LCZ696, a First‐in‐Class Angiotensin Receptor‐Neprilysin Inhibitor: The First Clinical Experience in Patients With Severe Hypertension

Abstract

The safety of LCZ696, a novel angiotensin receptor‐neprilysin inhibitor, was evaluated for the first time in patients with severe hypertension in this 8‐week, multicenter, open‐label study. Thirty‐five Japanese patients with either office systolic blood pressure (SBP) ≥180 mm Hg or diastolic blood pressure (DBP) ≥110 mm Hg received LCZ696 200 mg. If blood pressure was uncontrolled, the LCZ696 dose was increased to 400 mg after 2 weeks (if there were no safety concerns; n=32), followed by an optional addition of another antihypertensive drug (except angiotensin receptor blocker and angiotensin‐converting enzyme inhibitor) after 4 weeks (n=21). Reductions in office SBP/DBP (baseline, 173.4 mm Hg/112.4 mm Hg) and pulse pressure (baseline, 61.0 mm Hg) at week 8 were 35.3/22.1 mm Hg and 13.2 mm Hg, respectively. The overall incidence of adverse events was 48.6% with no reports of dizziness, hypotension, or angioedema. The LCZ696‐based regimen was generally well‐tolerated and could present a treatment option for severe hypertension in Asian patients especially in reducing SBP and pulse pressure.

Severe hypertension (grade 3; office systolic blood pressure [SBP] ≥180 mm Hg or office diastolic blood pressure [DBP] ≥110 mm Hg) is associated with a high risk of hypertensive emergencies and cardiovascular (CV) risk.1, 2 CV mortality was reported to increase exponentially with increasing levels of blood pressure (BP) from ≥115/75 mm Hg.3

Early, effective, and rapid BP control in patients with severe hypertension is needed to significantly reduce CV risk and long‐term adverse clinical outcomes.4 Antihypertensive agents with favorable efficacy and safety profiles are required for the treatment of severe hypertension. Guidelines recommend combination therapy for the treatment of severe hypertension, initially a thiazide‐type diuretic with an angiotensin‐converting enzyme (ACE) inhibitor, an angiotensin receptor blocker (ARB), a β‐blocker, or a calcium channel blocker (CCB).5 However, treatment of severe hypertension has been shown to be inadequate, with a small proportion of patients achieving BP control,4 which might be the result of a lack of lifestyle modifications or initiation of antihypertensive drug at inadequate doses or drug combinations.

Asian patients show several typical characteristics with respect to hypertension and BP‐lowering effect of drugs.6 A steeper association between BP and risk of stroke has been seen in Asians compared with Caucasians.7 In addition, high salt intake and genetically high salt‐sensitivity have been reported in Japanese.8 The effect of high salt intake would be greater in Asian patients with hypertension, considering the increasing prevalence of obesity and metabolic syndrome, which, in turn, are known to increase salt‐sensitivity.9, 10 Thus, there is a possibility that high salt intake and increased salt‐sensitivity could be a cause of severe hypertension in Asians.

Monotherapy with renin‐angiotensin‐aldosterone system (RAAS) inhibitors was found to be less effective in providing BP reductions than CCBs in Asian patients who tend to have high salt intake and salt‐sensitivity.11, 12 An antihypertensive drug that provides neprilysin inhibition with simultaneous RAAS inhibition may offer better target organ protection compared with other pharmacotherapies.

LCZ696 acts as an angiotensin receptor‐neprilysin inhibitor (ARNI). After ingestion, LCZ696 delivers systemic exposure to sacubitril (AHU377), a neprilysin inhibitor pro‐drug, and valsartan, an ARB. Subsequently, sacubitril gets rapidly metabolized by nonspecific esterases13 to the active neprilysin inhibitor LBQ657.

Neprilysin inhibitors enhance levels of active natriuretic peptides that confer protection to cardiac, vascular, and renal systems by vasodilation, natriuresis, diuresis, RAAS inhibition, sympathetic tone reduction, antiproliferative effects, and antihypertrophic effects.14 Thus, enhancing natriuretic peptide levels present a potentially important therapeutic option for the treatment of hypertension and heart failure.15 The significance of neprilysin inhibition with simultaneous RAAS inhibition would be particularly important in Asians because of their high salt intake and higher salt‐sensitivity.

