LCZ696 : a new paradigm for the treatment of heart failure?

Drug Evaluation

LCZ696: a new paradigm for the treatment of heart failure? Joan Minguet, Gemma Sutton, Carmen Ferrero, Timothy Gomez & Peter Bramlage†

1.

Introduction

2.

Effects of LCZ696 in vitro and in animal models

3.

Pharmacokinetics and

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pharmacodynamics of LCZ696 4.

Clinical efficacy -- HF-REF

5.

Safety

6.

Conclusion

7.

Expert opinion

†

Institute for Pharmacology and Preventive Medicine, Mahlow, Germany

Introduction: Heart failure (HF) represents a significant healthcare issue because of its ever-increasing prevalence, poor prognosis and complex pathophysiology. Currently, blockade of the renin--angiotensin--aldosterone system (RAAS) is the cornerstone of treatment; however, the combination of RAAS blockade with inhibition of neprilysin (NEP), an enzyme that degrades natriuretic peptides, has recently emerged as a potentially superior treatment strategy. Areas covered: Following the results of the recent Phase III Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure clinical trial in patients with chronic HF with reduced ejection fraction (HF-REF), this review focuses on LCZ696, a first-in-class angiotensin receptor NEP inhibitor. This drug consists of a supramolecular complex containing the angiotensin receptor inhibitor valsartan in combination with the NEP inhibitor prodrug, AHU377. Following oral administration, the LCZ696 complex dissociates and the NEP inhibitor component is metabolized to the active form (LBQ657). Aspects of the trial that might be relevant to clinical practice are also discussed. Expert opinion: Speculation that LCZ696 will pass the scrutiny of regulatory agencies for HF-REF appears to be justified, and it is likely to become a core therapeutic component in the near future. Replication of the eligibility criteria and titration protocol used in the PARADIGM-HF trial would be valuable in clinical practice and may minimize the risk of adverse events. Although long-term data remain to be generated, the promising results regarding hypertension are likely to expedite acceptance of the drug for HF-REF. Keywords: angiotensin receptor blocker, angiotensin receptor neprilysin inhibitor, heart failure, neprilysin, valsartan Expert Opin. Pharmacother. (2015) 16(3):435-446

1.

Introduction

Epidemiology, diagnosis and treatment of heart failure Heart failure (HF) is defined as a complex clinical syndrome resulting from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill or eject blood [1,2]. Estimates suggest that over 23 million patients worldwide have HF, with ~ 550,000 new cases per year reported in the US [3,4]. Following diagnosis, the estimated survival rate is 50% at 5 years and 10% at 10 years, and HF represents the most frequent cause of hospitalization in the elderly (‡ 65 years of age) [5]. In addition to its rising prevalence and poor prognosis, HF represents a major public health concern because it is associated with a variety of comorbidities, including other cardiovascular disorders and metabolic syndromes [3-6]. The diagnosis of HF is often challenging with few specific symptoms. An array of indicators are evaluated, including symptomatic severity, elevated filling pressures, 1.1

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Box 1. Drug summary. Drug name (generic) Phase (for indication under discussion) Indication (specific to discussion) Pharmacology description/ mechanism of action


Route of administration Chemical structure

LCZ696 Phase III Heart failure (HF) with reduced ejection fraction; HF with preserved ejection fraction; hypertension LCZ696 is a small molecule composed of an angiotensin receptor blocker, valsartan, coupled to the neprilysin inhibitor prodrug, AHU377. The twofold mechanism of action of LCZ696 suppresses harmful compensatory mechanisms that are mediated by the renin--angiotensin--aldosterone system, while simultaneously augmenting beneficial adaptive mechanisms by inhibiting degradation of natriuretic peptides Oral H

N Na+

N

O–

N

O

H

N N–

Na+

O O

O O H

N

O

O

O– Na+

Pivotal trial(s)

PARADIGM-HF (NCT01035255); NCT00549770

Pharmaprojects -- copyright to Citeline Drug Intelligence (an Informa business). Readers are referred to Pipeline (http://informa-pipeline.citeline.com) and Citeline (http://informa.citeline.com).

