Author + information
- Received August 7, 2014
- Revision received September 10, 2014
- Accepted September 10, 2014
- Published online December 1, 2014.
- ∗Department of Pharmacy, University of Wisconsin School of Pharmacy, Madison, Wisconsin
- †Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
- ↵∗Reprint requests and correspondence:
Dr. Orly Vardeny, University of Wisconsin School of Pharmacy, 777 Highland Avenue, Madison, Wisconsin 53705-2222.
Neprilysin is an enzyme that contributes to the breakdown of the biologically active natriuretic peptides and several other vasoactive compounds. Inhibiting neprilysin has been a therapeutic target for several compounds that have been tested in cardiovascular disease, including ecadotril, candoxatril, omapatrilat, and LCZ696. Although ecadotril, candoxatril, and omapatrilat were initially tested in hypertension and/or heart failure, lack of efficacy and side effects led to discontinuation of their development. LCZ696 (sacubitril valsartan) is a first-in-class angiotensin receptor neprilysin inhibitor that has been developed for use in heart failure. This compound is composed of 2 molecular moieties in a single crystalline complex—the angiotensin receptor blocker valsartan and a neprilysin inhibitor prodrug—and has now been tested in hypertension, in a phase 2 trial in heart failure with preserved ejection fraction, and has demonstrated greater efficacy than enalapril in a phase 3 trial in heart failure with reduced ejection fraction. Its ability to inhibit the renin-angiotensin-aldosterone axis and augment the endogenous natriuretic peptide system provides a distinctive mechanism of action in cardiovascular disease.
Natriuretic peptides (NPs) are a family of hormones that help maintain sodium and fluid balance. Three NPs have been identified: atrial NP (ANP), brain (or B-type) NP (BNP), and C-type NP (CNP) (1). ANP is primarily released from the cardiac atria in response to increased atrial pressure secondary to intravascular fluid overload. BNP is released mainly from the left ventricle as a result of increased filling pressure. The expression of ANP and BNP in the both the atria and ventricles is increased in the setting of cardiac hypertrophy and other conditions that increase cardiac chamber wall stress. Both ANP and BNP have multiple mechanisms of actions, including vasodilation, natriuresis, and diuresis. These mechanisms are mediated primarily through these peptides’ binding to the type A receptors, which are coupled to guanylyl cyclase; activation of the receptor increases intracellular cyclic guanosine monophosphate, which mediates the physiologic effects most relevant to the cardiovascular system (2). CNP is found mostly in the central nervous system, kidneys, and vascular endothelial cells and has antithrombotic and antifibrotic effects and binds to the type B receptor. The significance of CNP to the cardiovascular system is less clear (3,4).
By regulating fluid homeostasis, ANP and BNP help protect the cardiovascular system from negative effects of fluid overload (2). NPs are secreted in response to excess plasma volume and left ventricular filling pressures, commonly found in patients with heart failure (HF), and are thus elevated in these patients (1). NPs contribute to the regulation of sodium and water balance, blood volume, arterial pressure, and sympathetic inhibition through their effects on the venous system, kidneys, and brain. NPs cause direct vasodilation, which results in decreased ventricular preload, systemic vascular resistance, and arterial pressure. Additionally, NPs increase glomerular filtration rate, resulting in natriuresis and diuresis, thus decreasing total body sodium and fluid. Finally, the NPs also reduce renin release from renal juxtaglomerular cells, thereby reducing plasma angiotensin II (and subsequent secretion of aldosterone), resulting in vasodilation. Because NPs are released in the setting of fluid overload, measurement of NPs is a reliable diagnostic marker of dyspnea due to cardiac causes and of the severity of HF (5).
NPs are cleared in several ways: receptor-mediated degradation and breakdown by extracellular proteases (6). The NP type C receptor is thought to function primarily as a “clearing” receptor that can bind all 3 NPs, resulting in receptor-mediated internalization and degradation. NPs are also broken down by the neutral endopeptidase neprilysin, also known as membrane metalloendopeptidase. Neprilysin is expressed in several tissues but most commonly in the kidney. It catalyzes the degradation of numerous endogenous peptides, such as ANP, BNP, CNP, bradykinin, substance P, adrenomedullin, glucagon, and vasoactive intestinal peptide, and also contributes to the breakdown of angiotensin II (1). Other proteases, such as insulin-degrading enzyme, may play a role in NP degradation as well, and the absence of significant physiologic alterations in mice that lack neprilysin suggest that other degradation pathways may compensate when neprilysin is absent or inhibited (7).
