Forest Laboratories, Inc. (NYSE:FRX) today announced the
publication of data from its pivotal Phase III Study of an
Investigational Fixed-Dose Combination (FDC) of nebivolol and
valsartan in the May 30, 2014 issue of The Lancet. In the study,
the combination of nebivolol and valsartan met its primary and key
secondary endpoints, demonstrating statistically significant
reductions from baseline in diastolic and systolic blood pressure
vs. both nebivolol alone and valsartan alone at 8 weeks in patients
with hypertension.
“These data indicate that the combinations of nebivolol and
valsartan were effective at lowering blood pressure in patients
with hypertension,” said Thomas Giles, M.D., Professor of Medicine,
Tulane University School of Medicine. “To our knowledge, this is
the first study to assess the efficacy and safety of a fixed-dose
combination consisting of a beta-blocker and angiotensin II
receptor blocker in hypertensive patients. The data from this trial
show that the combination provided significantly greater blood
pressure reductions vs. nebivolol monotherapy and vs. valsartan
monotherapy with treatment-emergent adverse events that were
similar across all treatment groups, including placebo.”
The mean change in trough seated diastolic blood pressure from
baseline to week 8 for FDC 20/320 mg was significantly greater vs.
valsartan 320 mg, the highest approved valsartan dose (-15.7 ± 9.6
mmHg vs. -11.2 ± 9.3 mmHg; least squares mean difference (LSMD)
[95% CI]: -4.4 [-5.4, -3.3] mmHg, P<0.001) and significantly
greater vs. nebivolol 40 mg, the highest approved nebivolol dose
(-15.7 ± 9.6 mmHg vs. -14.4 ± 9.4 mmHg; LSMD [95% CI]: -1.2 [-2.3,
-0.1] mmHg, P=0.030). All other comparisons to protocol-specified
monotherapy arms at 8 weeks were also significant (FDC 10/320 mg
and FDC 10/160 mg), favoring the fixed-dose combinations (all
p<0.0001).
The baseline-to-endpoint decrease in trough seated systolic
blood pressure was significantly greater FDC 20/320 mg vs.
valsartan 320 mg: -17·8 ± 15·8 mmHg vs. -14.8 ± 15.1 mmHg;
LSMD [95% CI]: -3.1 [-4.9, -1.4] mmHg, P<0.001 and FDC 20/320 mg
vs. nebivolol 40 mg: -17.8 ± 15.8 mmHg vs. -15.1 ± 16.5
mmHg; LSMD [95% CI]: -2.9 [-4.7, -1.1] mmHg, P=0.001. All other FDC
doses were also significantly better than monotherapies at week 8,
(all p<0.01). Other nebivolol and valsartan fixed-dose
combinations examined (FDC 5/80 mg, FDC 5/160 mg) resulted in
significantly greater reductions from baseline in diastolic and
systolic blood pressure at week 4, except for FDC 5/160 mg vs.
valsartan 160 mg on systolic blood pressure.
Across all FDC doses the most common adverse reactions
(incidence ≥ 2% and greater than that observed in the placebo
group) were fatigue (0.9% to 2.3% vs. 1.1% in placebo), and
dizziness (1.6% to 2.3% vs. 0.4% in placebo).
Study Design
This pivotal 8-week randomized, double-blind, placebo-controlled
clinical trial in 4,161 hypertension patients studied nebivolol 5,
10, 20, and 40mg and valsartan 80, 160, and 320mg alone and in
various fixed-dose combinations. The study consisted of a 1-week
screening period, followed by 6 weeks of placebo wash-out, an
8-week double-blind treatment period, and a 1-week down-titration
period. During the double-blind treatment period, patients were
initially randomized to one of eight treatment groups: FDC
nebivolol/valsartan 5/80, 5/160, or 10/160mg; nebivolol 5 or 20mg;
valsartan 80 or 160mg or placebo. After four weeks, all dosages
were doubled.
