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FDA Advisors Say ‘No’ to Nebivolol/ Valsartan Combo for Hypertension

Agency decision expected later this year

The FDA’s Cardiovascular and Renal Drugs Advisory Committee (CRDAC) has voted to recommend against approving the new drug application (NDA) for a fixed-dose combination of nebivolol and valsartan (Actavis PLC) for the treatment of hypertension. The committee voted 6 to 4 against approval.

The panel’s recommendation is not binding on the FDA, which makes the final decision regarding approval. Agency action on the NDA for fixed-dose nebivolol/valsartan is expected by the fourth quarter of 2014.

Data presented at the advisory committee meeting included phase III efficacy and safety results from the nebivolol/valsartan clinical development program, which involved approximately 5,000 patients. In a pivotal efficacy study, published in The Lancet, the fixed-dose combination of nebivolol and valsartan met its primary and key secondary endpoints, demonstrating statistically significant reductions from baseline in diastolic and systolic blood pressure at 8 weeks in patients with hypertension compared with nebivolol alone and valsartan alone.

Nebivolol/valsartan (5/80 mg, 5/160 mg, 10/160 mg, 10/320 mg, and 20/320 mg) is an investigational fixed-dose combination. It 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 (Bystolic, Forest Laboratories) is indicated for the treatment of hypertension and is effective at lowering blood pressure when taken alone or in combination with other antihypertensive agents such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and/or diuretics. It is beta-1–selective up to and including the 10-mg dose and in extensive metabolizers.

While the mechanism of action of nebivolol has not been definitively established, possible factors include vasodilation and decreased peripheral vascular resistance, reduced heart rate and myocardial contractility, renin suppression, and reduced sympathetic activity.

Valsartan (Diovan, Novartis) has been studied in many different patient populations and is an effective antihypertensive agent. It is an 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.

According to the Centers for Disease Control and Prevention (CDC), hypertension has been called the “silent killer” because it often has no warning signs or symptoms, and because it has been associated with serious cardiovascular risks, such as stroke and myocardial infarction. The National Institute for Health Statistics estimates that approximately 30% of adults in the U.S. have hypertension. Two-thirds of hypertensive patients require more than one drug to achieve blood pressure goals.

Source: Actavis; September 9, 2014.

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