Pharmacology: Mechanism of action:
Sacubitril-valsartan (Entresto) exhibits the mechanism of action of an angiotensin receptor neprilysin inhibitor by simultaneously inhibiting neprilysin (neutral endopeptidase; NEP) via LBQ657, the active metabolite of the prodrug sacubitril, and by blocking the angiotensin II type-1 (AT1) receptor via valsartan. The complementary cardiovascular benefits in heart failure patients are attributed to the enhancement of peptides that are degraded by neprilysin, such as natriuretic peptides (NP), by LBQ657 and the simultaneous inhibition of the 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), which could result in 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.
Valsartan inhibits detrimental cardiovascular and renal effects of angiotensin II by selectively blocking the AT1 receptor, and also inhibits angiotensin II-dependent aldosterone release. This prevents sustained activation of the renin-angiotensin-aldosterone system that would result in vasoconstriction, renal sodium and fluid retention, activation of cellular growth and proliferation, and subsequent maladaptive cardiovascular remodelling.
The pharmacodynamic effects 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 sacubitril-valsartan resulted in an initial increase in natriuresis, increased urine cGMP, and decreased plasma levels of mid-regional pro-atrial natriuretic peptide (MR-proANP) and N-terminal prohormone brain natriuretic peptide (NT-proBNP) compared to valsartan. In a 21-day study in HFrEF patients, sacubitril-valsartan significantly increased urine ANP and cGMP and plasma cGMP, and decreased plasma NT-proBNP, aldosterone and endothelin-1 compared to baseline. The AT1-receptor was also blocked as evidenced by increased plasma renin activity and plasma renin concentrations. In the PARADIGM-HF study, sacubitril-valsartan decreased plasma NT-proBNP and increased plasma BNP and urine cGMP compared with enalapril. BNP is not a suitable biomarker of heart failure in patients because BNP is a neprilysin substrate. NT-proBNP is not a neprilysin substrate and is therefore a more suitable biomarker.
In a thorough QTc clinical study in healthy male subjects, single doses of sacubitril-valsartan (Entresto) 400 mg and 1200 mg had no effect on cardiac repolarisation.
Neprilysin is one of multiple enzymes involved in the clearance of amyloid-β (Aβ) from the brain and cerebrospinal fluid (CSF). Administration of 400 mg once daily for two weeks to healthy subjects was associated with an increase in CSF Aβ1-38 compared to placebo; there were no changes in concentrations of CSF Aβ1-40 and 1-42. The clinical relevance of this finding is not known (see Pharmacology: Toxicology: Non-Clinical Safety Data under Actions).
PARADIGM-HF: PARADIGM-HF was a multinational, randomised, double-blind study of 8,442 patients comparing sacubitril-valsartan (Entresto) to enalapril, both given to adult patients with chronic heart failure, NYHA class II-IV and reduced ejection fraction (left ventricular ejection fraction [LVEF] ≤40%, amended later to ≤35%) in addition to other heart failure therapy. The primary endpoint was the composite of cardiovascular (CV) death or hospitalisation for heart failure (HF). Patients with SBP <100 mmHg, severe renal impairment (eGFR <30 ml/min/1.73 m2
) and severe hepatic impairment were excluded at screening and therefore not prospectively studied.
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 (82%). 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 enter a sequential single-blind run-in period during which they received treatment with enalapril 10 mg twice daily, followed by single-blind treatment with sacubitril-valsartan (Entresto) 100 mg twice daily, increasing to 200 mg twice daily. They were then randomised to the double-blind period of the study, during which they received either sacubitril-valsartan (Entresto) 200 mg or enalapril 10 mg twice daily [sacubitril-valsartan (n=4,209); enalapril (n=4,233)].
The mean age of the population studied was 64 years of age and 19% were 75 years of age or older. At randomisation, 70% of patients were NYHA class II, 24% were class III and 0.7% were class IV. The mean LVEF was 29% and there were 963 (11.4%) patients with a baseline LVEF >35% and ≤40%.
In the sacubitril-valsartan 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).
Sacubitril-valsartan was superior to enalapril, reducing the risk of cardiovascular death or heart failure hospitalisations to 21.8% compared to 26.5% for enalapril treated patients. The absolute risk reductions were 4.7% for the composite of the CV death or HF hospitalisation, 3.1% for CV death alone, and 2.8% for first HF hospitalisation alone. The relative risk reduction was 20% versus enalapril (see Table 1). This effect was observed early and was sustained throughout the duration of the study (see figure). Both components contributed to the risk reduction. Sudden death accounted for 45% of cardiovascular deaths and was reduced by 20% in sacubitril-valsartan-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 sacubitril-valsartan-treated patients compared to enalapril-treated patients (HR 0.79, p=0.0338).
