Sacubitril

Structural formula
General
Non-proprietary name	Sacubitril
other names	4 - {[(2 S , 4 R ) -1 - ([1,1'-Biphenyl] -4-yl) -5-ethoxy-4-methyl-5-oxopentan-2-yl] amino} -4- oxobutanoic acid ( IUPAC ); AHU-377;
Molecular formula	C 24 H 29 NO 5
External identifiers / databases
PubChem	9811834
ChemSpider	7987587
DrugBank	DB09292
Wikidata	Q17811448
Drug information
Drug class	Antihypertensive drug
Mechanism of action	Neprilysin inhibitor
properties
Molar mass	411.49 g · mol -1
safety instructions
GHS hazard labeling ; no classification available
GHS hazard labeling ; no classification available
	As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Sacubitril (also: AHU-377 ) is a drug and acts as neprilysin - inhibitor . In a fixed combination with valsartan (trade name Entresto ) it shows positive results for the treatment of heart failure in approval studies .

Pharmacological properties

Sacubitril is a prodrug which is converted by an esterase into the actual active ingredient sacubitrilate (LBQ657) by removing an ethyl group . This is an inhibitor of neprilysin, a neutral endopeptidase from the group of metalloproteases , which breaks down numerous endogenous vasoactive peptides such as natriuretic peptides , bradykinin or adrenomedullin . By inhibiting the breakdown, the concentration of these substances increases, which together and then increasingly counteract the neurohormonal overactivation with vasoconstriction and sodium retention with maladaptive cardiac remodeling.

Sacubitril itself has no blood pressure lowering effect.

The medium-term and long-term effects of sacubitril have not yet been adequately investigated. Neprilysin physiologically degrades beta-amyloids , which play an important role in Alzheimer's disease . A side effect could therefore be an amyloid build-up. Mice in which neprilysin was switched off showed symptoms similar to Alzheimer's. This observation led the US drug regulatory authority FDA to oblige the Entresto manufacturer Novartis to carry out a long-term monitoring of the risks as part of a randomized, double-blind study. The results of this long-term observation are not expected until 2022.

The most common side effects reported so far are hypotension , hyperkalemia and renal dysfunction . Furthermore, there is an increased risk of angioedema, especially if an ACE inhibitor is taken at the same time . This must therefore be stopped at least 36 hours before the first dose of sacubitril.

PARADIGM-HF study with a fixed combination with valsartan

A double-blind , randomized, clinical study (PARADIGM-HF) at several institutes financed by Novartis had to be discontinued after a median of 27 months of follow-up because the pre-specified limit for an excessively positive effect was reached in a scheduled interim analysis.

The LCZ696 fixed combination of sacubitril and the AT1 antagonist valsartan was clearly superior to the ACE inhibitor enalapril . 8,442 patients with moderate to severe systolic heart failure , i.e. H. an ejection fraction of 40% or less . The primary study endpoint was death from cardiovascular cause or hospital treatment for heart failure. At the time the study was discontinued, the primary endpoint was reached by 21.8% of the patients treated with sacubitril / valsartan, in the control group it was 26.5% ( hazard ratio 0.80). 17.0% and 19.8% died in the verum and control group (HR 0.84). This means that 32 patients have to be treated with sacubitril / valsartan in order to prevent further death from heart failure ( Number Needed to Treat = 32). With sacubitril / valsartan, hospital admissions were also reduced by 21%, symptoms of heart failure were lower, and physical fitness was improved.

Individual evidence

↑ This substance has either not yet been classified with regard to its hazardousness or a reliable and citable source has not yet been found.
↑ Mariell Jessup: Neprilysin inhibition - a novel therapy for heart failure in: New England Journal of Medicine , 2014, Volume 371, pp. 1062-1064, doi : 10.1056 / NEJMe1409898 .
^ Govi-Verlag Pharmazeutischer Verlag GmbH: Heart failure: safety concerns about Entresto. In: www.pharmazeutische-zeitung.de. Retrieved June 20, 2016 .
↑ John JV McMurray, Milton Packer, Akshay S. Desai, Jianjian Gong, Martin P. Lefkowitz, Adel R. Rizkala, Jean L. Rouleau, Victor C. Shi, Scott D. Solomon, Karl Swedberg, Michael R. Zile, for the PARADIGM-HF Investigators and Committees: Angiotensin – Neprilysin Inhibition versus Enalapril in Heart Failure in: New England Journal of Medicine , 2014, Volume 371, pp. 993-1004; doi : 10.1056 / NEJMoa1409077 .

[NV-1] This substance has either not yet been classified with regard to its hazardousness or a reliable and citable source has not yet been found.

[2] Mariell Jessup: Neprilysin inhibition - a novel therapy for heart failure in: New England Journal of Medicine , 2014, Volume 371, pp. 1062-1064, doi : 10.1056 / NEJMe1409898 .

[3] Govi-Verlag Pharmazeutischer Verlag GmbH: Heart failure: safety concerns about Entresto. In: www.pharmazeutische-zeitung.de. Retrieved June 20, 2016 .

[4] John JV McMurray, Milton Packer, Akshay S. Desai, Jianjian Gong, Martin P. Lefkowitz, Adel R. Rizkala, Jean L. Rouleau, Victor C. Shi, Scott D. Solomon, Karl Swedberg, Michael R. Zile, for the PARADIGM-HF Investigators and Committees: Angiotensin – Neprilysin Inhibition versus Enalapril in Heart Failure in: New England Journal of Medicine , 2014, Volume 371, pp. 993-1004; doi : 10.1056 / NEJMoa1409077 .