Pharmacology: Pharmacodynamics: Mechanism of Action: Entresto exhibits the novel mechanism of action of an angiotensin receptor neprilysin inhibitor (ARNI) by simultaneously inhibiting neprilysin (neutral endopeptidase; NEP) via sacubitrilat, the active metabolite of the prodrug sacubitril, and by blocking the angiotensin II type-1 (AT1) receptor via valsartan. The complementary cardiovascular benefits and renal effects of Entresto in heart failure patients are attributed to the enhancement of peptides that are degraded by neprilysin, such as natriuretic peptides (NP), by sacubitrilat and the simultaneous inhibition of the deleterious effects of angiotensin II by valsartan. NPs exert their effects by activating membrane-bound guanylyl cyclase-coupled receptors, resulting in increased concentrations of the second messenger cyclic guanosine monophosphate (cGMP), thereby promoting vasodilation, natriuresis and diuresis, increased glomerular filtration rate and renal blood flow, inhibition of renin and aldosterone release, reduction of sympathetic activity, and anti-hypertrophic and anti-fibrotic effects. Sustained activation of the renin-angiotensin-aldosterone system results in vasoconstriction, renal sodium and fluid retention, activation of cellular growth and proliferation, and subsequent maladaptive cardiovascular remodeling. Valsartan inhibits detrimental cardiovascular and renal effects of angiotensin II by selectively blocking the AT1 receptor, and also inhibits angiotensin II-dependent aldosterone release.
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. 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 in the following text).
Clinical Studies: 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.)
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The 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.)
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Overall, 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).
TITRATION: 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).
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. 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 LBQ657), 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 (T1/2) 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: Elderly patients (aged over 65 years): 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.
Pediatric patients (aged below 18 years): Entresto has not been studied in pediatric patients.
Impaired renal function: 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.
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.
Impaired hepatic function: 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. A starting dose of 50 mg twice daily is recommended in patients with moderate hepatic impairment (Child-Pugh B classification). Entresto has not been studied in patients with severe hepatic impairment. Therefore, its use is not recommended in patients with severe hepatic impairment.
Ethnic groups: The pharmacokinetics of Entresto (sacubitril, sacubitrilat and valsartan) are comparable across different race and ethnic groups (Caucasians, Blacks, Asians, Japanese and others).
Effect of gender: The pharmacokinetics of Entresto (sacubitril, sacubitrilat and valsartan) are similar between male and female subjects.
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: Entresto did not show any effects on fertility or early embryonic development in rats up to a dose of 150 mg/kg/day (≤1.0 fold and ≤0.18 fold the MRHD on the basis of valsartan and LBQ657 AUC, respectively).
Entresto treatment during organogenesis resulted in increased embryo-fetal lethality in rats at doses ≥100 mg/kg/day [≤0.72 fold the MRHD on the basis of AUC] and rabbits at doses ≥10 mg/kg/day [2 fold and 0.03 fold the MRHD on the basis of valsartan and sacubitrilat AUC, respectively]. Entresto is teratogenic based on a low incidence of fetal hydrocephaly, associated with maternally toxic doses, which was observed in rabbits at a Entresto dose of ≥10 mg/kg/day. The adverse embryo-fetal effects of Entresto are attributed to the angiotensin receptor antagonist activity (see Use in Pregnancy & Lactation).
Pre- and postnatal development studies in rats conducted with sacubitril at doses up to 750 mg/kg/day [2.2 fold the MRHD on the basis of AUC] and valsartan at doses up to 600 mg/kg/day [0.86 fold the MRHD on the basis of AUC] indicate that treatment with Entresto during organogenesis, gestation and lactation may affect pup development and survival.
Other Preclinical Findings: The effects of Entresto on amyloid-β 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 Aβ clearance in cynomolgus monkeys, increasing CSF Aβ 1-40, 1-42, and 1- 38 levels; there was no corresponding increase in Aβ levels in the brain. Increases in CSF Aβ 1-40 and 1-42 were not observed in a 2 week healthy volunteer study in humans (see Pharmacology in the previous text). Additionally, in a toxicology study in cynomolgus monkeys treated with Entresto at 300 mg/kg/day for 39-weeks, there was no amyloid-β accumulation in the brain.