The U.S. Food and Drug Administration's (FDA) Cardiovascular and Renal Drugs Advisory Committee (CRDAC) has voted to recommend against approval of Actavis'New Drug Application (NDA) for the fixed-dose combination of nebivolol and valsartan for the treatment of hypertension. The committee vote was six to four recommending against approval.
However, the committee’s recommendation is not binding; the FDA makes the final decision regarding approval and Actavis expects FDA action on its NDA for the fixed-dose combination of nebivolol and valsartan by the fourth quarter of 2014.
"Although we are disappointed in the Committee's recommendation regarding the fixed-dose combination of nebivolol and valsartan, we remain fully committed to supporting the NDA for this important potential new treatment option for patients with hypertension," said David Nicholson, Senior Vice President, Global Brands Research and Development, Actavis. "We remain confident in the safety and efficacy of the combination of these two widely used and well-tolerated treatments, and we look forward to working with the FDA as it completes its review."
Data presented at today's Advisory Committee meeting included phase III efficacy and safety data from the almost 5,000-patient nebivolol/valsartan clinical development program. In the pivotal efficacy study published in The Lancet, the fixed-dose combination (FDC) of nebivolol and valsartan met its primary and key secondary endpoints, demonstrating statistically significant reductions from baseline in diastolic and systolic blood pressure at eight weeks in patients with hypertension versus both nebivolol alone and valsartan alone. The adverse event profile of the fixed dose combination was similar to that observed with the monotherapies and placebo. In addition, a 52-week open-label safety study further supported the favorable long-term safety profile of the nebivolol/valsartan combination.
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 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 U.S. as Bystolic) 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 ACEIs, ARBs, and/or diuretics. It is Beta-1 selective 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), reduced heart rate and myocardial contractility, suppression of renin, and reduced sympathetic activity.
Valsartan has been well studied in many different patient populations and is an effective antihypertensive agent. It 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.