This risk reduction was consistently observed across subgroups including: gender, age, race, geography, NYHA class (II/III), ejection fraction, renal function, history of diabetes or hypertension, prior heart failure therapy, and atrial fibrillation.
Sacubitril-valsartan (Entresto) improved survival with a significant reduction in all-cause mortality of 2.8% (sacubitril-valsartan, 17%, enalapril, 19.8%). The relative risk reduction was 16% compared with enalapril (see Table 1 and figure).
Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
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 received a starting dose of 50 mg twice daily and were up-titrated to 100 mg twice daily, then to the target dose of 200 mg twice daily, with either a 3-week or a 6-week regimen.
More patients who were naive to previous ACE inhibitor or ARB therapy or on low-dose therapy (equivalent to <10 mg enalapril/day) were able to achieve and maintain 200 mg when up-titrated over 6 weeks (84.8%) versus 3 weeks (73.6%). Overall, 76% of patients achieved and maintained the target dose of 200 mg twice daily without any dose interruption or down-titration over 12 weeks.
The valsartan contained within sacubitril-valsartan (Entresto) is more bioavailable than the valsartan in other marketed tablet formulations; 25.7 mg, 51.4 mg, and 102.8 mg of valsartan in sacubitril-valsartan (Entresto) is equivalent to 40 mg, 80 mg and 160 mg of valsartan in other marketed tablet formulations, respectively.
Following oral administration, the drug dissociates into valsartan and the prodrug sacubitril. Sacubitril is further metabolised to the active metabolite LBQ657. These reach peak plasma concentrations in 2 hours, 1 hour, and 2 hours, respectively. The oral absolute bioavailability of sacubitril and valsartan is estimated to be more than 60% and 23%, respectively.
Following twice daily dosing, steady-state levels of sacubitril, LBQ657 and valsartan are reached in three days. At steady state, sacubitril and valsartan do not accumulate significantly, while LBQ657 accumulates 1.6-fold. Administration with food has no clinically significant impact on the systemic exposures of sacubitril, LBQ657 and valsartan. Sacubitril-valsartan (Entresto) can be administered with or without food.
Sacubitril, LBQ657 and valsartan are highly bound to plasma proteins (94-97%). Based on the comparison of plasma and CSF exposures, LBQ657 crosses the blood brain barrier to a limited extent (0.28%). The average apparent volume of distribution of valsartan and sacubitril were 75 litres to 103 litres, respectively.
Sacubitril is readily converted to LBQ657 by carboxylesterases 1b and 1c; LBQ657 is not further metabolised to a significant extent. Valsartan is minimally metabolised, as only about 20% of the dose is recovered as metabolites. A hydroxyl metabolite of valsartan has been identified in plasma at low concentrations (<10%).
Since CYP450-enzyme-mediated metabolism of sacubitril and valsartan is minimal, co-administration with medicinal products that impact CYP450 enzymes is not expected to impact the pharmacokinetics.
Following oral administration, 52-68% of sacubitril (primarily as LBQ657) 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 faeces.
Sacubitril, LBQ657 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.
The pharmacokinetics of sacubitril, LBQ657 and valsartan were approximately linear over a sacubitril-valsartan (Entresto) dose range of 50 mg to 100 mg.
Elderly patients (aged over 65 years): LBQ657 and valsartan exposure are increased in subjects over 65 years of age by 42% and 30%, respectively, compared to younger subjects.
Pediatric patients (aged below 18 years): Sacubitril-valsartan (Entresto) has not been studied in pediatric patients.
Impaired renal function: A correlation was observed between renal function and systemic exposure to LBQ657 in patients with mild to severe renal impairment. The exposure of LBQ657 in patients with moderate (30 ml/min/1.73 m2
≤eGFR <60 ml/min/1.73 m2
) and severe renal impairment (15 ml/min/1.73 m2
≤eGFR <30 ml/min/1.73 m2
) was 1.4-fold and 2.2-fold higher compared to patients with mild renal impairment (60 ml/min/1.73 m2
≤eGFR <90 ml/min/1.73 m2
), the largest group of patients enrolled in PARADIGM-HF). The exposure of valsartan was similar in patients with moderate and severe renal impairment compared to patients with mild renal impairment. No studies have been performed in patients undergoing dialysis. However, LBQ657 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, LBQ657 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. However, in patients with mild to moderate hepatic impairment, the exposures of free concentrations of LBQ657 increased by 1.47- and 3.08-fold, respectively, and the exposures of free concentrations of valsartan increased by 1.09-fold and 2.20-fold, respectively, compared to matching healthy subjects. Sacubitril-valsartan (Entresto) has not been studied in patients with severe hepatic impairment, biliary cirrhosis or cholestasis (see Contraindications and Precautions).