Therapeutic Targeting of the NP System in HF
In HF, the natural increases in NPs are ineffective at alleviating fluid overload. One treatment strategy that has been used is exogenous administration of nesiritide, a synthetic BNP drug. In the VMAC (Vasodilation in the Management of Acute Congestive Heart Failure trial), nesiritide alleviated dyspnea at 3 h compared with placebo, and reduced pulmonary capillary wedge pressure compared with nitroglycerin, in patients with acute HF (8). Nesiritide was associated with significant hypotension, and a subsequent analysis raised concerns about its safety in HF (9). Moreover, nesiritide must be delivered intravenously, it is costly, and it has not been proven to reduce morbidity or mortality. In the largest trial to directly test the efficacy of nesiritide in acute HF, ASCEND (the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure Trial), participants with acute HF were randomized to nesiritide or placebo plus usual care (10). The coprimary endpoints were reductions in death or hospitalization for HF at 30 days or reduction in self-assessed dyspnea at 6 or 24 h. Nesiritide did not reduce the rate of death or HF hospitalization at 30 days but was associated with a nonsignificant reduction in dyspnea to a modest degree.
Neprilysin inhibition represents a potential alternative strategy to exogenous BNP administration by preventing the breakdown of endogenous NPs. Candoxatril, the first neprilysin inhibitor available orally, was associated with a dose-dependent increase in ANP and natriuresis but also increased concentrations of angiotensin II because of the effect of neprilysin on the breakdown of angiotensin II (11). Candoxatril was not shown to reduce BP in patients with hypertension, it failed to show reduction in systemic vascular or pulmonary resistance in patients with HF, and its development was discontinued (12). Another neprilysin inhibitor, ecadotril, was tested in a dose-ranging study in 279 patients with HF with reduced ejection fraction (HFrEF) in which safety and efficacy were assessed (13). Patients were randomized to 1 of 5 doses of ecadotril or placebo. Plasma and urinary cyclic guanosine monophosphate were increased in a dose-dependent manner, but there were no changes in plasma renin activity, angiotensin II levels, endothelin I, norepinephrine, and N-terminal pro-BNP (NT-proBNP). There were numerically more deaths in the patients receiving ecadotril and no evidence of efficacy, so development of the compound was stopped.
Omapatrilat was the first representative drug acting through a dual neprilysin and renin-angiotensin system inhibition mechanism. As an inhibitor of both neprilysin and the angiotensin-converting enzyme (ACE), this drug proved more potent than candoxatril in lowering blood pressure (BP) and improving hemodynamics in patients with HF (14,15). Although these initial results with omapatrilat in both hypertension and HF were promising, an outcomes trial in patients with HF failed to show substantial benefit in comparison with the ACE inhibitor enalapril (16). Moreover, the high occurrence and greater severity of angioedema observed in several hypertension clinical studies resulted in withdrawal of the drug from its route to United States Food and Drug Administration approval. The increased risk for angioedema was thought to be due to an increased circulating concentration of bradykinin resulting from the inhibition of 3 proteases—ACE, aminopeptidase, and neprilysin—which all contribute to its degradation, with resulting increased vasodilation and vascular permeability.
The Angiotensin Receptor Neprilysin Inhibitor LCZ696
LCZ696 (sacubitril valsartan) is a first-in-class angiotensin receptor neprilysin inhibitor. LCZ696 is a novel, dual-acting crystalline complex composed of the neprilysin inhibitor sacubitril and the angiotensin receptor blocker valsartan in their anionic forms, sodium cations, and water molecules (Figure 1). Soon after oral ingestion, LCZ696 dissociates into sacubitril (a neprilysin inhibitor prodrug, AHU-377, which is enzymatically cleaved to the active form, LBQ657) and valsartan (17). LCZ696 was designed to have a reduced risk for angioedema because it inhibits only one of the enzymes responsible for bradykinin breakdown.