About Nebivolol and Valsartan
Nebivolol/valsartan (5/80mg, 5/160mg, 10/160mg, 10/320mg, and
20/320mg) is an investigational fixed-dose combination. It combines
two U.S. Food and Drug Administration (FDA) approved, once daily,
blood pressure lowering agents with different mechanisms of action.
It is being evaluated as a potential treatment for hypertension in
patients who need combination therapy. Forest recently submitted a
New Drug Application to the FDA for the nebivolol/valsartan FDC for
the treatment of hypertension
Nebivolol (marketed in the US as Bystolic) is cardioselective up
to and including the 10mg dose and in extensive metabolizers. While
nebivolol’s mechanism of action has not been definitively
established, possible factors include vasodilation and decreased
peripheral vascular resistance, reduced heart rate and myocardial
contractility, suppression of renin, and reduced sympathetic
activity. Nebivolol is indicated for the treatment of hypertension
and is effective at lowering blood pressure when taken alone or in
combination with other antihypertensive agents.
Valsartan is an angiotensin II receptor blocker that blocks the
binding of angiotensin II to the AT1 receptor in many tissues, such
as vascular smooth muscle and the adrenal gland, thereby preventing
its vasoconstrictor and aldosterone-secreting effects. Valsartan
has been well studied in many different patient populations and is
an effective antihypertensive agent.
About Hypertension
According to the CDC, hypertension has been called the “silent
killer” because it often has no warning signs or symptoms and has
been associated with serious cardiovascular (CV) risks, such as
stroke and myocardial infarction. Hypertension represents a
significant public health issue with high prevalence. According to
the National Institute for Health Statistics, approximately 30% of
adults in the United States have hypertension. Inadequate control
of hypertension is a significant public health problem, with nearly
half of all patients still not achieving target goals. Numerous
antihypertensive drugs, from a variety of pharmacologic classes and
with different mechanisms of action, have been shown in randomized
controlled trials to reduce CV morbidity and mortality, and it can
be concluded that it is BP reduction that is largely responsible
for those benefits. Two-thirds of hypertensive patients will
require more than one drug to achieve blood pressure goals.
About Forest Laboratories
Forest Laboratories (NYSE:FRX) is a leading, fully integrated,
specialty pharmaceutical company largely focused on the United
States market. Forest markets a portfolio of branded drug products
and develops new medicines to treat patients suffering from
diseases principally in five therapeutic areas: central nervous
system, cardiovascular, gastrointestinal, respiratory, and
anti-infective. Forest’s strategy of acquiring product rights for
development and commercialization through licensing, collaborative
partnerships and targeted mergers and acquisitions allows Forest to
take advantage of attractive late-stage development and commercial
opportunities, thereby managing the risks inherent in drug
development. In January 2014, Forest acquired Aptalis
Pharmaceuticals for $2.9 billion in cash in order to gain access to
its GI and Cystic Fibrosis products, including treatments for
Ulcerative Proctitis, Duodenal Ulcers, H. Pylori, Anal Fissures,
and Pancreatic Insufficiency. In February 2014, Forest and Actavis
plc announced an agreement where Forest would be acquired for about
$25 billion in cash and stock. The acquisition of Forest by Actavis
is contingent upon regulatory and shareholder approvals.
Forest is headquartered in New York, NY. To learn more, visit
www.frx.com.
Except for the historical information contained herein, this
release contains forward-looking statements within the meaning of
the Private Securities Litigation Reform Act of 1995. These
statements involve a number of risks and uncertainties, including
the difficulty of predicting FDA approvals, the acceptance and
demand for new pharmaceutical products, the impact of competitive
products and pricing, the timely development and launch of new
products, and the risk factors listed from time to time in Forest
Laboratories' Annual Report on Form 10-K, Quarterly Reports on Form
10-Q, and any subsequent SEC filings. Forest assumes no obligation
to update forward-looking statements contained in this release to
reflect new information or future events or developments.
Forest Laboratories, Inc.Frank J. Murdolo, 212-224-6714Vice
President - Investor Relationsmedia.relations@frx.comorAmanda
KaufmanMedia Relationsamanda.kaufman@frx.com
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