Effect of gender: The pharmacokinetics of Entresto (sacubitril, LBQ657 and valsartan) are similar between male and female subjects.
Toxicology: Non-Clinical Safety Data:
Non-clinical data (including studies with sacubitril and valsartan components and/or Entresto) reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and fertility.
Fertility, reproduction and development: Treatment during organogenesis resulted in increased embryofetal lethality in rats at doses ≥49 mg sacubitril/51 mg valsartan/kg/day (≤0.72-fold the maximum recommended human dose [MRHD] on the basis of AUC) and rabbits at doses ≥4.9 mg sacubitril/5.1 mg valsartan/kg/day (2-fold and 0.03-fold the MRHD on the basis of valsartan and LBQ657 AUC, respectively). It is teratogenic based on a low incidence of fetal hydrocephaly, associated with maternally toxic doses, which was observed in rabbits at a dose of ≥4.9 mg sacubitril/5.1 mg valsartan/kg/day. Cardiovascular abnormalities (mainly cardiomegaly) were observed in rabbit fetuses at a maternally non-toxic dose (1.46 mg sacubitril/1.54 mg valsartan/kg/day). A slight increase in two fetal skeletal variations (misshapen sternebra, sternebra bipartite ossification) was observed in rabbits at a dose of 4.9 mg sacubitril/5.1 mg valsartan/kg/day.
The adverse embryofetal effects are attributed to the angiotensin receptor antagonist activity (see Use in Pregnancy & Lactation).
Sacubitril treatment during organogenesis resulted in embryo-fetal lethality and embryo-fetal toxicity (decreased fetal body weights and skeletal malformations) in rabbits at doses associated with maternal toxicity (500 mg/kg/day; 5.7-fold the MRHD on the basis of LBQ657 AUC). A slight generalised delay in ossification was observed at doses of >50 mg/kg/day. This finding is not considered adverse. No evidence of embryo-fetal toxicity or teratogenicity was observed in rats treated with sacubitril. The embryo-fetal no-observed adverse effect level (NOAEL) for sacubitril was at least 750 mg/kg/day in rats and 200 mg/kg/day in rabbits (2.2-fold the MRHD on the basis of LBQ657 AUC).
Pre- and postnatal development studies in rats conducted with sacubitril at high 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 during organogenesis, gestation and lactation may affect pup development and survival.
Other preclinical findings: Entresto: The effects on amyloid-β concentrations in CSF and brain tissue were assessed in young (2-4 years old) cynomolgus monkeys (24 mg sacubitril/26 mg valsartan/kg/day) for two weeks. In this study CSF Aβ clearance in cynomolgus monkeys was reduced, increasing CSF Aβ1-40, 1-42 and 1-38 levels; there was no corresponding increase in Aβ levels in the brain. Increases in CSF Aβ1-40 and 1-42 were not observed in a two-week healthy volunteer study in humans. Additionally, in a toxicology study in cynomolgus monkeys at a dose 146 mg sacubitril/154 mg valsartan/kg/day for 39 weeks, there was no evidence for the presence of amyloid plaques in the brain. Amyloid content was not, however, measured quantitatively in this study.
Sacubitril: In juvenile rats treated with sacubitril (postnatal days 7 to 70), there was a reduction in age-related bone mass development and bone elongation. A study in adult rats showed only a minimal transient inhibitory effect on bone mineral density but not on any other parameters relevant for bone growth, suggesting no relevant effect of sacubitril on bone in adult patient populations under normal conditions. However, a mild transient interference of sacubitril with the early phase of fracture healing in adults cannot be excluded.
Valsartan: In juvenile rats treated with valsartan (postnatal days 7 to 70), doses as low as 1 mg/kg/day produced persistent irreversible kidney changes consisting of tubular nephropathy (sometimes accompanied by tubular epithelial necrosis) and pelvic dilatation. These kidney changes represent an expected exaggerated pharmacological effect of angiotensin converting enzyme inhibitors and angiotensin II type 1 blockers; such effects are observed if rats are treated during the first 13 days of life. This period coincides with 36 weeks of gestation in humans, which could occasionally extend up to 44 weeks after conception in humans.