Forest Laboratories, Inc., a company  identifies, develops, and delivers pharmaceutical products that make a difference in people's lives, has reported positive topline results from an eight-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 eight weeks, which was the primary endpoint. The FDC also met the key secondary endpoint of change from baseline in systolic blood pressure (SBP) at eight 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.

This pivotal eight-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 one-week screening period, followed by six weeks of placebo wash-out, an eight-week double-blind treatment period, and a one-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 eight 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 eight 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).

Nebivolol/ valsartan (5/80mg, 5/160mg, 10/160mg, 10/320mg, and 20/320mg) is an investigational fixed dose combination. Nebivolol/valsartan FDC combines two US 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 anti-hypertensive 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.

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.

Forest Laboratories' 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.