In a single-dose pharmacokinetic study, valsartan and AHU377 were rapidly absorbed after LCZ696 administration, with maximal concentrations achieved at between 1.7 to 2.2 h and 0.5 to 1.1 h after dosing, respectively (18). Conversion of the prodrug sacubitril to LBQ657, the active compound, occurs within 3.5 h of ingestion. The LBQ657 component exhibits dose-related increases in maximal concentration and area under the concentration-versus-time curve. The half-lives of LBQ657 and valsartan are similar at 12 and 14 h, respectively, allowing twice-daily administration.
In a multidose study, similar to the single-dose study, peak plasma concentrations were rapidly reached for LCZ696, sacubitril, and LBQ657, which indicates rapid breakdown and absorption. A comparison of maximal concentration and areas under the curve between days 1 and 14 of the trial revealed no significant accumulation for valsartan or sacubitril and only a minor amount of accumulation of LBQ657.
The dose-normalized bioavailability of the valsartan component of LCZ696 is 40% to 60% higher than would be delivered by the equimolar amount of valsartan as an individual drug. This increased bioavailability may be due in part to the fact that valsartan in LCZ is present in its anionic form, whereas is normally in the form of a free acid. In a bioavailability study, the mean plasma concentration-time curves of valsartan 320 mg and LCZ696 400 mg were very similar, meeting criteria for drug bioequivalence for systemic exposure of valsartan. There are limited data regarding metabolic pathways for sacubitril and LBQ657 and their alteration of metabolism of drugs that are substrates for the CYP450 system.
Clinical Trials of LCZ696
There have been relatively few clinical trials of LCZ696 (Table 1), although these include trials in hypertension, HF with preserved ejection fraction (HFpEF) and HFrEF.
Similarly to omapatrilat, LCZ696 is a potent BP-reducing agent. In a randomized, double-blind, placebo-controlled, active-comparator study, the antihypertensive effects of LCZ696 were compared with those of the angiotensin-receptor blocker valsartan (19). The study enrolled 1,328 patients 18 to 75 years of age with mild to moderate hypertension. Patients were randomly assigned to 1 of 8 treatment arms for a duration of 8 weeks: LCZ696 at doses of 100 mg, 200, and 400 mg was compared with valsartan at doses of 80, 160, and 320 mg, or AHU377 (the neprilysin inhibitor alone) at a dose of 200 mg, or placebo. All patients underwent a 2-week washout period and a 2-week placebo period before randomization to control for previous treatment with other antihypertensive agents. The primary endpoint of this trial was the mean BP difference across 3 single-dose pairwise comparisons between LCZ696 and valsartan (100 vs. 80 mg, 200 vs. 160 mg, and 400 vs. 320 mg). In the 1,215 patients who completed 8 weeks of therapy, both systolic and diastolic BPs were significantly reduced in participants receiving LCZ 200 mg compared with valsartan 160 mg and in those receiving LCZ 400 mg compared with valsartan 320 mg. Ambulatory BP was also significantly reduced at these doses. The study reported similar overall numbers of adverse events and no occurrences of angioedema.
A second hypertension trial evaluating the safety and efficacy of LCZ696 in 389 Asian subjects using 24-h BP monitoring showed similar efficacy with LCZ696 (20). Patients were randomized to LCZ696 100, 200, or 400 mg or placebo for 8 weeks. In 362 completers, all doses of LCZ696 were associated with significant reductions in systolic and diastolic BPs and pulse pressure, as well as significant reductions in 24-h, daytime, and nighttime ambulatory systolic, diastolic, and pulse pressures for all doses. Moreover, in this study, LCZ696 was well tolerated.
HFpEF accounts for up to 50% of patients with heart failure (21). Although patients hospitalized with HFpEF have similar overall mortality as patients with HFrEF, no specific therapies have proven benefit in HFpEF. The ability of the angiotensin receptor neprilysin inhibitor to simultaneously inhibit the renin-angiotensin-aldosterone axis and augment endogenous NPs provided the rationale for testing this therapy in HF across the spectrum of ejection fraction. The PARAMOUNT (Prospective Comparison of ARNI With ARB on Management of Heart Failure With Preserved Ejection Fraction) trial assessed the efficacy of LCZ696 in patients with HFpEF (22). Inclusion in this trial required patients to have ejection fractions ≥45%, signs and symptoms of HF, and elevations of NT-proBNP. Patients were randomized to LCZ696 200 mg twice daily or valsartan 160 mg twice daily, which is the bioequivalent amount of valsartan in that dose of LCZ696. The primary endpoint of the trial was change in NT-proBNP level from baseline to 12 weeks. NT-proBNP is not a substrate for neprilysin and thus remains an accurate measure of the severity of HF, even in the setting of neprilysin inhibition. Patients were followed through 36 weeks for additional endpoints.
