Hypertension: LCZ696, a Novel Dual Inhibitor of Neprilysin and the Angiotensin II Receptor, Shows Promise in Phase II Trial

research highlights hypertension lCZ696, a novel dual inhibitor of neprilysin and the angiotensin ii receptor, shows promise in phase ii trial

he dual-action agent lCZ696 inhibitors without [an] increased risk of blocks the angiotensin ii receptor angioedema,” write the researchers. t(via a valsartan moiety) and inhibits ruilope and colleagues conducted neprilysin (via an aHu377 moiety). in a randomized, double-blind, placebo- a phase ii trial, this drug “demonstrated controlled study to compare the superior [blood pressure]-lowering effectiveness and safety of lCZ696 with efficacy as compared to [valsartan] in that of valsartan in the reduction of patients with hypertension,” says luis blood pressure. the participants were ruilope, the study’s principal investigator. 1,328 patients with uncomplicated mild “these study results demonstrate the to moderate essential hypertension potential for managing cardiovascular (mean sitting diastolic blood pressure diseases through enhancement of the 90–109 mmHg at baseline). after a 2-week beneficial effects of the body’s own washout period and a 2-week, single-blind, natriuretic peptides,” he continues. placebo run-in period, each patient was inhibition of neprilysin results in randomly assigned to 8 weeks of treatment increased concentrations of natriuretic in one of eight groups: 100 mg, 200 mg, peptides, which inhibit the activity of or 400 mg lCZ696 daily; 80 mg, 160 mg, or the renin–angiotensin–aldosterone 320 mg valsartan daily; 200 mg aHu377 system and have potent natriuretic and daily; or placebo. Dosages were chosen so vasodilating properties. increased plasma that patients treated with the low, medium, levels of these compounds might confer and high doses of lCZ696, respectively, cardiovascular and renal protection in would have the same exposure to the active patients with hypertension. unfortunately, agents as the patients in the corresponding however, inhibition of this enzyme single-agent groups (which facilitated alone does not seem to decrease blood pairwise comparisons). pressure, perhaps because neprilysin Patients treated with lCZ696 showed sitting diastolic blood pressure, through its degrades vasoconstricting peptides such as greater reductions in mean sitting diastolic two modes of action. angiotensin ii. blood pressure than did those treated adverse events during the 8-week omapatrilat, a vasopeptidase inhibitor with valsartan (an average difference treatment period were rare, mild and that inhibits both neprilysin and across all groups of 2.17 mmHg). the dose-independent. no serious adverse angiotensin-converting enzyme (aCe), largest reductions in mean sitting diastolic events were thought to be related to reduces blood pressure to a greater extent blood pressures were seen with the two lCZ696 administration, and no cases of than either single-action aCe inhibitors highest doses of lCZ696: 2.97 mmHg angioedema were recorded. or calcium-channel blockers. treatment reduction in patients treated with 200 mg ruilope et al. conclude that lCZ696 with omapatrilat is associated with an lCZ696 versus those treated with 160 mg could be a useful treatment for increased incidence of angioedema, valsartan, and 2.70 mmHg reduction in hypertension and cardiovascular diseases however, probably because the three patients treated with 400 mg lCZ696 characterized by vasoconstriction, enzymes the drug inhibits (aCe, versus those treated with 320 mg valsartan. pulmonary overload and neurohormonal aminopeptidase P and neprilysin) are aHu377 treatment slightly reduced activation. the effects of lCZ696 in involved in the breakdown of bradykinin, mean sitting diastolic blood pressure patients with these disorders should be a peptide described by ruilope et al. as compared with placebo. Furthermore, explored in the future. “the putative mediator of angioedema since patients who received 200 mg Baldo Lucchese induced by aCe inhibitors”. aHu377 daily had equivalent exposure to lCZ696 was designed to overcome this agent to those who received 400 mg Original article Ruilope, L. M. et al. Blood-pressure the problem of angioedema. “Drugs that lCZ696 daily but achieved a smaller reduction with LCZ696, a novel dual-acting inhibitor of concurrently inhibit neprilysin and block blood pressure reduction, the researchers the angiotensin II receptor and neprilysin: a randomised, angiotensin ii receptors could offer the demonstrated that lCZ696 has additive double-blind, placebo-controlled, active comparator study. cardioprotective benefits of vasopeptidase and complementary effects on mean Lancet 375, 1255–1266 (2010)