medical history, physical examination and chest radiographs [5]. Symptomatic severity is categorized using the New York Heart Association (NYHA) scale, with classes corresponding to asymptomatic, mild, moderate and severe symptoms (classes I, II, III and IV, respectively). HF is also assessed according to the left ventricular ejection fraction (LVEF). A preserved ejection fraction (PEF) is defined as LVEF ‡ 50%, but definitions of borderline reduced ejection fraction (BREF) and reduced ejection fraction (REF) are inconsistent. The European Society of Cardiology guidelines define BREF as > 35 to < 50% and REF as £ 35%, whereas in the American College of Cardiology/American Heart Association guidelines, BREF and REF are defined as LVEF > 40 to < 50% and £ 40%, respectively [1,2]. Evidence-based treatments for HF with REF (HF-REF) do not enhance survival in patients presenting HF with PEF (HF-PEF) [7-9]. Indeed, the pathophysiology of HF-REF is 436

relatively well understood, whereas the underlying mechanisms of HF-PEF remain to be delineated [8,10]. Epidemiological studies indicate that HF-REF and HF-PEF each account for 50% of HF cases [5,7,11,12]. HF-REF is linked to male sex and ischemic heart disease, whereas HF-PEF is more common in elderly individuals (‡ 65 years), females and patients with other cardiovascular comorbidities (e.g., renal dysfunction, hypertension, atrial fibrillation, dyslipidemia, obesity and diabetes) [10,11,13-15]. HF-REF is associated with an increased risk of sudden death, whereas patients with HF-PEF are more likely to die from non-cardiovascular comorbidities [16]. Data from multicenter, randomized, double-blinded clinical trials have provided the basis for the standard-of-care treatment for HF-REF [1,2,17-21]. Current guidelines recommend that the majority of patients with HF-REF receive three classes of drugs: either an ACE inhibitor (ACEI) or an angiotensin II (AngII) type I receptor blocker (ARB), both of which

Expert Opin. Pharmacother. (2015) 16(3)

LCZ696

Angiotensinogen Renin

DRi

ANP

ACEi

NEP

ACE

NEPi

Hydrolysis of NPs

Angll


CNP

BNP

Angl

ARB

ATR1

NPRB

NPRA

Vasoconstriction/BP increase Hypertrophy Fibrosis Salt and fluid retention

Vasodilation Nateiuresis Diuresis BP reduction

Figure 1. Key neurohormonal signaling pathways in the development and progression of cardiovascular disease [26] are discussed. ACEI: ACE inhibitor; AngII: Angiotensin II; ANP: Atrial natriuretic peptide; ARB: Angiotensin II type I receptor blocker; ATR1: Type-1 angiotensin receptor; BNP: Brain natriuretic peptide; CNP: C-type natriuretic peptide; DRi: Direct renin inhibitors; NEP: Neprilysin; NEPi: Neprilysin inhibitors; NP: Natriuretic peptide; NPRA: Natriuretic peptide receptor A; NPRB: Natriuretic peptide receptor B.

act on the renin--angiotensin--aldosterone system (RAAS); a b-blocker to attenuate sympathetic nervous system activity and a mineralocorticoid antagonist (MRA) [1,22]. ACEIs are preferred over ARBs because improvements in mortality and hospitalization rates have been unequivocally demonstrated, whereas less consistent evidence is available for ARBs [1,2,22]. However, an ARB is recommended for patients who are intolerant to ACEIs, most often because of cough, rash or angioedema [1,2,23]. Other drug classes, such as diuretics, statins and calcium channel blockers, are frequently added to the therapeutic regimen for HF, with the aim of ameliorating HF symptoms as well as coexisting conditions [1,2]. 1.2

Pathophysiology of HF-REF Neurohormonal systems

1.2.1

Neurohormonal systems are important regulators of cardiorenal homeostasis, and their activation is a common theme across the spectrum of cardiovascular diseases. These systems, predominantly the RAAS, the sympathetic nervous system and the endothelin and natriuretic peptide (NP) systems influence blood pressure by controlling natriuresis and diuresis. The development and progression of HF-REF is strongly linked

to two neurohormonal systems with opposing effects: the RAAS, which causes vasoconstriction, and the vasodilationinducing NP system. In addition to vasoactive properties, overstimulation of the RAAS leads to cardiac remodeling effects (e.g., fibrosis and hypertrophy), which are counteracted by the cardioprotective NP system [24,25]. Figure 1 provides an overview of the key neurohormonal signaling pathways that are implicated in cardiovascular disease. Activation of the RAAS and NP systems results in production of effector peptides via membrane-bound metallopeptidase action (ACE and neprilysin [NEP], respectively), as well as cell signaling that is triggered by effector peptide--receptor interactions. Within the RAAS system, the effector peptides AngII and aldosterone are believed to be fundamental for the maintenance of cardiovascular structure and function [24,26]. The NP system includes three related NPs: atrial (A), brain (B), and C-type (C) NP, as well as an atrial NP (ANP) subtype found in the kidneys, which is known as urodilatin. ANP and brain NP (BNP) are released from cardiac myocytes in response to atrial stretch under high venous pressures [27]. They both have diuretic, natriuretic and antihypertensive effects. C-type NP (CNP) is predominantly expressed by


