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Pharmacodynamics: The pharmacodynamic effects of Entresto were evaluated after single and multiple dose administrations in healthy subjects and in patients with heart failure, and are consistent with simultaneous neprilysin inhibition and RAAS blockade. In a 7-day valsartan-controlled study in patients with reduced ejection fraction (HFrEF), administration of Entresto resulted in a significant non-sustained increase in natriuresis, increased urine cGMP, and decreased plasma MR-proANP and NT-proBNP compared to valsartan. In a 21-day study in HFrEF patients, ENTRESTO significantly increased urine ANP and cGMP and plasma cGMP, and decreased plasma NT-proBNP, aldosterone and endothelin-1 compared to baseline. Entresto also blocked the AT1-receptor as evidenced by increased plasma renin activity and plasma renin concentrations. In PARADIGM-HF, Entresto decreased plasma NT-proBNP and increased plasma BNP and urine cGMP compared with enalapril. In PARAGON-HF, Entresto decreased NT-proBNP, troponin and soluble ST2 (sST2) and increased urine cGMP compared to valsartan. While BNP is a neprilysin substrate, NT-proBNP is not. Therefore, NT-proBNP (but not BNP) is a suitable biomarker for monitoring of heart failure patients treated with ENTRESTO.
In a thorough QTc clinical study in healthy male subjects, single doses of 400 mg and 1200 mg Entresto had no effect on cardiac repolarization.
Neprilysin is one of multiple enzymes involved in the clearance of amyloid-beta (A-beta) from the brain and cerebrospinal fluid (CSF). Administration of Entresto 400 mg once daily for 2 weeks to healthy subjects was associated with an increase in CSF A-beta 1-38 compared to placebo; there were no changes in concentrations of CSF A-beta 1-40 and 1-42. The clinical relevance of this finding is unknown (see Toxicology: NON-CLINICAL SAFETY DATA as follows).
CLINICAL STUDIES: Heart Failure: PARADIGM-HF: PARADIGM-HF was a multinational, randomized, double-blind study of 8,442 patients comparing Entresto to enalapril, both given to adult patients with chronic heart failure, NYHA class II - IV, and systolic dysfunction (left ventricular ejection fraction ≤ 40%), in addition to other heart failure therapy. The primary endpoint was the composite of cardiovascular (CV) death or hospitalization for heart failure (HF).
Prior to study participation, patients were well treated with standard of care therapy which included ACE inhibitors/ARBs (>99%), beta-blockers (94%), mineralocorticoid antagonists (58%), and diuretics (83%). The median follow-up duration was 27 months and patients were treated for up to 4.3 years.
Patients were required to discontinue their existing ACE inhibitor or ARB therapy and entered a sequential single-blind run-in period during which patients received treatment with enalapril 10 mg twice daily, followed by treatment with Entresto 100 mg twice daily, increasing to 200 mg twice daily. Patients were then randomized to the double-blind period of the study to receive either Entresto 200 mg or enalapril 10 mg twice daily [Entresto (n=4,209); enalapril (n=4,233)].
The mean age of the population studied was 64 years of age and 19% were 75 years or older. At randomization, 70% of patients were NYHA Class II and 25% were Class III/IV.
In the Entresto group, 76% of patients remained on the target dose of 200 mg twice daily at the end of the study (mean daily dose of 375 mg). In the enalapril group, 75% of patients remained on the target dose of 10 mg twice daily at the end of the study (mean daily dose of 18.9 mg).
Entresto demonstrated clinically relevant and statistically significant superiority to enalapril, reducing the risk of cardiovascular death or heart failure hospitalizations by 20% (hazard ratio (HR): 0.80, 95% CI [0.73; 0.87], 1-sided p=0.0000002) versus enalapril. This effect was observed early and was sustained throughout the duration of the trial. The absolute risk reduction was 4.69%. A statistically significant reduction for CV death and first HF hospitalization was observed (CV death, RRR 20%, HR 0.80; 95% CI [0.71, 0.89], 1-sided p=0.00004; and hospitalization for heart failure RRR 21%; HR 0.79; 95% CI 0.71, 0.89], 1-sided p=0.00004); see Table 1 and Figure 1. Sudden death accounted for 45% of cardiovascular deaths and was reduced by 20% in Entresto treated patients compared to enalapril treated patients (HR 0.80, p=0.0082). Pump failure accounted for 26% of cardiovascular deaths and was reduced by 21% in Entresto treated patients compared to enalapril treated patients (HR 0.79, p = 0.0338).
This risk reduction was consistently observed across subgroups including: age, gender, race, geography, NYHA class, ejection fraction, renal function, history of diabetes or hypertension, prior heart failure therapy, and atrial fibrillation.