By 4 weeks, NT-proBNP levels were reduced in the LCZ696 arm, and were significantly reduced by 26% compared with valsartan at 12 weeks, meeting the primary endpoint. In addition, at 36 weeks, patients in the LCZ696 arm had greater improvements in left atrial size and greater improvements in New York Heart Association (NYHA) class. These findings were similar in all prespecified subgroups. NT-proBNP reduction was sustained in the LCZ696 arm through 36 weeks, though by 36 weeks, NT-proBNP had declined in the valsartan arm so that levels were no longer significantly different. BP was lowered to a greater extent in the LCZ696 arm. Nevertheless, subsequent analyses have shown that the effects on reduction in NT-proBNP and improvements in left atrial size and NYHA class were independent of the BP-lowering effect (23). Moreover, despite the substantial reduction in BP in the LCZ696 arm, estimated glomerular filtration rate was not reduced in patients receiving LCZ696 and was significantly higher than in those receiving valsartan. LCZ696 was well tolerated in these patients, with no significant differences in adverse events between groups.
These hypothesis-generating findings have provided the rationale for a large outcomes trial in HFpEF. PARAGON-HF (Prospective Comparison of ARNI With ARB Global Outcomes in Heart Failure With Preserved Ejection Fraction; NCT01920711) will use a similar overall study design to that of PARAMOUNT to determine whether LCZ696 can reduce cardiovascular death or total HF hospitalizations in patients with HFpEF. PARAGON-HF will enroll 4,300 patients with HFpEF, left ventricular ejection fractions (LVEFs) ≥ 45%, histories of HF hospitalization within 9 months or elevated NPs, and evidence of structural heart disease, demonstrated by left ventricular hypertrophy or left atrial enlargement. The primary endpoint for the trial will be a composite of cardiovascular death or total HF hospitalizations using recurrent event methods.
The PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial was designed to test the hypothesis that LCZ696 could result in reduced morbidity and mortality in patients with HFrEF (LVEF ≤40%). Inclusion criteria were NYHA functional class II to IV, LVEF ≤40%, plasma BNP ≥150 pg/ml (or NT-proBNP ≥600 pg/ml), or BNP ≥100 pg/ml (or NT-proBNP ≥400 pg/ml) if the patient was previously hospitalized for HF within the past 12 months. Patients were required to be taking stable doses of ACE inhibitors or angiotensin receptor blockers equivalent to enalapril ≥10 mg/day for at least 4 weeks before screening. Other inclusion criteria were estimated glomerular filtration rate ≥30 ml/min/1.73 m2, systolic BP ≥95 mm Hg, and potassium ≤ 5.4 mmol/l. The primary endpoint was the composite of cardiovascular mortality or hospitalization for HF. Secondary endpoints included time to worsening of renal function and all-cause mortality. PARADIGM-HF used a unique study design, with a single-blind active run-in period designed to ensure that patients tolerated both study drugs. Participants who completed run-in were randomly assigned to LCZ696 200 mg twice daily or enalapril 10 mg twice daily in a double-blind fashion (24). The run-in period afforded the data and safety monitoring board early information regarding measures of safety, including hypotension, renal function, and hyperkalemia, because prior experience with this drug in HF had been extremely limited. Enalapril 10 mg twice daily was used as the active comparator, as this has been considered both standard of care and the regulatory gold standard in HF. A sample size of approximately 8,000 patients was required to have 80% power to reduce cardiovascular death by 15%. This number of patients provided >97% power to reduce the primary composite endpoint by 15%. By powering the study for cardiovascular death, it was overpowered for the primary endpoint.
Ultimately, 8,442 patients were randomized from 947 sites in 47 countries (of these, 43 were removed from final analysis because of misrandomization or major good clinical practice violations at the sites) (25). Baseline characteristics represented a typical HFrEF population, with a mean LVEF of 29 ± 6% and optimized background therapy including β-blockers (93%) and mineralocorticoid receptor antagonists (60%). The study population was predominantly NYHA class II (70%) and class III (24%). NPs were elevated (mean NT-proBNP level 1,600 pg/ml, mean BNP level 250 pg/ml).