LCZ696 has demonstrated significant dose‐dependent reductions in office and ambulatory BP compared with valsartan or placebo, in particular, SBP and pulse pressure (PP) reductions, and was found to be generally well tolerated in Caucasians and Asian patients with mild to moderate hypertension.16, 17 In patients with heart failure in the Prospective Comparison of Angiotensin Receptor‐Neprilysin Inhibitor With Angiotensin‐Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial (PARADIGM‐HF), LCZ696 was superior in reducing the risk of CV death and HF hospitalization compared with the ACE inhibitor, enalapril.18 This is the first study that aimed to evaluate the safety and efficacy of LCZ696 in Asian patients with severe hypertension.

Materials and Methods

Patients

Men and women of Japanese origin, aged 20 years and older, diagnosed with severe hypertension, and either untreated or treated with antihypertensive agents for during 4 weeks prior to screening were enrolled. Untreated patients (newly diagnosed or not receiving antihypertensive agents during 4 weeks prior to screening) who had office SBP ≥180 mm Hg and <220 mm Hg or office DBP ≥110 mm Hg and <120 mm Hg at screening and after the no‐treatment run‐in period were eligible. Treated patients who had office SBP ≥180 mm Hg and <220 mm Hg or office DBP ≥110 mm Hg and <120 mm Hg after the no‐treatment run‐in period were eligible.

Other key exclusion criteria included history of angioedema or a secondary form of hypertension; history of significant CV/cerebrovascular disease, active liver disease, renal dialysis, or renal transplantation; previous or current diagnosis of heart failure; diabetes mellitus not well controlled; malignancy; and any significant laboratory abnormalities at screening such as serum potassium >5.5 mmol/L, alanine aminotransferase or aspartate aminotransferase >2 times the upper limit of the normal range, and serum creatinine >1.5 times the upper limit of the normal range.

Study Design

This was an 8‐week, multicenter, open‐label, efficacy and safety trial. The study protocol was reviewed and approved by an independent institutional review board at each center (Clinicaltrials.gov NCT01646671). Written informed consent was obtained from each patient before participation in any of the study procedures. The study was conducted in accordance with the International Conference on Harmonization Guidelines for Good Clinical Practice, the Declaration of Helsinki, and other applicable local regulations.

After screening, eligible patients had to withdraw their existing antihypertensive medication during a 1‐ to 4‐week run‐in period. However, if required for the safety of the patient, antihypertensive medications (other than ARBs, ACE inhibitors, or fixed combinations containing an ARB/ACE inhibitor) were allowed to continue during the study, at the discretion of the investigator.

Eligible patients entered the treatment period as early as 1 week after beginning the run‐in period. Treated patients, if not qualified after 1 week, continued the run‐in period for an additional 3 weeks to determine their eligibility, after which ineligible patients were excluded. Patients were to be discontinued if confirmed to have office SBP ≥220 mm Hg and/or DBP ≥120 mm Hg at any time during the study.

All eligible patients received an initial treatment of LCZ696 200 mg, which was uptitrated to 400 mg for patients who did not achieve an office DBP <100 mm Hg and SBP <160 mm Hg at 2 weeks or an office DBP <90 mm Hg and SBP <140 mm Hg at or after 4 weeks and had no safety concerns. For patients who did not achieve an office DBP <90 mm Hg and SBP <140 mm Hg with LCZ696 400 mg, addition of other antihypertensive agents (except an ARB or an ACE inhibitor or fixed combinations containing ARBs or ACE inhibitors) or increasing the dose of concomitant antihypertensive agent(s) as per the package insert(s) and investigator's opinion was allowed (Figure 1).

Figure 1.

Study design.

Patients with signs or symptoms of clinically significant hypotension, office DBP <55 mm Hg, or SBP <100 mm Hg at any time during the study were evaluated by the investigator and the study treatment was continued if clinically permissible. Laboratory abnormalities such as serum potassium >6.0 mEq/L, serum creatinine >3.0 mg/dL, and clinically significant hyponatremia (serum sodium <130 mEq/L with/without relevant symptoms or <135 mEq/L associated with persistent symptoms) were evaluated by the investigator and the study treatment was continued if clinically permissible.

Study Assessments

BP was measured using an automated BP device (Omron BP monitor HEM‐7080IC, OMRON HEALTHCARE Co., Ltd, Kyoto, Japan) with an appropriately sized cuff. Sitting and standing BP measurements were performed at trough (immediately prior to dosing at the clinic). An average of four sitting BP measurements (office BP), which were obtained with a 2‐minute interval and fully deflated cuff between measurements, was considered for efficacy. PP was calculated as the difference between office SBP and DBP measurements.