Entresto also significantly reduced all-cause mortality by 16% compared with enalapril (RRR 16%, HR 0.84; 95% CI [0.76 to 0.93], 1-sided p=0.0005) (Table 1). The absolute risk reduction was 2.84%. (See Table 1.)
Click on icon to see table/diagram/imageThe Kaplan-Meier presented in the figure as follows (left) shows time to first occurrence of the primary composite endpoint of CV death or heart failure hospitalization. Entresto treatment effect was evident early and sustained for the duration of the study. The Kaplan-Meier figure presented as follows (right) shows the time to CV death endpoint. (See Figure 1.)
Click on icon to see table/diagram/imageOverall, there were fewer all cause hospital admissions in patients treated with Entresto compared to enalapril, including a 12% relative risk reduction for the first hospitalization (HR 0.88 [95% CI: 0.82, 0.94], P<0.001), and a 16% relative rate reduction for total number of hospitalizations (RR 0.84 [95% CI: 0.78, 0.91], P<0.001).
Entresto demonstrated a significantly better clinical summary score for the domains related to HF symptoms and physical limitations as assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ), a self-administered questionnaire. More patients had improved NYHA functional class from baseline to Month 8 on Entresto (16%) compared to enalapril (14%), and fewer patients had worsened NYHA functional class (10% vs 13%, respectively).
PARAGON-HF: PARAGON-HF, was a multicenter, randomized, double-blind trial comparing Entresto and valsartan in 4,796 adult patients with symptomatic heart failure with preserved ejection fraction (left ventricular ejection fraction ≥45%), and structural heart disease [either left atrial enlargement (LAE) or left ventricular hypertrophy (LVH)]. Patients with a systolic blood pressure of < 110 mmHg and patients with any prior echocardiographic LVEF < 40% at screening were excluded.
The primary endpoint of PARAGON-HF was the composite of total (first and recurrent) heart failure (HF) hospitalizations and cardiovascular (CV) death.
After discontinuing their existing ACE inhibitor or ARB therapy, patients entered sequential single-blind run-in periods during which they received valsartan 80 mg twice-daily, followed by Entresto 100 mg twice-daily. Patients on prior low doses of an ACEi or ARB began the run-in period receiving valsartan 40 mg twice-daily for 1-2 weeks. Patients who successfully completed the sequential run-in periods were randomized to receive either Entresto 200 mg (N=2,419) twice-daily or valsartan 160 mg (N=2,403) twice-daily. The median follow-up duration was 35 months and patients were treated for up to 4.7 years.
The mean age of the population studied was 73 years and 52% were female. At randomization, 77% of patients were NYHA Class II, 19% were NYHA Class III, and 0.4% were NYHA Class IV. The median left ventricular ejection fraction was 57%. The underlying cause of heart failure was of ischemic etiology in 36% of patients. Furthermore, 96% had a history of hypertension, 23% had a history of myocardial infarction, 46% had an eGFR < 60 mL/min/1.73 m2, and 43% had diabetes mellitus. Most patients were taking beta-blockers (80%) and diuretics (95%).
In PARAGON-HF, Entresto reduced the rate of the composite endpoint of total (first and recurrent) HF hospitalizations and CV death, based on an analysis using a proportional rates model, by 13% compared to valsartan (rate ratio [RR]; 0.87; 95% CI [0.75, 1.01], p = 0.059). The treatment effect was primarily driven by the reduction in total HF hospitalizations in patients randomized to Entresto of 15% (RR 0.85; 95% CI [0.72, 1.00]).
Entresto reduced by 14% the rate of the composite endpoint of total worsening heart failure (HF hospitalizations and urgent HF visits) and CV death (RR 0.86; 95% CI [0.75, 0.99]).
A wide range of demographic characteristics, baseline disease characteristics, and baseline concomitant medications were examined for their influence on outcomes (Figure 2). (See Figure 2.)
Click on icon to see table/diagram/imageIn an analysis of the relationship between LVEF and outcome in PARADIGM-HF and PARAGON-HF, patients with LVEF below normal (up to approximately 60%) treated with Entresto experienced greater risk reduction (Table 1 and Figure 3, and Figure 4). LVEF is a variable measure that can change over time, and the normal range differs according to patient characteristics and method of assessment; prescribers should use clinical judgment in deciding whom to treat. In both studies the treatment effect with Entresto was demonstrated early and sustained throughout the duration of the trials (Figures 1 and 4). (See Table 2, Figures 3 and 4.)
Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
Click on icon to see table/diagram/imageTITRATION: TITRATION was a 12 week safety and tolerability study in 538 patients with chronic heart failure (NYHA class II-IV) and systolic dysfunction (left ventricular ejection fraction ≤ 35%) naive to ACE inhibitor or ARB therapy or on varying doses of ACE inhibitors or ARBs prior to study entry. Patients initiated Entresto 50 mg twice daily, were uptitrated to 100 mg twice daily and then to the target dose of 200 mg twice daily with either a 3-week or 6-week regimen.
Overall, 76% of patients achieved and maintained the target dose of Entresto 200 mg twice daily without any dose interruption or down-titration over 12-weeks. More patients who were naïve to previous ACE inhibitor or ARB therapy or on low dose therapy (equivalent to < 10 mg of enalapril/day) were able to achieve and maintain Entresto 200 mg when uptitrated over 6 weeks versus 3 weeks.
PARAMOUNT: PARAMOUNT, a randomized, double-blind trial in patients with left ventricular ejection fraction ≥ 45% comparing 200 mg of Entresto (n=149) to 160 mg of valsartan (n=152) twice daily, demonstrated statistically greater reduction (p=0.0050) in NT pro-BNP from baseline to Week 12. The reduction from baseline in NT-proBNP was similar at Weeks 12 and 36 in patients treated with Entresto, while NT-proBNP decreased from Week 12 to 36 in patients treated with valsartan. Significant reductions in left atrial size, both left atrial volume index (p=0.0069) and left atrial dimension (p=0.0337) were observed at Week 36. A statistically significant improvement in NYHA class was noted at Week 36 (p=0.0488).
Essential Hypertension: The antihypertensive effect of Entresto was evaluated in two randomized, double-blind, active-controlled, 8-week studies evaluating the efficacy and safety of Entresto in comparison to olmesartan (CLCZ696A2315 and CLCZ696A1306) in more than 2,500 adult patients of which more than 1,700 patients received Entresto. Both studies demonstrated non-inferiority as well as superiority of the mean sitting systolic blood pressure (msSBP) lowering effect of both Entresto 200 mg once daily (2.3 and 5.0 mmHg in each study, respectively) and Entresto 400 mg once daily (3.5 and 7.0 mmHg) compared to olmesartan 20 mg once daily. Consistent results were observed in mean diastolic BP.
Additionally, persistency of blood pressure lowering effect was demonstrated in a 52-week, safety, tolerability and efficacy, open-label, extension study (CLCZ696A2219E1) in which 341 patients were receiving Entresto as a monotherapy or in combination with amlodipine and hydrochlorothiazide.
Pharmacokinetics: Absorption: Following oral administration, Entresto dissociates into sacubitril, which is further metabolized to sacubitrilat, and valsartan, which reach peak plasma concentrations in 0.5 hours, 2 hours, and 1.5 hours, respectively. The oral absolute bioavailability of sacubitril and valsartan is estimated to be ≥ 60% and 23%, respectively. The valsartan in Entresto is more bioavailable than the valsartan in other marketed tablet formulations.
Following twice daily dosing of Entresto, steady state levels of sacubitril, sacubitrilat, and valsartan are reached in 3 days. At steady state, sacubitril and valsartan do not accumulate significantly, while sacubitrilat accumulates by 1.6-fold. Following once daily dosing of Entresto, steady state levels of sacubitril, sacubitrilat and valsartan are achieved in 5 days with no accumulation in sacubitril and valsartan and 1.2-fold accumulation in sacubitrilat. Entresto administration with food has no clinically significant impact on the systemic exposures of sacubitril, sacubitrilat and valsartan. Although there is a decrease in exposure to valsartan when Entresto is administered with food, this decrease is not accompanied by a clinically significant reduction in the therapeutic effect. Entresto can therefore be administered with or without food.
Distribution: Entresto is highly bound to plasma proteins (94% - 97%). Based on the comparison of plasma and CSF exposures, sacubitrilat does cross the blood brain barrier to a limited extent (0.28%). Entresto has an apparent volume of distribution ranging from 75 L to 103 L.
Biotransformation/metabolism: Sacubitril is readily converted to sacubitrilat by esterases; sacubitrilat is not further metabolized to a significant extent. Valsartan is minimally metabolized, as only about 20% of the dose is recovered as metabolites. A hydroxyl metabolite has been identified in plasma at low concentrations (<10%). Since CYP450 enzyme mediated metabolism of sacubitril and valsartan is minimal, co-administration with drugs that impact CYP450 enzymes is not expected to impact the pharmacokinetics.
Elimination: Following oral administration, 52 - 68% of sacubitril (primarily as sacubitrilat) and ~13% of valsartan and its metabolites are excreted in urine; 37-48% of sacubitril (primarily as sacubitrilat), and 86% of valsartan and its metabolites are excreted in feces.
