Mechanism of Action
Natriuretic peptides are a group of hormones that have potent effects on sodium and fluid balance. Additionally, they act to inhibit RAAS, reduce sympathetic drive, and have both antihypertensive and anti-proliferative effects. Three types of NPs have been identified: Atrial NP (ANP) and Brain or B-type NP (BNP), released from the atria and left ventricle, respectively, in response to increased filling pressures and increased cardiac chamber wall stress, act to promote natriuresis, diuresis, and vasodilation. The third, C-type NP (CNP) is found in the central nervous system, kidneys, and vascular endothelial cells; however, the significance of this peptide on the cardiovascular system has not been well established. Neprilysin (also known as neutral endopeptidase 24.11) is a zinc-dependent metallopetidase that catalyses the degradation of various peptides including ANP, BNP, and bradykinin, as well as contributes to the breakdown of angiotensin II. Thus inhibition of neprilysin in order to increase circulating levels of NPs has been studied for its therapeutic effect on BP. Though neprilysin inhibition alone has little, if any, antihypertensive effect, concomitant inhibition of both neprilysin and RAAS has demonstrated to synergistically lower BP.
Omapatrilat, an inhibitor of neprilysin and ACE is the most studied vasopeptidase inhibitor. In monotherapy, it has shown greater efficacy in lowering BP than ACE-inhibitors and calcium-channel blockers. However, it was associated with an unacceptable risk of angioedema due to excessive inhibition of bradykinin degradation (presumably via neprilysin, ACE, and aminopeptidase P). In contrast to omapatrilat, in LCZ696, the ACE inhibition has been replaced with an angiotensin II-receptor blocker (ARB) which has lesser effect on bradykinin and thus a lower risk of angioedema. Conceptually, this drug provides the vasodilatory and natriuretic properties of NPs concomitant with inhibitory effects on endothelin, vasopressin, sympathetic activity, and RAAS, but with an improved adverse effect profile (Figure 1).
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Figure 1.
Schematic diagram showing mechanism of action of LCZ696.
Pharmacokinetics and Pharmacodynamics
LCZ696 is an oral tablet composed of a prodrug AHU377 (which is rapidly metabolized in to the active neprilysin inhibitor LBQ657 by enzymatic cleavage of its ethyl ester) and valsartan, a well-established ARB. These two molecular components are present in a 1:1 molar ratio. The maximal concentration of the valsartan component of LCZ696 is reached in 1.7–2.2 h, and 0.5–1.1 h for AHU377 with the active metabolite LBQ657 at peak concentration within 1.9–3.5 h. Mean t1/2 values range from 1.1 to 3.6 h for AHU377, 9.9–11.1 h for LBQ657, and 8.9–16.6 h for valsartan. LBQ657 exerts its inhibitory effect on neprilysin leading to an observed increase in both atrial natruretic peptide and guanosine monophosphate (cGMP). A dose escalation study in 83 healthy participants showed a maximal 40% increase mean cGMP levels at 4 h and significant increases at 12 h post-dose with return to baseline levels at 24 h after administration of LCZ696. In the same study, significant dose-dependent effects of the valsartan moiety lead to increases in renin concentration (93–634%), plasma renin activity (280–1768%), and angiotensin II (241–1188%) compared with placebo. A significant increase of RAAS biomarkers were still observed 24 h after dosing.
These results demonstrated a potent dual neurohormonal effect of LCZ696 on neprilysin and the angiotensin receptor. Peak concentrations of LBQ657 and valsartan were reached within a similar time frame demonstrating comparable pharmacokinetic properties. The pharmacodynamics of these two agents is also similar, exemplified by the maximal concentrations of cGMP and RAAS biomarkers being reached in parallel at 4 h. This is in contrast with omapatrilat which exerted delayed neprilysin inhibition when compared with ACE inhibition. Though the clinical significance of this distinction is not currently known, LCZ696 may have a more balanced participation of its two mechanisms of action in controlling BP which may potentiate its overall efficacy. Moreover, the sustained pharmacodynamic effect of both the valsartan and LBQ657 moieties allows for once-daily dosing of LCZ696 for treatment of hypertension.