March 18, 2010

March 18, 2010 (Atlanta, Georgia) — A novel, first-in-class antihypertensive agent, which inhibits both the angiotensin II receptor and neprilysin, showed greater reductions in blood pressure than valsartan alone in a new study in more than 1200 patients reported at the American College of Cardiology 2010 Scientific Sessions and simultaneously published in the Lancet [1].

Lead author Dr Luis Miguel Ruilope (Hospital 12 de Octubre, Madrid, Spain) told heartwire : "This is a new compound with a dual effect that will help us to control blood pressure in a better way." Given that it suppresses the angiotensin system and prolongs the life of natriuretic peptides, it may also have other ancillary effects, he said. The drug, LCZ696 (Novartis), was safe and effective in the trial, said Ruilope, and although further investigation is needed, he envisages that it could be useful in arterial hypertension, heart failure, and pulmonary hypertension, with particular benefit in diabetics and the elderly.

In an editorial accompanying the published study [2], Drs Bernard Waeber and Francois Feihl (Université de Lausanne, Switzerland) agree: there are "sufficient encouraging data [with LCZ696] to justify undertaking large clinical trials in various clinical disorders, notably hypertension, diabetes, and heart or renal failure."

LCZ696, an Omapatrilatlike Drug Without the ACE Inhibition

Ruilope explained that LCZ696 increases the concentration of natriuretic peptides by inhibiting neprilysin (also known as neutral endopeptidase); prior to this agent, the most extensively studied inhibitor of neprilysin was omapatrilat (Bristol-Myers Squibb), a drug that was never marketed because it had an unacceptable side effect of angioedema.

But omapatrilat concomitantly inhibited three enzymes: angiotensin-converting enzyme, aminopeptidase P, and neprilysin, the researchers explain, whereas the new drug inhibits only two and substitutes angiotensin II blockade for ACE inhibition. Because angiotensin-receptor blockers have a lower risk of angioedema than do ACE inhibitors, it is hoped that LCZ696 will offer cardioprotective effects without the side effect of angioedema.

In the double-blind study, 1328 patients with mild to moderate hypertension from 18 countries were assigned to eight weeks of treatment in one of eight groups: 100 mg, 200 mg, or 400 mg of LCZ696; 80 mg, 160 mg or 320 mg of valsartan; 200 mg of AHU377, which represented the neprilysin-inhibitor moiety alone of LCZ696; or placebo.

The study of AHU377, which blocks neprilysin but not the angiotensin II inhibitor, illustrated that while this compound did reduce BP as a monotherapy, its effects were slight.

But "dual inhibition of the angiotensin II receptor and neprilysin have complementary effects," say Ruilope et al. LCZ696 reduced blood pressure in a dose-dependent way; 200 mg of the study drug led to a significantly greater reduction in BP than did 160 mg of valsartan (-2.97 mm Hg diastolic; p=0.0023), and 400 mg of LCZ696 bettered 320 mg of valsartan (-2.70 mm Hg; p=0.0055).

And "in all study groups, the occurrence of adverse effects did not exceed those recorded with placebo," note Waeber and Feihl in their editorial. "Crucially, no cases of angioneurotic edema occurred in the trial, suggesting that inhibition of neprilysin does not lead to bradykinin accumulation when the activity of angiotensin-converting enzyme is preserved. Such a possibility should be verified in a larger sample."

Ruilope and colleagues do note some limitations of their study. First, although pulse pressure was assessed during the trial, central BP and aortic stiffness were not, "precluding a more thorough assessment of the antihypertensive properties of LCZ696," they note.

Second, although the absence of angioedema in this study "is positive," this "needs to be confirmed, particularly in black patients, because angioedema was more frequently reported by black patients" in the OCTAVE trial [3]. Only 8% of patients in the current trial of LCZ696 were black, they note.

Future studies should identify hypertensive populations that would most benefit from LCZ696, with the current findings indicating it could be of benefit in a range of cardiovascular diseases, particularly in disorders in which vasoconstriction, volume overload, and neurohormonal activation play a part in pathophysiology, they conclude.

The study of LCZ696 was funded by Novartis. Ruilope has been an adviser and speaker for Novartis. Disclosures for the coauthors are listed in the paper. Waeber and Feihl report no conflicts of interest.

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