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endothelial cells; however, there is evidence of its secretion by myocytes in damaged heart tissue [28]. Evidence suggests that it decreases cardiac hypertrophy and remodeling [29]. NPs mediate their effects via two types of NP receptors (NPRs), NPR-A (ANP and BNP) and NPR-B (CNP), both of which are coupled to cGMP-dependent signaling [27]. Levels of ANP and BNP are elevated in patients with HF-REF, and they may be used as diagnostic and prognostic markers [30,31]. Moreover, NPs were recently demonstrated to play a role in normal aging processes in the kidney and heart, and genetic polymorphisms that increase NP precursor levels are associated with lower blood pressure and a favorable metabolic profile [27,32]. However, attempts to harness the therapeutic potential of NPs by exogenous administration have been unsuccessful, in part due to the high turnover of NPs in heart disease [26]. Neprilysin Although the metallopeptidase, neutral endopeptidase (NEP), is expressed throughout the body, it is most abundant in the brush border of proximal renal tubular cells. It is responsible for the processing and catabolism of several vasoactive peptides, including members of the RAAS (e.g., AngI, AngII and endothelin-1), as well as NPs and bradykinin. Thus, inhibition of NEP targets (both harmful and protective pathways), as well as clinical trials using specific small-molecule inhibitors (thiorphan and candoxatril), indicated that isolated NEP blockade is an ineffective approach [27,32]. Nevertheless, NEP inhibitors have been demonstrated to increase circulating NP levels and enhance natriuretic/diuretic processes in healthy and cardiovascular disease models [26,27,32]. With this in mind, the dual ACEI/NEP inhibitor, omapatrilat, was evaluated in patients with hypertension and HF. Although omapatrilat displayed a good efficacy profile, its development was suspended because of off-target effects, primarily an increased frequency of angioedema among hypertensive patients [26,33]. It is now known that both ACE and NEP metabolize bradykinin, such that concurrent ACE/NEP inhibition causes a substantial rise in bradykinin levels [27,32,34]. Indeed, the most frequent reason for intolerance to ACEIs is cough (up to 20%), which is also attributed to bradykinin. Notably, ARBs represent a suitable alternative to ACEIs because the mechanism of RAAS blockade is specific to the AngII receptor, rather than directly targeting ACE [35,36].

in HF-PEF was ongoing. On July 2014, the FDA granted fast-track designation to LCZ696 for HF-REF, and a marketing authorization application for this indication was to be filed in late 2014 [38]. Following the FDA’s positive opinion on LCZ696, results of the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in HF Trial (PARADIGM-HF) were highly anticipated. Indeed, this trial represented the largest study ever conducted in patients with HF-REF. LCZ696 significantly reduced cardiovascular mortality and other measures of efficacy, with no safety concerns [39]. Therefore, LCZ696 is expected to be the first new drug approved for a broad HF-REF population since 2005. The following sections describe the characteristics of LCZ696 in the setting of HF-REF, with an emphasis on issues that may be pertinent to its use in clinical practice.

1.2.2

Effects of LCZ696 in vitro and in animal models

2.

Adult male rats were used to determine the impact of LCZ696 (68 mg/kg, orally for 4 weeks; n = 11) relative to vehicle (n = 6) on cardiac remodeling, when administered 1 week after induction of myocardial infarction (MI) [40]. At 4 weeks, LCZ696-treated hearts had a lower weight (1168 ± 35 vs 1319 ± 21 mg), and echocardiography revealed a lower left ventricular end-diastolic diameter (9.7 ± 0.2 vs 10.5 ± 0.3 mm) and a higher LVEF (60 ± 2 vs 47 ± 5%; all p < 0.05 vs vehicle). Studies in rat cell lines demonstrated that compared with valsartan (up to 1.0 mM), LCZ696 (1 µM) suppressed AngII (100 nM)-induced hypertrophy in cardiomyocytes more effectively, as assessed by 3[H]leucine uptake over 60 h, and inhibited collagen accumulation in cardiac fibroblasts and renal mesangial cells, as assessed by 3 [H]proline incorporation over 48 h (all p < 0.001). Incubation of neonatal rat cardiac fibroblasts with a combination of LBQ657 (10 mM; the active metabolite of LCZ696) and valsartan (1.0 mM) resulted in complete inhibition of AngII-induced collagen production. These data indicate that LCZ696 attenuated cardiac remodeling following experimental MI in rats, an effect that might be attributed to anti-hypertrophic and anti-fibrotic properties [40].

