Forest Laboratories, Inc. (NYSE:FRX) today announced positive
topline results from an 8-week pivotal Phase III clinical trial
evaluating the efficacy and safety of investigational fixed dose
combination (FDC) of nebivolol and valsartan for the treatment of
hypertension.
The combination of nebivolol and valsartan demonstrated
statistically significant reductions in diastolic blood pressure
(DBP) vs. both nebivolol alone and valsartan alone at 8 weeks,
which was the primary endpoint. The FDC also met the key secondary
endpoint of change from baseline in systolic blood pressure (SBP)
at 8 weeks.
The single pivotal nebivolol/valsartan FDC trial was designed to
meet the required regulatory “Combination Rule,” comparing a FDC
against the highest approved dose of each component drug.
“These Phase III results in patients with Stage 1 or Stage 2
hypertension are exciting and demonstrate the potential benefits of
this novel FDC -- a first-in-class beta blocker/ARB combination,”
said Marco Taglietti, MD, Senior Vice President of Research and
Development and President, Forest Research Institute. “We are very
pleased with these results which demonstrate the efficacy and
safety profile of this combination and support the potential use of
the nebivolol/valsartan FDC as a new treatment option for patients
with hypertension who need dual therapy to reach their blood
pressure goals.”
Based on these positive results, Forest plans to submit a
regulatory filing with the Food and Drug Administration (FDA) in
the first quarter of calendar year 2014.
About the Phase III Study
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
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.
The primary endpoint was change from baseline in mean sitting
trough DBP at 8 weeks for FDC dose 20/320mg versus nebivolol 40mg
(the highest approved nebivolol dose) and versus valsartan 320mg
(the highest approved valsartan dose), and FDC doses 10/320mg and
10/160mg versus corresponding monotherapies. Across these doses,
the incremental reduction in DBP for the combination vs. nebivolol
was -1.2 to -2.4 mm Hg; (p value 0.03 to <0.0001) and versus
valsartan was -3.7 to -4.4 mm Hg (p value <0.0001).
The key secondary endpoint was change from baseline in sitting
trough SBP at 8 weeks for the FDC doses 20/320mg, 10/320mg and
10/160mg vs. the same monotherapy components evaluated for DBP.
Across these doses, the incremental reduction in SBP for the
combination vs. nebivolol was -2.9 to -3.6 mm Hg; (p value 0.0013
to <0.0001) and versus valsartan was -3.0 to -3.9 mm Hg (p value
0.0011 to <0.0001).
Treatment with nebivolol/valsartan FDC was well-tolerated in the
study. Across all FDC doses the most common adverse events
(incidence ≥ 2% and greater than placebo) were fatigue (0.9% to
2.3% vs. 1.1% in placebo) and dizziness (1.6% to 2.3% vs. 0.4% in
placebo).
About Nebivolol/Valsartan FDC
Nebivolol/valsartan (5/80mg, 5/160mg, 10/160mg, 10/320mg, and
20/320mg) is an investigational fixed dose combination.
Nebivolol/valsartan FDC combines two 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.
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 (PVR). Other possible factors
include 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 (ARB) 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
Hypertension has been described as a “neglected disease” because
of the lack of attention given to it and the serious cardiovascular
(CV) consequences of having high BP, such as strokes and MI. The
prevalence of hypertension is on the rise. According to the
National Institute of Health Statistics, 28.6% of adults in the
United States (~88 million) have hypertension. Inadequate treatment
of hypertension is a significant public health problem. 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. Elevated systolic or diastolic pressure causes
increased CV risk, and the absolute risk increase per mm Hg is
greater at higher blood pressures, so even modest reductions of
severe hypertension can provide substantial benefit.
Two-thirds of patients will require more than one drug to
achieve BP goals. The Seventh Report of the Joint National
Committee on Prevention, Detection, Evaluation, and Treatment of
High Blood Pressure (JNC 7) recommends initial combination therapy
for most patients with stage II hypertension, and add-on therapy
for treated patients in all stages whose BP remains
uncontrolled.
About Forest Laboratories
Forest Laboratories' (NYSE: FRX) longstanding global
partnerships and track record developing and marketing
pharmaceutical products in the United States have yielded its
well-established central nervous system and cardiovascular
franchises and innovations in anti-infective, respiratory,
gastrointestinal and pain management medicine. Forest’s pipeline,
the most robust in its history, includes product candidates in all
stages of development across a wide range of therapeutic areas. The
Company 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.
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