-- First-Line Combination of Letairis and
Tadalafil Reduced Risk of Disease Progression by Nearly 50 Percent
Compared to Either Therapy Individually in Study of 605 PAH
Patients with WHO Functional Class II-III Symptoms --
Gilead Sciences, Inc. (Nasdaq:GILD) today announced that the
U.S. Food and Drug Administration (FDA) has approved the use of
Letairis® (ambrisentan) in combination with tadalafil for the
treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to
reduce the risks of disease progression and hospitalization for
worsening PAH, and to improve exercise ability. Letairis is an
endothelin receptor antagonist that was first approved in 2007 in
the U.S. as monotherapy for PAH to improve exercise ability and
delay clinical worsening. Tadalafil is a PDE5 inhibitor that was
initially approved for PAH in the U.S. in 2009 to improve exercise
ability.
“The evidence to support the use of ambrisentan and tadalafil in
PAH is well-established, however an outstanding question has been
whether combining these two medications up front may further delay
the progression of this disease over the long term for patients who
are newly starting PAH therapy,” said Ronald J. Oudiz, MD,
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. “Based
on the data supporting today’s approval, we now know that patients
receiving ambrisentan and tadalafil up front are less likely to
experience disease progression or be hospitalized, and have more
improvement in exercise ability than patients receiving either
effective therapy alone. As such, this combination represents a new
treatment strategy for patients living with this debilitating and
life-threatening disease.”
The new labeling is supported by data 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, 605 patients with WHO Functional
Class II or III PAH were randomized (2:1:1) to receive once-daily
Letairis plus tadalafil (n=302) or to Letairis (n=152) or tadalafil
(n=151) alone. Treatment was initiated with Letairis 5 mg and
tadalafil at 20 mg. If tolerated, tadalafil was increased to 40 mg
at four weeks and Letairis was increased to 10 mg at eight weeks.
The primary endpoint was time to first occurrence of death,
hospitalization for worsening PAH, greater than 15 percent decrease
from baseline in six-minute walk distance (6MWD) combined with WHO
Functional Class III or IV symptoms sustained over 14 days
(short-term clinical worsening) or reduction in 6MWD sustained over
14 days combined with WHO Functional Class III or IV symptoms
sustained over 6 months (inadequate long-term clinical
response).
In the study, combination therapy with Letairis and tadalafil
demonstrated superiority in reducing the risk of the composite
primary endpoint by 49 percent and 45 percent, respectively, versus
monotherapy with Letairis (hazard ratio = 0.51; 95 percent CI:
0.35, 0.73; p=0.0002) or tadalafil (hazard ratio = 0.55; 95 percent
CI: 0.37, 0.81; p=0.002). Overall, 20 percent of patients receiving
combination therapy experienced a primary endpoint event compared
to 35 percent and 30 percent, respectively, in patients receiving
Letairis or tadalafil.
Combination therapy also demonstrated a reduced risk of
hospitalization for worsening PAH of 67 percent and 56 percent,
respectively, compared to Letairis (hazard ratio = 0.33; 95 percent
CI: 0.19, 0.55) or tadalafil (hazard ratio = 0.44; 95 percent CI:
0.25, 0.79). Overall, 8 percent of patients receiving combination
therapy were hospitalized for worsening PAH compared to 22 percent
and 15 percent, respectively, in patients receiving Letairis or
tadalafil.
Patients receiving Letairis plus tadalafil also experienced
statistically significant improvements from baseline in 6MWD versus
individual monotherapy, with a median difference of 24 meters and
20 meters, respectively, from Letairis (95 percent CI: 11, 37;
p=0.0004) or tadalafil (95 percent CI: 8, 32; p=0.0016) at Week
24.
When Letairis is used in combination with tadalafil, the common
adverse reactions (>5 percent than on either monotherapy) were
peripheral edema (Combination: 45 percent; Letairis: 38 percent;
tadalafil: 28 percent), headache (Combination: 41 percent;
Letairis: 34 percent; tadalafil: 35 percent), nasal congestion
(Combination: 19 percent; Letairis: 16 percent; tadalafil: 11
percent), cough (Combination: 18 percent; Letairis: 13 percent;
tadalafil: 16 percent), anemia (Combination: 15 percent; Letairis:
7 percent; tadalafil: 11 percent), dyspepsia (Combination: 11
percent; Letairis: 3 percent; tadalafil: 12 percent) and bronchitis
(Combination: 10 percent; Letairis: 4 percent; tadalafil: 9
percent). 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.