1.3

Pharmacokinetics and pharmacodynamics of LCZ696

LCZ696 (Box 1) is a first-in-class, angiotensin receptor NEP inhibitor (ARNI) that consists of a supramolecular complex of a molecule of the ARB valsartan in combination with a molecule of the NEP inhibitor prodrug AHU377 (also known as sacubitril). The AHU377 component is metabolized to the active form (LBQ657) by enzymatic cleavage of its ethyl ester. LCZ696 is under development by Novartis for the treatment of hypertension, HF-REF and HF-PEF [37]. At the time of publication, a Phase III clinical trial

The pharmacokinetic profiles of valsartan, as well as AHU377 (the inactive prodrug), and LBQ657 (the active metabolite) were evaluated in a randomized, double-blind, placebo-controlled, parallel-group, dose-escalation clinical trial in which LCZ696 (200 -- 900 mg/day for 14 days) was administered to healthy individuals (n = 65) [41]. Reported steady-state pharmacokinetic parameters for the three species are presented in Table 1, where the short t1/2 of AHU377 demonstrates its rapid conversion to the active

3.

Angiotensin receptor NEP inhibition as a therapeutic strategy

438


LCZ696

Table 1. Steady-steady pharmacokinetics of valsartan, the prodrug AHU377 and the active metabolite LBQ657: doses of 200 mg/day LCZ696 in healthy individuals.

Valsartan AHU377 LBQ657

Cmax (ng/ml)

Tmax (h)

t1/2 (h)

AUC0

3990 (685) 1974 (678) 8563 (2652)

1.8 (0.5) 0.6 (0.2) 1.8 (0.5)

22.1 (16.5) 1.7 (0.9) 13.0 (3.0)

24,097 (4680) 2083 (803) 82,903 (16,136)

-- last


Mean values (± standard deviation) are provided for the Cmax, t1/2 and AUC between the first (0.5 h) and the last observation (72 h post-dose; AUC0 Median values (range) are provided for the Tmax. Data taken from [41].

(h.ng/ml)

-- last).

Table 2. Steady-state pharmacokinetics of valsartan, the prodrug AHU377 and the active metabolite LBQ657: doses of 400 mg/day of LCZ696 in individuals with varying extents of renal impairment. Mild/matched control Cmax (ng/ml) Valsartan 6873 (4348)/ 6275 (2242) AHU377 3904 (1,780)/ 3125 (1729) LBQ657 27,150 (6449)/ 16,838 (3063) Tmax (h) Valsartan 2.5 (1 -- 4)/ 2 (1 -- 3) AHU377 1 (0.5 -- 2)/ 0.5 (0 -- 2) LBQ657 3 (2 -- 4)/ 3 (2 -- 3) t1/2 (h) Valsartan 15.4 (4.7)/ 14.5 (3.7) AHU377 1.6 (0.6)/ 4.7 (6.0) LBQ657 21.1 (8.3)/ 12.6 (1.7) AUC0 -- 24 (h.ng/ml) Valsartan 59,223 (50,669)/ 39,517 (17,227) AHU377 5,656 (1,859)/ 5,221 (1,162) LBQ657 371,331 (99,259)/ 172,335 (21,925)

Moderate/matched control

Severe/matched control

7664 (2612)/ 8006 (3895) 4,109 (1,739)/ 3,756 (1,644) 28,988 (7861)/ 18,375 (3215)

5,852 (3306)/ 5672 (1314) 4,960 (3430)/ 2,407 (1,780) 30,650 (11,462)/ 18,233 (1975)

2 (2 -- 2)/ (2 -- 2) 0.5 (0.5 -- 1)/ 0.5 (0.5 -- 1) 3 (2 -- 4)/ 3 (2 -- 4)

2 (1 -- 3)/ 2 (1 -- 2) 0.5 (0.5 -- 1.0)/ (0.5 -- 0.5) 2 (2 -- 4)/ 2.5 (2 -- 4)

22.7 (14.6)/ 12.4 (3.0) 2.9 (2.3)/ 1.8 (1.2) 23.7 (5.0)/ 12.3 (2.2)

26.4 (9.20)/ 13.0 (2.99) 2.0 (1.3)/ 1.9 (0.7) 38.5 (17.3)/ 13.2 (2.68)

51,777 (18,967)/ 56,460 (31,412) 5,283 (2267)/ 5716 (1849) 437,134 (146,930)/ 190,598 (44,468)

51,084 (33,780)/ 32,474 (8687) 5,459 (2890)/ 4336 (746) 538, 342 (268,653)/ 185,549 (29,759)

Mean values (± standard deviation) are provided for Cmax, t1/2 and AUC0 Data taken from [42,43].

-- -24h.

form. Concerning AUC values, the rank order was AHU377 < valsartan < LBQ657. Pharmacodynamic analyses demonstrated that at 12 h, the 200-mg dose of LCZ696 increased cGMP/AngII levels and enhanced plasma renin activity (all p < 0.05 vs placebo) [41]. In patients with mild (creatinine clearance [CrCl]: 50 to £ 80 ml/min), moderate (CrCl: 30 to £ 50 ml/min) or severe (CrCl: < 30 ml/min) renal impairment, Cmax values for LBQ657 were shown to be higher than for healthy individuals, with increasing severity of impairment correlating with increasing LBQ657 levels (Table 2) [42,43]. The same trend can be seen for t1/2 and AUC values. 4.