Change in office SBP and DBP from baseline to the end of study (week 8), the proportion of patients achieving BP control (office SBP <140 mm Hg and DBP <90 mm Hg), SBP response (office SBP <140 mm Hg or ≥20 mm Hg reduction from baseline), and DBP response (office DBP <90 mm Hg or ≥10 mm Hg reduction from baseline) were assessed.

Safety assessments (primary objective) included monitoring and recording of all adverse events (AEs), serious AEs (SAEs), discontinuations because of AEs, and other notable laboratory abnormalities. As a part of the safety assessments, physical examination, measurement of vital signs, electrocardiography, and hematology, blood chemistry, and urine examinations were performed at regular intervals during the study period.

Statistical Analyses and Sample Size

A total of 48 enrolled patients were planned to achieve a sample size of 30 patients completing the 8‐week treatment period, assuming a dropout rate of 30% prior to and 10% during the treatment period. This sample size was considered sufficient to evaluate overall safety and tolerability and was estimated to provide 79% chance to observe at least one AE for an AE with an underlying incidence of 5%.

Safety analyses were performed in all patients who received at least one dose of LCZ696, while efficacy analyses were performed in the full analysis set comprising all patients who entered the treatment phase. Descriptive statistics are provided for patient demographic characteristics and all safety and efficacy variables. Correlation between baseline and change from baseline to week 8 in PP, SBP, and DBP was tested.

Results

Patient Disposition and Baseline Characteristics

Of the 38 patients who entered the run‐in period, 35 entered and completed the treatment period. Three patients who did not meet the inclusion criteria discontinued the study during the run‐in period. Demographic and baseline characteristics are summarized in Table 1. The mean age of the patients was 51.3 years and 11.4% of the study population were 65 years and older (elderly). The majority of patients were men (94.3%) and the mean duration of hypertension was 9.3 years. The mean office SBP and DBP was 173.4 mm Hg and 112.4 mm Hg, respectively. Baseline office SBP ≥180 mm Hg and DBP ≥110 mm Hg was reported in 14 and 31 patients, respectively. Of the five patients who continued the background antihypertensive treatment, two received CCBs, two received diuretics, and one received a β‐blocker.

Table 1.

Demographic and Baseline Characteristics

Characteristic at Study Entry	Total (N=35)
Age, y, No. (%)	51.3 (9.5)
<65 y	31 (88.6)
≥65 y	4 (11.4)
Sex, No. (%)
Male	33 (94.3)
Female	2 (5.7)
Japanese ethnicity, No. (%)	35 (100.0)
Duration of hypertension, y	9.3 (8.1)
Body mass index, kg/m2	27.3 (4.1)
Office BP, mm Hg
SBP	173.4 (12.7)
DBP	112.4 (6.8)
PP	61.0 (14.4)
eGFR group, No. (%)
30 ≤eGFR <60 mL/min/1.73 m2	10 (28.6)
60 ≤eGFR <90 mL/min/1.73 m2	25 (71.4)
Diabetes, No. (%)	2 (5.7)
Smoking status, No. (%)
Never	14 (40.0)
Current	8 (22.9)
Former	13 (37.1)
Cholesterol, mmol/L	5.4
Triglycerides, mmol/L	2.4

Abbreviations: BP, blood pressure; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; PP, pulse pressure; SBP, systolic blood pressure. Data are presented as mean (standard deviation) unless otherwise indicated.

Of the 35 patients who completed the study, 32 had their dose uptitrated from 200 mg to 400 mg; of these, 21 (60%) patients received add‐on antihypertensive agents such as CCBs (n=17), diuretics (n=3), or β‐blockers (n=1) to achieve BP target during the study.

Efficacy

Clinically significant reductions in office SBP and DBP were observed with the LCZ696‐based regimen from baseline to the week 8 endpoint (Figure 2). BP reductions with LCZ696 were observed as early as week 1 (18.7/10.3 mm Hg) with the greatest reductions observed at the week 8 endpoint (35.3/22.1 mm Hg) (Figure 3). At week 4, until which no additional antihypertensive therapies were added, LCZ696 provided a reduction of 23.1/14.0 mm Hg in office BP. The patients taking the LCZ696‐based regimen showed a progressive reduction in BP over the treatment duration.

Figure 2.

Time course of reduction in office systolic blood pressure (SBP) and diastolic blood pressure (DBP) with the LCZ696‐based regimen. Error bars represent standard deviation.

Figure 3.

