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New ‘Paradigm’ in heart failure; Novartis’ combo pill to have ‘major impact’

By Nuala Moran, Staff Writer

LONDON – Novartis AG hailed the results of its Paradigm trial of LCZ696 as “a historical moment in the treatment of heart failure,” with the combined ACE/neprilysin inhibitor reducing deaths by 20 percent, cutting hospitalizations by 21 percent and offering better quality of life, compared to treatment with ACE inhibitor enalapril alone.

“Finally, we have a medicine which allows patients to live longer, have fewer hospitalizations and feel better while taking the drug,” said David Epstein, division head, Novartis Pharmaceuticals, commenting on the data, which were released at the European Society of Cardiology meeting in Barcelona, Spain, on Saturday.

The results were presented by co-leader of the Paradigm study, Milton Packer, professor and chair of the Department of Clinical Sciences at the University of Texas Southwestern Medical Center, who said the trial will dramatically change the way physicians treat patients with heart failure. “It will give patients longer life, fewer symptoms, a better quality of life, being in hospital less frequently. It’s going to have a major impact on patients and patient care,” Packer said.

Basel, Switzerland-based Novartis announced in March that the trial was closing early after the data monitoring committee confirmed the primary endpoint of reduced mortality and fewer hospitalizations had been met in the 8,442-patient trial, which is the largest-ever study in heart failure.

With more than 26 million people afflicted with the condition in the U.S. and Europe alone, Novartis is evidently sitting on a blockbuster.

Epstein refused to be drawn on any company sales projections for LCZ696, saying it has to be approved and priced before the level of uptake can be assessed. However, he claimed that once the drug is approved, “there will be no place” for the use of ACE inhibitors alone in the treatment of chronic heart failure.

Nor would Epstein comment on the pricing of LCZ696, which despite showing a superior effect will have to compete with standard-of-care generic ACE inhibitors costing a few dollars per week.

While “cognizant of the economic pressure payers and patients are under, it is very rare that a drug like this comes along,” Epstein said. Companies have a responsibility to price reasonably, but the cost of a generic “is not the way to think about it.” In addition to lower mortality and improved quality of life, LCZ696 will bring economic benefits by reducing the cost of care, with hospital treatment for heart failure patients costing $108 billion a year in the U.S. and Europe combined, according to Epstein.

Novartis said it will file for FDA approval of LCZ696 before the end of the year and for European approval in 2015.

Overall, patients with heart failure with reduced ejection fraction who were given LCZ696 were more likely to be alive and less likely to have been hospitalized for sudden deterioration of their heart failure than those given enalapril, over the 27 months follow-up of the study. Patients received LCZ696 or enalapril on top of current best treatment.

The magnitude of benefit with LCZ696 was highly statistically significant and clinically important. The benefit was seen early, was sustained and was consistent across subgroups. The 20 percent reduction in deaths from cardiovascular disease delivered a “p” value of 0.00004, while the 16 percent reduction in the risk of all-cause mortality gave a “p” value of 0.0005.

In demonstrating a very significant reduction in cardiovascular deaths while improving quality of life, LCZ696 represents “one of the most important cardiology advances of the last decade,” Epstein claimed.

The safety data showed the side effects of LCZ696 were manageable, and while there was a greater incidence of hypotension and nonserious angioedema, there was less renal impairment, hyperkalemia and cough in patients receiving LCZ696, than in the enalapril group.

In total, 10.7 percent of patients on LCZ696 dropped out because of an adverse event, compared to 12.3 percent on enalapril (p=0.03).

LCZ696 contains equal amounts of the angiotensin II inhibitor valsartan and the neprilysin inhibitor sacubitril (AHU377). Neprilysin is an endopeptidase enzyme that degrades several endogenous vasoactive peptides, including natriuretic peptides, bradykinin, and adrenomedullin. Its inhibition reduces vasoconstriction and sodium retention. Combined inhibition of the renin-angiotensin system and neprilysin has a superior effect compared to using either drug alone.

In the study, which ran from December 2009, 4,187 patients received LCZ696 and 4,212 enalapril. Writing in the New England Journal of Medicine, Packer and his co-investigator, John McMurray, of Glasgow University, UK, said the magnitude of the benefit from LCZ696 over enalapril was particularly significant, since the drug was compared with a dose of enalapril that reduces mortality by 16 percent compared to placebo. “The benefit of LCZ696, which was apparent early in the trial, was seen in patients who were already receiving all other drugs known to improve survival among patients with heart failure, that is beta-blockers and mineralocorticoid-receptor antagonists,” Packer and McMurray said.

The Paradigm study was designed to provide evidence to support the replacement of ACE inhibitors with LCZ696 in the management of chronic heart failure. The investigators said the findings are applicable to a broad spectrum of patients, providing “strong evidence that combined inhibition of the angiotensin receptor and neprilysin is superior to inhibition of the renin-angiotensin system alone, in patients with chronic heart failure.”