Sacubitril, sacubitrilat, and valsartan are eliminated from plasma with a mean elimination half-life (T½) of approximately 1.43 hours, 11.48 hours, and 9.90 hours, respectively.
Linearity/non-linearity: The pharmacokinetics of sacubitril, sacubitrilat, and valsartan are linear in the dose range tested (50 - 400 mg of Entresto).
Special populations: Pediatric patients (aged below 18 years of age): Entresto has not been studied in pediatric patients.
Geriatric patients (65 years of age and above): The exposures of sacubitrilat and valsartan are increased in elderly subjects by 42% and 30%, respectively, compared to younger subjects. However, this is not associated with clinically relevant effects and therefore no dosage adjustment is necessary.
Gender: The pharmacokinetics of Entresto (sacubitril, sacubitrilat and valsartan) are similar between male and female subjects.
Race/Ethnicity: The pharmacokinetics of Entresto (sacubitril, sacubitrilat and valsartan) are comparable across different race and ethnic groups (Caucasians, Blacks, Asians, Japanese and others).
Renal impairment: A correlation was observed between renal function and systemic exposure to sacubitrilat, but not to valsartan. In patients with mild (60 mL/min/1.73 m2 < eGFR <90 mL/min/1.73 m2) to moderate (30 mL/min/1.73 m2 ≤ eGFR <60 mL/min/1.73 m2) renal impairment the AUC for sacubitrilat was up to 2-fold higher. No dosage adjustment is required in patients with mild or moderate renal impairment. A 2.7-fold higher AUC for sacubitrilat was observed in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2). A starting dose of 50 mg twice daily is recommended in patients with severe renal impairment. Caution is recommended when administering Entresto to these patients due to limited data. Safety and efficacy of Entresto in patients with essential hypertension and with severe renal impairment have not been established.
No studies have been performed in patients undergoing dialysis. However, sacubitrilat and valsartan are highly bound to plasma protein and, therefore, unlikely to be effectively removed by dialysis.
Hepatic impairment: In patients with mild to moderate hepatic impairment, the exposures of sacubitril increased by 1.5- and 3.4-fold, sacubitrilat increased by 1.5- and 1.9-fold, and valsartan increased by 1.2-fold and 2.1-fold, respectively, compared to matching healthy subjects. No dosage adjustments is recommended when administering Entresto to patients with mild hepatic impairment (Child-Pugh A classification) including patients with biliary obstructive disorders. In patients with moderate hepatic impairment (Child-Pugh B classification), a starting dose of 50 mg twice daily is recommended in patients with heart failure and 100 mg once daily in hypertensive patients. Entresto has not been studied in patients with severe hepatic impairment. Therefore, its use is not recommended in patients with severe hepatic impairment.
Toxicology: NON-CLINICAL SAFETY DATA: Non-clinical safety studies conducted with Entresto included assessment of safety pharmacology, repeated dose toxicity genotoxicity carcinogenicity and reproductive and development toxicity Entresto had no adverse effects on vital organ systems. Most findings seen in repeated toxicity studies were reversible and attributable to the pharmacology of AT1 receptor blockade.
Carcinogenicity, mutagenesis and genetic toxicity: Carcinogenicity studies conducted in mice and rats with sacubitril and valsartan did not identify any carcinogenic potential for Entresto. The doses of sacubitril studied (high dose of 1200 and 400 mg/kg/day in mice and rats, respectively) were about 29 and 19 times, respectively, the maximum recommended human dose (MRHD) on a mg/m2 basis. The doses of valsartan studied (high dose of 160 and 200 mg/kg/day in mice and rats, respectively) were about 4 and 10 times, respectively, the maximum recommended human dose on a mg/m2 basis.
Mutagenicity and clastogenicity studies conducted with Entresto, sacubitril, and valsartan did not reveal any effects at either the gene or chromosome level.
Fertility, reproduction and development: See USE IN PREGNANCY & LACTATION.
Other preclinical findings: The effects of Entresto on amyloid-beta concentrations in cerebrospinal fluid (CSF) and brain tissue were assessed in young (2-4 years old) cynomolgus monkeys treated with Entresto (50 mg/kg/day) for 2 weeks. In this study, Entresto had a pharmacodynamic effect on CSF A beta clearance in cynomolgus monkeys, increasing CSF Aβ 1-40, 1-42, and 1-38 levels; there was no corresponding increase in A beta levels in the brain. Increases in CSF A beta 1-40 and 1-42 were not observed in a 2 week healthy volunteer study in humans (see PHARMACOLOGY as previously mentioned). Additionally, in a toxicology study in cynomolgus monkeys treated with Entresto at 300 mg/kg/day for 39-weeks, there was no amyloid-beta accumulation in the brain.