Mean change in office systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP) from baseline to end of study with the LCZ696‐based regimen. Error bars represent standard deviation.

A reduction of 8.3±10.1 mm Hg (mean±standard deviation) in office PP was observed at week 1, which was further reduced by 8.2±10.4 mm Hg, 9.2±10.6 mm Hg, and 10.1±11.1 mm Hg at weeks 2, 4, and 6, respectively, with the greatest mean reduction observed at the week 8 endpoint (13.2±12.6 mm Hg) from baseline (Figure 3). Patients following the LCZ696‐based regimen demonstrated favorable reductions in office PP from treatment initiation, which persisted until the end of the study. BP control was observed in 40% of patients at the week 8 endpoint. SBP and DBP response were achieved in 85.7% and 100% of patients, respectively, by the week 8 endpoint.

Safety and Tolerability

LCZ696 was generally tolerated, with 17 (48.6%) patients reporting at least one AE during the treatment period. Nasopharyngitis, increase in blood creatine phosphokinase and hyperuricemia were reported in more than one patient (Table 2). Dizziness, hypotension, or other low BP‐related signs and symptoms were not observed. The proportion of patients who had orthostatic BP changes (defined as a decrease of ≥20 mm Hg in SBP or a decrease of ≥10 mm Hg in DBP when a patient moves from a sitting position to a standing position) at any visit after baseline was the same as that at baseline (8.6%) for total patients. There were no reports of angioedema, deaths, or discontinuations caused by AEs during this study.

Table 2.

Safety and Tolerability Profile of LCZ696

Adverse Event (Preferred Term)	Total (N=35)
Any adverse events	17 (48.6)
Nasopharyngitis	6 (17.1)
Blood creatine phosphokinase increased	3 (8.6)
Hyperuricemia	2 (5.7)
Alanine aminotransferase increased	1 (2.9)
Aspartate aminotransferase increased	1 (2.9)
Blood alkaline phosphatase increased	1 (2.9)
Blood bilirubin increased	1 (2.9)
Cystitis	1 (2.9)
Dyslipidemia	1 (2.9)
Gamma‐glutamyltransferase increased	1 (2.9)
Gout	1 (2.9)
Headache	1 (2.9)
Hyperlipidemia	1 (2.9)
Pharyngitis	1 (2.9)
Protein urine present	1 (2.9)
Clinically notable changes in laboratory values
Potassium
≥6.0 mmol/L	0 (0.0)
>5.5 mmol/L	0 (0.0)
<3.5 mmol/L	2 (5.7)
Creatinine
>176.8 μmol/L	0 (0.0)
BUN
>14.28 mmol/L	0 (0.0)
Sodium
<130 mmol/L	0 (0.0)

Abbreviation: BUN, serum urea nitrogen. Values are presented as number (percentage).

All AEs were mild in severity except two moderate AEs. An increase in blood bilirubin in one patient and hyperuricemia in one patient were considered to be related to the study drug. Increases in aspartate aminotransferase and alanine aminotransferase to >8 times the upper limit of normal were reported in one patient on day 10, which was considered an SAE. However, these values returned to normal levels after temporary cessation of LCZ696 and did not recur after resuming LCZ696. Incidence of serum potassium >5.5 mmol/L was not observed and serum potassium <3.5 mmol/L was reported in two (5.7%) patients who recovered during the treatment period.

Discussion

While a strong BP‐lowering effect is essential for the treatment of hypertension, patients with severe hypertension constitute a special challenge to antihypertensive treatment, as the treatment needs to be effective without causing any safety concerns including those related to the excessive BP‐lowering such as hypotension. This study indicates that an LCZ696‐based regimen could be effective in lowering BP and generally well tolerated in this difficult to treat population.

Substantial evidence suggests that pharmacotherapy, which reduces BP to <140/80 mm Hg, is associated with a significant reduction in CV events.19 Each difference in SBP/DBP by 20/10 mm Hg has been shown to be associated with more than a two‐fold increase in CV death rates.3 Furthermore, a steep association between BP and hemorrhagic stroke was observed, more so in Asians than Caucasians.7 A recent meta‐analysis reported a clear benefit of reduction in BP to <140/80 mm Hg in Asian patients with hypertension wherein the intervention group, compared with the reference group, showed a greater reduction in composite CV disease events (−27%), myocardial infarction (−21%), stroke (−29%), and CV disease mortality (−19%).19 This demonstrates that severe hypertension poses a greater risk than mild or moderate hypertension and emphasizes the importance of BP control in protecting target organs including cardiac, renal, vascular, and metabolic systems. LCZ696 provides a novel approach to neurohormonal modulation by simultaneous neprilysin inhibition and angiotensin receptor blockade. In the current study, an LCZ696‐based regimen demonstrated a clinically significant reduction in office SBP/DBP (35.3/22.1 mm Hg) by the end of the study period in Asian patients with severe hypertension. By 8 weeks, BP control (DBP <90 mm Hg and SBP <140 mm Hg) was achieved in 40% of patients with a good SBP response rate of 85.7% and a DBP response rate of 100%.