Clinical efficacy -- HF-REF

Study protocol, eligibility criteria and end points The randomized, double-blind, parallel-group, activecontrolled, two-arm, event-driven, PARADIGM-HF clinical trial enrolled adults (n = 8442) with chronic HF-REF (£ 35%; originally £ 40% [amendment 1]) and NYHA 4.1

Median values (range) are provided for Tmax.

symptoms that were mainly class II -- III, with a small proportion of patients having class I or class IV. Key inclusion criteria included plasma BNP ‡ 150 pg/ml (or NT-proBNP ‡ 600 pg/ml) at screening or BNP ‡ 100 pg/ml (or NTproBNP: N-Terminal prohormone of BNP ‡ 400 pg/ml) and HF-related hospitalization during the prior 12 months. For at least 4 weeks prior to screening, all patients were receiving stable doses of an ACEI or an ARB at a dose level equivalent to the evidence-based dose of enalapril of 10 mg/day, as well as a b-blocker (unless contraindicated or intolerable). Table 3 shows the most commonly prescribed ACEIs and ARBs at screening, as well as the mean daily dose of each agent. The protocol also indicated that an MRA should be considered for all patients with more serious HF. Patients who had a history of angioedema were excluded. The trial consisted of a screening period, a 2 -- 4 weeks enalapril single-blind run-in, discontinuation of enalapril for 36 h, a 3 -- 6 weeks LCZ696 single-blind run-in, followed by a 36-h washout prior to randomization to either enalapril or LCZ696. During the first 1 -- 2 weeks of the run-in period,


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Table 3. Mean daily doses of ACE inhibitor; A and ARB; B at the screening visit of the PARADIGM-heart failure trial.

Type of ACE inhibitor Enalapril Ramipril Perindopril Lisinopril Type of ARB Losartan Valsartan Telmisartan Candesartan

Frequency *

Daily dose (mg)

38.0 32.5 19.5 10.0

16.4 (8.3) 7.0 (3.1) 5.9 (2.7) 18.2 (12.1)

50.3 25.3 12.5 11.9

67.1 (30.2) 181.5 (71.1) 60.1 (23.9) 20.0 (9.6)

Mean values (± standard deviation) are reported for the daily dose. *Calculated from a total of 5750 and 1572 patients for whom data on the drug prescribed for each respective type of drug at screening were available. The total number of patients who attended a screening visit was not reported. Data taken from [39]. ARB: Angiotensin receptor blockers.

enalapril was administered at a dose of 5 mg twice daily for patients treated with an ARB and those taking a low-dose ACEI, with up-titration to a target dose of 10 mg twice daily. For LCZ696, doses of 100 mg twice daily were administered for 1 -- 2 weeks, and the dose was up-titrated to a target of 200 mg twice daily for 2 -- 4 weeks. During randomized, double-blind treatment, follow-up visits were conducted every 2 -- 8 weeks during the first 4 months, followed by every 4 months over a median follow up of 27 months. The composite primary outcome was the occurrence of cardiovascular death or a first hospitalization for HF, but the trial was powered to detect a significant difference between the two arms in cardiovascular death as a sole outcome. The specified event rate for the co-primary end point was 2410 patients, at which point the trial could be halted [23,39,44]. A schematic representation of the screening, run-in, randomization and doubleblind phases of the trial, including patient numbers, is provided in Figure 2.

Patient demographics and treatment characteristics at baseline

4.2

At baseline, the characteristics of patients in the LCZ696 (n = 4187) and enalapril (n = 4212) arms were similar in terms of age, gender, ethnicity, systolic blood pressure, heart rate, body mass index and serum creatinine [39]. In regard to the clinical features of HF, ischemic cardiomyopathy was present in ~ 60% of patients, and the mean LVEF was ~ 29.5%. Median levels of BNP and NT-pro-BNP were also similar in the LCZ696 (255 and 1631 pg/ml, respectively) and enalapril (251 and 1594 pg/ml, respectively) arms. The majority of patients were NYHA functional class II (70 -- 71%), whereas almost one-quarter were class III, £ 5% were class I and £ 1% were class IV. Medical histories demonstrated that 440