In late March 2014, the PARADIGM-HF data-monitoring committee reviewed the interim safety and efficacy data and recommended early termination of the trial for efficacy, indicating significant reductions in both the primary endpoint (cardiovascular death or HF hospitalization) and cardiovascular death. The final results confirmed the benefit observed by the data-monitoring committee. After a median duration of follow-up of 27 months, 17.8% of patients in the LCZ696 group and 19.8% of patients in the enalapril group had been discontinued from study drug. The mean daily doses of LCZ696 and enalapril received were 375 and 18.9 mg, respectively.
LCZ696 reduced the primary composite endpoint of cardiovascular death or HF hospitalization by 20% (hazard ratio [HR]: 0.80; 95% confidence interval [CI]: 0.73 to 0.87; p = 0.0000004) (26). Similar reduction was observed for cardiovascular death (HR: 0.80; 95% CI: 0.71 to 0.89; p = 0.00008) and hospitalization for HF (HR: 0.79; 95% CI: 0.71 to 0.89; p = 0.00008). All-cause mortality was reduced by 16% (HR: 0.84; 95% CI: 0.76 to 0.93; p < 0.0002). These findings were consistent across all prespecified subgroups. Hypotension was more common in patients receiving LCZ696 (p < 0.001), although discontinuation because of hypotension was similar in both arms. Elevations in serum creatinine and potassium and cough were less frequent in those assigned to LCZ696. Serious angioedema was rare and similar between groups, although numerically greater in the LCZ696 arm (19 vs 10) and did not result in airway compromise.
The results of PARADIGM-HF must be viewed in the context of the trials that established ACE inhibitors as the gold standard in HF. LCZ696 resulted in similar incremental reduction in mortality as the SOLVD-T (Studies of Left Ventricular Dysfunction–Treatment Arm), which established ACE inhibitors as first-line therapy, with the dose of the active comparator, enalapril, higher than that achieved in SOLVD-T. Although LCZ696 still needs to undergo regulatory approval, the results of PARADIGM-HF provide support for the use of LCZ696 instead of ACE inhibitors as first-line therapy in patients with chronic HF.
Dual inhibition of the renin-angiotensin-aldosterone system and neprilysin inhibition represent a novel approach to treating patients with HF. The results of PARADIGM-HF, showing significant reductions in the primary composite endpoint, cardiovascular death, and all-cause mortality in patients receiving LCZ696 in comparison with those receiving enalapril, suggest that this drug could replace ACE inhibitors and ARBs as first-line therapy in the treatment of patients with HFrEF, once regulatory approval is obtained. Further studies will determine whether this agent has a role in HFpEF and for other indications.
Dr. Solomon has received research support in the form of grants to Brigham and Women’s Hospital from Novartis; and he has consulted for Novartis and Bayer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- angiotensin-converting enzyme
- atrial natriuretic peptide
- brain (or B-type) natriuretic peptide
- confidence interval
- C-type natriuretic peptide
- heart failure with preserved ejection fraction
- heart failure with reduced ejection fraction
- hazard ratio
- left ventricular ejection fraction
- natriuretic peptide
- N-terminal pro–brain (or B-type) natriuretic peptide
- New York Heart Association
- Received August 7, 2014.
- Revision received September 10, 2014.
- Accepted September 10, 2014.
- American College of Cardiology Foundation
- Daniels L.B.,
- Maisel A.S.
- Scotland R.S.,
- Cohen M.,
- Foster P.,
- et al.
- Soeki T.,
- Kishimoto I.,
- Okumura H.,
- et al.
- Maisel A.S.,
- Daniels L.B.
- Lu B.,
- Gerard N.P.,
- Kolakowski L.F. Jr..,
- et al.
- Kostis J.B.,
- Packer M.,
- Black H.R.,
- Schmieder R.,
- Henry D.,
- Levy E.
- Packer M.,
- Califf R.M.,
- Konstam M.A.,
- et al.
- Ruilope L.M.,
- Dukat A.,
- Bohm M.,
- Lacourciere Y.,
- Gong J.,
- Lefkowitz M.P.
- Komajda M.,
- Lam C.S.
- Jhund P.S.,
- Claggett B.,
- Packer M.,
- et al.
- McMurray J.J.,
- Packer M.,
- Desai A.S.,
- et al.