PP is an independent predictor of CV events such as myocardial infarction, congestive heart failure, or CV death in hypertensive and healthy populations.20 The Framingham Heart Study suggests an association between elevated PP and onset of CV events, reporting that an elevation in PP by 10 mm Hg increased the onset of CV events by 23%.21 The LCZ696‐based regimen demonstrated a mean reduction of 13.2 mm Hg in office PP by the end of this study. Previously, Ruilope and colleagues¹⁶ and Kario and colleagues17 reported significant reductions in 24‐hour ambulatory and office PP with LCZ696 compared with valsartan and placebo.

The majority of antihypertensive therapies used by patients as continued background therapy or as add‐on therapy were CCBs followed by diuretics. The beneficial effects of the combination of an RAAS inhibitor (ACE inhibitors, ARBs, or direct renin inhibitors) with a CCB or a diuretic in patients with moderate to severe hypertension are well recognized.22, 23

The safety profile of LCZ696 reported in this study was favorable and in line with that reported in earlier studies with LCZ696 in Caucasians and Asians with mild to moderate hypertension16, 17 and healthy subjects.13 No specific drug‐related event was seen in patients with severe hypertension. In this study, AEs associated with excessive BP‐lowering such as dizziness, hypotension, or syncope, or specific safety issues related to renal function impairment and electrolyte dysfunction were not observed. Nasopharyngitis was the most frequently reported AE. All nasopharyngitis events were mild in severity and were not suspected to be related to the study drug. The incidence of nasopharyngitis was similar to that in a study conducted in Japanese patients with hypertension and renal dysfunction.24 With regard to the liver enzyme elevation, the investigator stated that the patient who experienced SAEs had a concurrent condition of alcohol allergy (reported as such by the investigator) and the patient consumed beer 2 days before day 10; therefore, an effect of drinking alcohol could not be ruled out. However, the reported increase in aspartate aminotransferase and alanine aminotransferase (to >8 times the upper limit of normal) returned to normal levels after temporary cessation of LCZ696 and did not recur after resuming LCZ696. AEs that are frequently reported with ACE inhibitors13, 25, 26 and the known effects of thiazides27 were not observed in this study.

In this study, LCZ696 was generally safe and achieved a clinically meaningful BP reduction in Japanese patients with severe hypertension. LCZ696 enhances natriuretic peptide levels and may be an attractive treatment option, particularly in Asian patients who generally have high salt‐sensitivity and salt intake. This may also confer protection to the cardiac, vascular, and renal systems beyond BP‐lowering.^15,16

Study Limitations

The open‐label nature, small sample size, lack of active comparator, and short study duration are the main limitations of this study. Further long‐term and randomized clinical trials are warranted for better understanding of the efficacy and safety profiles of LCZ696, particularly in patients with severe hypertensive. In addition, monitoring ambulatory PP and central BP, and measurement of arterial stiffness in future studies add value to its potential in offering CV protection. In this study, patients received increasing doses of LCZ696 or other add‐on antihypertensive agents only if they did not respond to a low dose of LCZ696 (200 mg) during the treatment period. Hence, the BP‐lowering efficacy of different doses could not be compared.

Conclusions

This 8‐week study indicates that LCZ696, a first‐in‐class ARNI, is generally safe and effective, particularly for SBP and PP reductions, in the treatment of severe hypertension in Asian patients.

Disclosures

This study was supported by Novartis Pharma AG. K.K. received a research grant from Novartis, Teijin, and Takeda, a consultant fee from Novartis, and is on the speakers' bureau of Takeda, Mochida, and Daiichi Sankyo. Y.T., H.G., M.Z., N.O., and J.Z. are employees of Novartis Pharmaceutical Corporation.

J Clin Hypertens (Greenwich). 2016;18:308–314. DOI: 10.1111/jch.12667 © 2015 Wiley Periodicals, Inc.