cardiovascular risk factors were common, including hypertension (71%), prior hospitalization for HF (62 -- 63%), MI (43%), atrial fibrillation (36 -- 37%) and diabetes (35%). Mean daily doses of LCZ696 and enalapril among patients who remained on treatment were 375 ± 71 and 18.9 ± 3.4 mg, respectively, at the last visit [39]. Concomitant HF medications were continued throughout all trial phases; specific details regarding these are summarized in Table 4. Trial outcomes After a median follow-up period of 27 months, the primary outcome of cardiovascular death or a first hospitalization for HF had occurred in 914 (21.8%) patients in the LCZ696 arm compared with 1117 (26.5%) patients in the enalapril arm (p < 0.001). When assessed individually, both cardiovascular death and first HF hospitalization occurred in a lower proportion of patients in the LCZ696 arm in comparison to the enalapril arm (p < 0.001 for both outcomes). Death from any cause was also less frequent in the LCZ696 arm (17.0%) than the enalapril arm (19.8%; p < 0.001). Moreover, disease symptoms and physical function, as measured using Kansas City Cardiomyopathy Questionnaire scores, deteriorated less in the LCZ696 arm (-2.99 ± 0.36 vs -4.63 ± 0.36 points; p = 0.001). The incidence of atrial fibrillation and renal function decline was similar among the patients in the two groups (Figure 3). Subanalyses demonstrated that the risk of the composite primary end point or cardiovascular death occurring in the LCZ696 or enalapril arms was not affected by patient-specific risk factors, including age, race, comorbidities and prior use of ACEIs or MRAs [39]. 4.3

5.

Safety

Patients with HF-REF In the PARADIGM-HF trial, the intention-to-treat safety population comprised 4187 patients in the LCZ696 arm and 4212 patients in the enalapril arm. The most frequent reasons for permanently discontinuing LCZ696 or enalapril were similar: hypotension (36 [0.9%] and 29 [0.7%] patients, respectively; p = 0.38), renal impairment (29 [0.7%] and 59 [1.4%] patients, respectively; p = 0.002) and hyperkalemia (11 [0.3%] and 15 [0.4%] patients, respectively; p = 0.56). Overall, a lower proportion of patients in the LCZ696 arm discontinued treatment because of an adverse event (10.7 vs 12.3%; p = 0.03). Hypotensive episodes, defined as symptomatic and asymptomatic with systolic blood pressure < 90 mmHg, were more common in LCZ-treated patients (n = 588 [14.0%] and n = 112 [2.7%], respectively) than in enalapril-treated subjects (n = 388 [9.2%] and n = 59 [1.4%]; p < 0.001 for both types of hypotensive episode). Elevated serum creatinine (‡ 2.5 mg/dl), was observed in a lower proportion of patients in the LCZ696 arm (n = 139 [3.3%]) compared to the enalapril arm (n = 188 [4.5%]; p 0.007), whereas the proportion of patients with elevated serum potassium levels (> 5.5 mmol/l) 5.1


LCZ696

A.

10,513 Patients entered enalapril run-in phase (median duration, 15 days; IQR, 14 – 21)


1102 Discontinued study 591 (5.6%) Had adverse event 66 (0.6%) Had abnormal laboratory or other test result 171 (1.6%) Withdrew consent 138 (1.3%) Had protocol deviation, had administrative problem, or were lost to follow-up 49 (0.5%) Died 87 (0.8%) Had other reasons

9419 Entered LCZ696 run-in phase (median duration, 19 days; IQR, 26 – 35)

977 Discontinued study 547 (5.8%) Had adverse event 58 (0.6%) Had abnormal laboratory or other test result 100 (1.1%) Withdrew consent 146 (1.6%) Had protocol deviation, had administrative problem, or were lost to follow-up 47 (0.5%) Died 79 (0.8%) Had other reasons

8442 Underwent randomization

43 Were excluded 6 Did not undergo valid randomization 37 Were from four sites prematurely closed because of major GCP violations

4187 Were assigned to receive LCZ696 4176 Had known final vital status 11 Had unknown final vital status

4212 Were assigned to receive enalapril 4203 Had known final vital status 9 Had unknown final vital status

Figure 2. Schematic representation of the run-in, randomization (A) and treatment (B) phases of the PARADIGM-HF clinical trial. Data taken from [39,44]. bid: Twice daily; GCP: Good clinical practice; IQR: Interquartile range; m: Months; w: Weeks.

was similar (n = 674 [16.1%] and n = 727 [17.3%] in the two respective arms; p = 0.15). The frequency of cough was 11.3% (n = 474) with LCZ696 and 14.3% (n = 601) with enalapril. In regard to angioedema, which was evaluated in a blinded manner by an expert committee and classified into four categories of severity, the overall event rate was 19 (0.45%) and

10 (0.24%) in the LCZ696 and enalapril arms, respectively. No cases of angioedema causing airway compromise were reported in either arm, and no differences were observed when analyzing according to the severity of angioedema. Using data from the total safety population (n = 4203 and n = 4229 patients in the LCZ696 and enalapril arms,


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Single-blind active run-in period

B.

