In summary the CV and renal benefits of sacubitril valsartan

In summary, the CV and renal benefits of sacubitril/valsartan in HF patients are attributed to the increased levels of peptides that are degraded by neprilysin and the simultaneous inhibition of the effects of AT1 receptor by valsartan (Fig. 1).
Physical and chemical properties Sacubitril/Valsartan complex comprises of anionic forms of sacubitril and valsartan, sodium cations, and water molecules in the molar ratio of 1:1:3:2.5, respectively. A single complex consists of 6 valsartan anions, 6 sacubitril anions, 18 sodium cations, and 15 molecules of water, resulting in the molecular formula C288H330N36Na18O48·15H2O and a molecular mass of 5748.03 g/mol.6, 13 The substance is a white powder consisting of thin hexagonal plates. It is stable in solid form as well as in aqueous (watery) solution with a pH of 5 to 7, and a melting point of about 138 °C (280 °F)6, 13 (Fig. 2).
Pharmacokinetics
Pharmacodynamics In a 7-day valsartan-controlled study in Heart Failure with Reduced Ejection Fraction (HFrEF) patients, administration of sacubitril/valsartan 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 patients with HFrEF, sacubitril/valsartan significantly increased urine ANP and cGMP and plasma cGMP, and decreased plasma NT-proBNP, Netilmicin Sulfate and endothelin-1. It also blocked the AT1-receptor as evidenced by increased plasma renin activity and plasma renin concentrations.13, 17 In PARADIGM-HF, sacubitril/valsartan decreased plasma NT-proBNP (not a neprilysin substrate) and increased plasma BNP (a neprilysin substrate) and urine cGMP compared with enalapril.7, 18 Administration of sacubitril/valsartan for 2 weeks to healthy subjects was associated with an increase in CSF Aβ1-38 with no changes in concentrations of CSF Aβ1-40 or CSF Aβ1-42. Notably, though sacubitrilat crosses blood–brain barrier (BBB), no corresponding increase in amyloid-β levels or amyloid-β accumulation were noted in the brain tissues of cynomolgus monkeys.7, 18 Co-administration did not significantly alter the BP effect of intravenous nitroglycerin.
Clinical trials
Omapatrilat vs sacubitril/valsartan Though Omapatrilat, an investigational vasopeptidase inhibitor (VPi), too have shown sustained, favourable, haemodynamic and neurohumoral actions in past, it failed to beat enalapril 10 mg BID in a head-to-head comparison in patients with chronic HFrEF in the OVERTURE (Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events) trial.28, 29 The results weren’t encouraging for the other two trials namely OPERA (Omapatrilat in Persons With Enhanced Risk of Atherosclerotic Events) and OCTAVE (Omapatrilat Cardiovascular Treatment Assessment Versus Enalapril). Omapatrilat angioedema was attributed to its dual mechanism of action i.e., inhibiting both angiotensin-converting enzyme and neprilysin. Both of these enzymes are responsible for the metabolism of bradykinin which causes vasodilation, angioedema, and airway obstruction. Omapatrilat was not approved by USFDA due to angioedema safety concerns. The final vote from the Committee was 5-1 against approval.32, 33
Dosage and administration ARNIs have been recently approved for patients with symptomatic HFrEF and it is intended to be substituted for ACE inhibitors or ARBs and should replace ACE or ARBs when stable patients with mild-to-moderate HF on these agents have an adequate blood pressure and are otherwise tolerating standard therapies.8, 9, 10, 13 Starting dose of 24/26 mg BID is recommended for patients not currently taking an ACE inhibitor or an angiotensin II receptor blocker (ARB), patients previously taking low doses of these agents, patients with severe renal impairment (eGFR <30 mL/min/1.73 m2) and patients with moderate hepatic impairment (Child-Pugh classification Class B, 7–9 points score). Dose can be doubled every 2–4 weeks to the target maintenance dose of 97/103 mg BID, as tolerated by the patient.8, 9, 10, 13