Entresto Label: Strong Efficacy, Complex Dosing

Labeling for Novartis AG's heart failure drug Entresto (sacubitril/valsartan) reflects strong efficacy and an emphasis on dose titration to reduce the risk of angioedema and hypotension.

Approval was based on the 8,442-patient PARADIGM-HF study, which compared the combination product to the ACE inhibitor enalapril in chronic heart failure patients with reduced ejection fraction.

PARADIGM-HF was the largest heart failure trial ever conducted. It was stopped early based upon favorable efficacy findings in interim analyses (Also see "Study Suggests Novartis’ LCZ696 May Transform Heart Failure Treatment" - Pink Sheet, 1 Sep, 2014.).

Entresto reduced the risk of the combined endpoint of cardiovascular death and heart failure hospitalization by 20%. The drug showed similar risk reductions for the individual endpoints of CV death (20%), heart failure hospitalizations (21%) and all-cause mortality (16%) – data points that are all reflected in labeling.

In a July 8 investor call, Novartis also highlighted some data points on exploratory endpoints that did not make it into labeling but which the company believes payers will find persuasive in understanding the value of Entresto and its potential savings to the health care system.

These include reductions in: the risk of sudden death (19%), total number of emergency room visits for heart failure (30%), and total number of hospitalizations for heart failure (23%).

Labeling contains a boxed warning about fetal toxicity, and warnings and precautions about the risk of angioedemia, hypotension and the need to monitor renal function and potassium in certain patients.

Entresto is contraindicated in patients with a history of angioedema related to previous ACE inhibitor or ARB therapy. It is also contraindicated with concomitant use of ACE inhibitors and concomitant use of aliskiren (Novartis' Tekturna) in patients with diabetes.

For patients switching from an ACE inhibitor to Entresto, there must be a washout period of 36 hours between administration of the two drugs. This is aimed at reducing the risk of angioedema, David Epstein, division head of Novartis Pharmaceuticals, said.

Titration 'A Little Bit More Complex' Than Ideal

The drug is available in three doses: 24 mg sacubitril/26 mg valsartan; 49 mg sacubitril/51 mg valsartan; and 97 mg sacubitril/103 mg valsartan.

Vasant Narasimhan, global head of development at Novartis Pharmaceuticals, acknowledged that the labeled dosing schedule is "a little bit more complex" than the company ideally would have liked.

The recommended starting dose is 49/51 mg twice daily. This dose should be doubled after two to four weeks to the target maintenance dose of 97/103 mg twice daily.

However, the starting dose should be reduced to 24/26 mg twice daily for patients not currently taking an ACE inhibitor or ARB or previously taking a low dose of these agents, and individuals with severe renal impairment or moderate hepatic impairment. The dose should then be doubled every two to four weeks to the target maintenance dose of 97/103 mg twice daily.