Double-blind treatment period

Enalapril run-in Visit 2A Enalapril 5 mg b.i.d. (optional) 1 – 2w

LCZ696 200 mg b.i.d.

LCZ696 run-in

Screening


Enalapril 10 mg b.i.d.

Visit Time

LCZ696 LCZ696 100 mg b.i.d. 200 mg b.i.d.

2 1w

3 2w

4 1 – 2w

2-4w

Enalapril 10 mg b.i.d.

5

6

7

8

9

10

Up to end of study

0

2w

4w

8w

4m

8m

Visit every 4m

Figure 2. Schematic representation of the run-in, randomization (A) and treatment (B) phases of the PARADIGM-HF clinical trial. Data taken from [39,44]. bid: Twice daily; GCP: Good clinical practice; IQR: Interquartile range; m: Months; w: Weeks.

Table 4. Treatments prescribed for heart failure at baseline. Type of treatment

Percentage of patients

b-blocker Diuretic Mineralocorticoid antagonist Anticoagulant Digoxin Any antiplatelet Lipid lowering Aspirin ADP antagonist

93 80 60 32 30 57 56 52 15

respectively), at least one adverse event (regardless of the relationship to study drug) was reported by 81.4 and 82.8% of patients in two respective treatment arms. Additionally, one serious adverse event (irrespective of the relationship to study drug) occurred in 46.1 and 50.7% of patients in the two respective arms. Details regarding adverse events that occurred in ‡ 5% of patients and serious adverse events that occurred in ‡ 2% of patients, in either treatment group, are displayed in Figures 4 and 5, respectively [39]. Specific patient populations Renal failure

5.2.1

The effects of LCZ696 in patients with renal impairment are of interest because NEP inhibition is expected to improve kidney function [27]. This idea is supported by data from the PARADIGM-HF trial, where elevated serum creatinine levels (‡ 2.5 mg/dl) were found in fewer patients in the LCZ696 arm in comparison to the enalapril arm, although 442

Diabetes mellitus Interestingly, a recent study demonstrated that low levels of NPs correlate with the onset of diabetes mellitus [45], suggesting that restoration of healthy NP levels may delay or prevent disease development. NEP inhibition with omapatrilat improved glucose hemostasis, but to the authors’ knowledge, the effects of LCZ696 on glucose and lipid metabolism have not been explored. It has been suggested that metabolic effects, such as changes in lipolysis, may be observed on use of ARNIs [45,46]. 5.2.2

Data taken from [39].

5.2

no significant difference in proportions of patients with a decline in renal function (based on estimated glomerular filtration rate) were found [39]. The OVERTURE trial found that renal impairment was documented less frequently in patients taking omapatrilat in comparison to those receiving enalapril [33]. At the time of publication, the effect of LCZ696 on renal function was being assessed in comparison to irbesartan in patients with chronic kidney disease (UK HARP III trial).

Susceptibility to angioedema Angioedema is a rare but potentially fatal adverse effect of RAAS-blocking drugs [35]. In this regard, among ACEIs, ARBs and renin inhibitors, ARBs are associated with the lowest risk of angioedema [35,36,47]. In a meta-analysis of seven clinical trials directly comparing ACEIs with ARBs, the risk of angioedema was 2.2-fold higher with ACEIs; when compared with placebo, the risk of angioedema was 2.8-fold higher with ACEIs but not different for ARBs [35]. The relationship between different RAAS-blocking agents and the frequency of angioedema was also clearly demonstrated by an observational, retrospective study in which US health records were used to compile data from almost 4 million patients who initiated treatment with an ACEI, an ARB or a b-blocker. 5.2.3


LCZ696

2.6 2.2

Decline in renal function

p = 0.28

Enalapril LCZ696

3.1 3.1

New-onset atrial fibrillation

p = 0.83 19.8 p < 0.001

All-cause mortality

17

First hospitalization for worsening HF

15.6 12.8

Cardiovascular mortality

13.3 0

5

10 15 Frequency (%)

p < 0.001 20

Figure 3. Primary and secondary outcomes in the PARADIGM-HF clinical trial are shown.

14.0 15.4

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Figure 4. Incidence of serious adverse events, irrespective of the relationship to study drug, which occurred in $ 1% of patients in either treatment arm in the PARADIGM-HF trial is shown.