Data from AMBITION were published in The New England Journal of
Medicine and Letairis plus tadalafil was the only recommended
initial combination therapy option for PAH in the “2015 European
Society of Cardiology / European Respiratory Society Guidelines for
the Diagnosis and Treatment of Pulmonary Hypertension” published in
the European Heart Journal in August 2015.
AMBITION was cosponsored by Gilead and GlaxoSmithKline (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
U.S.
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.
About Letairis
Letairis is indicated for the treatment of pulmonary arterial
hypertension (PAH) (WHO Group 1) to improve exercise ability and
delay clinical worsening; and in combination with tadalafil to
reduce the risks of disease progression and hospitalization for
worsening PAH, and to improve exercise ability. Studies
establishing effectiveness included predominantly patients with WHO
Functional Class II-III symptoms and etiologies of idiopathic or
heritable PAH (60 percent) or PAH associated with connective tissue
diseases (34 percent).
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
- Pregnancy: Letairis can cause
fetal harm
- Idiopathic Pulmonary Fibrosis
(IPF), including IPF patients with pulmonary hypertension (WHO
Group 3)
Warnings and Precautions
- Embryo-fetal toxicity and Letairis
REMS Program requirements:
- Prescribers must be certified with the
program by enrolling in and completing training
- All female patients, regardless of
reproductive potential, must enroll in the Letairis REMS
Program
- Male patients are not enrolled in the
program
- Pharmacies must be certified with the
program and must dispense to female patients who are authorized to
receive Letairis
Further information is available at
www.letairisrems.com or 1-866-664-5327.
- Peripheral edema: Peripheral
edema is a known class effect of endothelin receptor antagonists,
and is also a clinical consequence of PAH and worsening PAH.
Further evaluate patients who develop clinically significant fluid
retention to determine the cause and possible need for edema
treatment or to discontinue Letairis. In clinical studies,
peripheral edema was more common with Letairis than with placebo
(most edema was mild to moderate in severity); and with Letairis
plus tadalafil than with either drug alone. There have also been
postmarketing reports of fluid retention occurring within weeks
after starting Letairis that required a diuretic, fluid management,
or hospitalization for decompensating heart failure.
- Pulmonary edema with pulmonary
veno-occlusive disease (PVOD): Consider PVOD in patients who
develop acute pulmonary edema during Letairis initiation and
discontinue Letairis if PVOD is confirmed.
- Decreased sperm counts 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: Measure
hemoglobin prior to initiation of Letairis, at 1 month, and
periodically thereafter. Letairis initiation is not recommended for
patients with clinically significant anemia. Consider discontinuing
Letairis if clinically significant decreases in hemoglobin occur
and other causes have been excluded. Decreases in hemoglobin and
hematocrit have been observed within the first few weeks of
Letairis treatment, which may persist during treatment. There have
also been postmarketing reports of anemia requiring
transfusion.
Adverse Reactions
- Most common adverse reactions when
used as monotherapy compared to placebo were peripheral edema
(17% vs 11%), nasal congestion (6% vs 2%), sinusitis (3% vs 0%) and
flushing (4% vs 1%).
- Most common adverse reactions in
combination with tadalafil compared to Letairis or tadalafil
monotherapy were peripheral edema (45% vs 38% or 28%), headache
(41% vs 34% or 35%), nasal congestion (19% vs 16% or 11%), cough
(18% vs 13% or 16%), anemia (15% vs 7% or 11%), dyspepsia (11% vs
3% or 12%) and bronchitis (10% vs 4% or 9%).
Drug Interactions
- Cyclosporine increases
ambrisentan exposure by 2-fold; limit Letairis to 5 mg once
daily
Use in Specific Populations
- Breastfeeding: Choose Letairis
or breastfeeding.
- Hepatic impairment: Letairis is
not recommended in patients with moderate or severe hepatic
impairment. Fully investigate cause of liver injury in patients who
develop hepatic impairment; discontinue Letairis if liver
aminotransferases 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.
Dosage and Administration
- Adult dosage: Initiate Letairis
5 mg once daily, with or without tadalafil 20 mg once daily. At
4-week intervals, consider either increasing to Letairis 10 mg or
tadalafil 40 mg. Do not split, crush, or chew tablets.
- Pregnancy testing: Initiate
Letairis in females of reproductive potential only after a negative
pregnancy test. Obtain monthly pregnancy tests during
treatment.
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 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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