II patients where we observed
nearly an 80 percent reduction in risk of clinical failure versus
monotherapy.”
AMBITION was a multicenter, randomized, double-blind phase 3/4
study designed to compare the safety and efficacy of
investigational first-line combination therapy (Letairis and
tadalafil) to first-line monotherapy (Letairis or tadalafil) in
patients with WHO/NYHA functional class II and III PAH. In the
primary study analysis, 500 patients were randomized (2:1:1) to
receive Letairis and tadalafil (n=253) or monotherapy with Letairis
(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 Letairis and
tadalafil, respectively).
The primary endpoint was time to first clinical failure event, a
composite endpoint that incorporates both the traditional
components of clinical worsening (death, hospitalization and
disease worsening) with a component of unsatisfactory long-term
clinical response (all events adjudicated by an independent,
blinded committee).
The treatment effect for the composite primary endpoint of time
to clinical failure was driven mainly by a reduced number of
hospitalizations due to PAH, with a reduced risk of hospitalization
due to PAH of 63 percent (hazard ratio = 0.37; 95 percent CI: 0.22,
0.64; p<0.001).
Consistently favorable reductions in clinical failure events
were observed based on etiology, WHO functional class, age,
geographical area and gender. The predefined subgroup analysis of
the primary endpoint suggested that patients with WHO functional
class II (n=155; hazard ratio = 0.21; 95 percent CI: 0.07, 0.63);
p=0.005) responded even more positively than patients with WHO
functional class III (n=345; hazard ratio = 0.58; 95 percent CI:
0.39, 0.86; p=0.006).
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 percent vs. -50 percent;
p<0.001), percentage of patients with satisfactory clinical
response at week 24 (39 percent vs. 29 percent; odds ratio 1.56;
p=0.03) and median change from baseline to week 24 in six-minute
walk distance (6MWD) (49 meters vs. 24 meters; p<0.001). 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
Letairis and tadalafil. Adverse events occurring more frequently in
the combination arm than in either monotherapy arm were peripheral
edema (Combination: 45 percent; Letairis: 33 percent; tadalafil: 28
percent), headache (Combination: 42 percent; Letairis: 33 percent;
tadalafil: 35 percent), nasal congestion (Combination: 21 percent;
Letairis: 15 percent; tadalafil: 12 percent) and anemia
(Combination: 15 percent; Letairis: 6 percent; tadalafil: 12
percent).
Additional results from the study are available at
www.nejm.org.
Gilead submitted the AMBITION data in a Letairis supplemental
new drug application (sNDA) to the U.S. Food and Drug
Administration (FDA) on December 5, 2014. FDA has granted a
standard review and set a target review date under the Prescription
Drug User Fee Act (PDUFA) of October 5, 2015.
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
Important U.S. Safety Information for Letairis.
About AMBITION
AMBITION 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.
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.
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.
Contraindications
- Do not administer Letairis to a
pregnant woman because it can cause fetal harm.
- Letairis is contraindicated in patients
with Idiopathic Pulmonary Fibrosis (IPF) including IPF patients
with pulmonary hypertension (WHO Group 3).
Warnings and precautions
- Mild to moderate peripheral
edema: Peripheral edema occurred more frequently in elderly
patients (age ≥65 years) receiving Letairis (29 percent; 16/56)
compared to placebo (4 percent; 1/28). Peripheral edema is a known
class effect of endothelin receptor antagonists. In addition, there
have been postmarketing reports of fluid retention occurring within
weeks after starting Letairis that required intervention with a
diuretic, fluid management, or, in some cases, hospitalization for
decompensating heart failure.
- Pulmonary Edema with PVOD: If
patients develop acute pulmonary edema during initiation of therapy
with vasodilating agents such as Letairis, pulmonary veno-occlusive
disease should be considered, and if confirmed, Letairis should be
discontinued.
- Decreases in sperm count have
been observed in patients taking endothelin receptor antagonists
and in animal fertility studies with ambrisentan. Counsel patients
about potential effects on fertility.
- Hematologic changes: Decreases
in hemoglobin have been observed within the first few weeks of
treatment with Letairis, and may persist during treatment. There
have been postmarketing reports of anemia requiring transfusion.
Measure hemoglobin prior to initiation, at 1 month, and
periodically thereafter. Initiation of Letairis therapy is not
recommended for patients with clinically significant anemia.
Adverse reactions
Most Common Adverse Reactions (>3% compared to placebo)
Placebo (N=132)
LETAIRIS (N=261)
Adverse reaction n (%)
n (%) Placebo-adjusted (%)
Peripheral edema 14 (11) 45 (17) 6 Nasal congestion 2 (2) 15 (6) 4
Sinusitis 0 (0) 8 (3) 3 Flushing 1 (1) 10 (4) 3
- During 12-week controlled clinical
trials, the incidence of liver aminotransferase (AST, ALT)
elevations >3x ULN was 0 percent for Letairis and 2.3 percent
for placebo.
- In postmarketing experience, elevations
of aminotransferases have been reported with Letairis use; in most
cases alternative causes of liver injury could be identified (heart
failure, hepatic congestion, hepatitis, alcohol use, hepatotoxic
medications). In practice, cases of hepatic injury should be
carefully evaluated for cause.
- Other ERAs have been associated with
aminotransferase elevations, hepatotoxicity, and cases of liver
failure.
- Discontinue Letairis if
aminotransferase elevations are >5x ULN or if elevations are
accompanied by bilirubin >2x ULN or by signs or symptoms of
liver dysfunction, and other causes are excluded.
Drug interactions
- Multiple-dose co-administration of
Letairis and cyclosporine resulted in an approximately two-fold
increase in Letairis exposure in healthy volunteers. Limit the dose
of Letairis to 5 mg once daily when co-administered with
cyclosporine.
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 treatment.
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 these patients.
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. Gilead
has operations in more than 30 countries worldwide, with
headquarters in Foster City, California.
Forward-Looking
Statement
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 possibility that the FDA and other regulatory
authorities may not approve the sNDA in the currently anticipated
timelines or at all. In addition, any marketing approvals, if
granted, may have significant limitations on use. Further, even if
approved, physicians may not see the benefit of combination therapy
with Letairis and 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, 2015, 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.
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version on businesswire.com: http://www.businesswire.com/news/home/20150826006141/en/
Gilead Sciences, Inc.Patrick O’Brien, 650-522-1936
(Investors)Nathan Kaiser, 650-522-1853 (Media)
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