During the 10-year follow-up period, the rate of angioedema was 0.18% for ACEIs, 0.06% for ARBs and 0.06% for bblockers [47]. Although the risk of angioedema with ARBbased treatment appears to be very low, clinicians should be aware of patient-related factors that increase the risk of angioedema following exposure to RAAS-blocking agents. These include black ethnicity, female sex and old age [36,48], although no genetic correlation has been identified [49]. 6.

significance in comparison to an ACEI, the standard of care for HF-REF. Hypotensive episodes occurred more frequently in the LCZ696 arm, but the rates of elevated serum creatinine levels and cough were higher in the enalapril arm. Importantly, LCZ696 did not increase the risk of angioedema relative to enalapril, and trials of LCZ696 in patients with hypertension have confirmed the safety profile of the drug in this respect. Published findings suggest that LCZ696 may have a greater impact on the prognosis of patients with HF-REF than the current standard treatment. Thus, on the basis of future studies demonstrating long-term safety, it may be anticipated that LCZ696 will take a central role in the pharmacotherapy of HF-REF.

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HF: Heart failure.

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p < 0.001 16.5

Conclusion

LCZ696 displayed an exemplary profile in the PARADIGMHF clinical trial. Indeed, both primary end points, as well as two out of four secondary end points, were met with high

Expert opinion

Patients with HF-REF experience a progressive decline in their quality of life, and they often present with multiple comorbidities that further diminish functioning and well-being. Moreover, cardiovascular disease is the most common cause of death worldwide [50], and hospitalizations from HF cover a substantial proportion of healthcare budgets. Effective treatments for HF-REF represent an unmet need, and an agent that has a relevant impact on the most distressing outcomes, death and hospitalizations, would be extremely valuable. This has been demonstrated with LCZ696 in the setting of a single, Phase III clinical trial. In fact, because of the significant benefits associated with LCZ696, it is likely to be introduced into clinical practice in the near future. Nevertheless, the long-term safety of LCZ696 and its efficacy and safety within the general HF-REF population remains to be confirmed. Several features of the PARADIGM-HF clinical trial are worth noting because they are relevant to the use of LCZ696 on a wider scale. A careful up-titration scheme was adhered to during the run-in, and a washout period of 36 h was implemented to prevent concomitant exposure to ACE inhibition and NEP inhibition. The run-in period, during


443

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J. Minguet et al.

Figure 5. Incidence of adverse events, irrespective of the relationship to study drug, which occurred in $ 2% of patients in either treatment arm in the PARADIGM-HF trial is shown.

which patients were exposed to both drugs, enabled those who were intolerant to either drug to be identified and eliminated from the randomized treatment period. Moreover, patients with a history of angioedema and/or known or suspected hypersensitivity, allergic reactions or contraindications to either of the study drugs were excluded. In addition, all patients had been receiving treatment with a RAAS-blocking agent (either an ACEI or an ARB) prior to the trial. As demonstrated by the low rate of adverse events, in particular angioedema, with both enalapril and LCZ696, this selection process was effective in limiting the number of cases. The demographics of the PARADIGM-HF patient population have been reported to be similar to those in other large randomized trials in HF-REF [39,51,52]. Patients of black ethnicity were underrepresented, comprising ~ 5%; however, this phenomenon has been demonstrated in previous HF trials and could be because of a high prevalence of ACEI intolerance within that specific population [53]. It has been reported that > 80% of HF deaths occur in patients at ‡ 65 years of age [54], which is older than the mean age of the PARADIGM-HF population. Thus, more detailed analyses of LCZ696 in different patient populations are awaited (e.g., non-diabetic and diabetic patients with HF).

444

In addition, the influence of LCZ696 on other disease parameters in patients with HF-REF remains to be examined, including changes in the LVEF, glucose metabolism and heart rate. Because LCZ696 is able to simultaneously enhance anti-fibrotic and suppress pro-fibrotic and hypertrophic effects, visualization of the cardiac structure of treated patients may reveal amelioration or modulation of remodeling processes. Furthermore, preclinical data are necessary to fully characterize the mechanisms of action of LCZ696. Given that NEP is widely expressed in the body, making it a therapeutic target for other diseases, LCZ696 may influence an array of physiological processes. Indeed, clinical trials in patients with HF-PEF are underway, and it is hoped that the success of LCZ696 in HF-REF can be replicated in HF-PEF.

Declaration of interest P Bramlage is a consultant for a number of pharmaceutical companies producing HF drugs. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.


LCZ696

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Affiliation Joan Minguet1,2 MSc, Gemma Sutton1 MSc, Carmen Ferrero3 PhD, Timothy Gomez1 PhD & Peter Bramlage†1,2,3 MD PhD † Author for correspondence 1 Institute for Research and Medicine Advancement (IRMEDICA), Barcelona, Spain 2 Institute for Pharmacology and Preventive Medicine, Menzelstrasse 21, 15831 Mahlow, Germany Tel: +49 3379 3147890; Fax: +49 3379 3147892; E-mail: [email protected] 3 University of Sevilla, Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, Sevilla, Spain

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