An incident happened to the representative heart disease products with TCM characteristics several days ago, which attracted broad attention of the industry. Therefore, I hereby focus on blockbuster products in the future heart disease drug market, and regard the heart failure product Entresto® of Novartis as the foremost, which will not only be the absolute dominant of the future heart failure drug market, but also the leader of the future heart disease drug market.

I. Numerous patients with chronic heart failure (CHF) that causes heavy medical burden

CHF is the severe and end stage of various cardiovascular diseases, with high morbidity and mortality and poor prognosis, being one of the diseases seriously threatening human health at present.

CHF is a disease that causes ventricular filling and ejection function impairment and eventually causes low ventricular blood pumping function due to various causes. According to the current statistical results, the morbidity of CHF in global population aged above 45 is 3-5%, and this figure may be higher in reality. World FS Society estimated the prevalence of CHF to be 2.5% in the West. The heart failure is also an important and increasingly severe public health problem, with global funds spent on heart failure of USD 108 billion every year, wherein, the hospitalization expenses account for 60%-70% of the treatment expenses.

In 2006, the American Heart Association estimated that Americans with heart failure approached 5.80 million, and predicted the patient population to increase by about 50% to reach over 8 million by 2030. Over 1 million people with heart failure need hospitalization in the U.S. and Europe every year. The prevalence of heart failure in Chinese adults is 0.9% and the patient population is at least 7 million, with high case fatality rate and poor prognosis. The heart failure treatment rate and control rate in China are still far lower than those in developed countries despite years of efforts.

II. Double-effect mechanism of action of Entresto®

Entresto® (Sacubitril/valsartan tablets, LCZ696) is a first-in-class angiotensin receptor-neprilysin inhibitor (ARNI) developed by Novartis and approved for marketing on July 7, 2015 and November 19, 2015 separately by the U.S. Food and Drug Administration (FDA) and the EU for treating heart failure patients with reduced ejection fraction.

Novartis announced on July 28, 2017 that Entresto® was formally approved by CFDA for marketing to treat adult patients with CHF and reduced ejection fraction, to reduce their risks of cardiovascular death and heart failure hospitalization.

The chemical structure of Entresto® is 1:1 combination of the ARB valsartan and NEP inhibitor precursor Sacubitril, i.e., it has two action targets, with the former blocking RAAS and the latter metabolizing to LBQ657 to inhibit NEP, thereby inhibiting RAAS.

Therefore, the treatment of CHF by Entresto® mainly functions as vasodilation, prevention and reversal of cardiovascular remodeling, and natriuresis, etc. through inhibiting the angiotensin II receptor in RASS and NEP.

Inhibiting angiotensin II receptor in RASS

As an important humoral regulation system, RASS exists in the circulatory system and also vascular wall, heart, central nerve, kidney and adrenal gland, etc., to jointly participate in target organ regulation. A series of fundamental and clinical research proves that the neuroendocrine activation, especially the RASS and sympathetic nervous system activation, plays a key role in the occurrence and development of heart failure.

ARB can block RASS and function as vasodilation, blood pressure reduction, vascular endothelial cell protection, inhibition of sympathetic transmitter release, anti-atherosclerosis, and prevention and reversal of cardiovascular remodeling, etc. ARB can be used to treat CHF, and can continuously improve hemodynamics and prevent CHF aggravation, wherein, the valsartan is the ARB representative, and one of the clinically most commonly used drugs for hypertension and CHF, etc.

Inhibiting NEP

NEP (Neutral endopeptidase, also called Neprilysin) is a type II transmembrane glycoprotein of M13 zinc-dependent metalloproteases, with the zinc atoms thereon in enzyme’s active site. NEP molecular weight is about 97kDa constituted by 750 amino acids, including one signal peptide and two hydrophilic domains, 26 amino acids in intracellular domain and 700 amino acids in extracellular region. NEP can act on the polypeptide amino terminal to hydrolyze polypeptide chain. Since first defined in 1974, NEP, a kind of neuropeptide-degrading enzyme, has been discovered to widely distribute in endothelial cells, vascular smooth muscle cells, heart muscle cells, renal epithelial cells, and fibroblasts, and exist in lungs, intestines, adrenal gland, and brain, etc., with many tissue specific functions. Natriuretic peptide is mainly degraded by NEP, and NEP can also catalyze adrenal medulla and bradykinin. NEP selective inhibitor inhibits NEP activity, which can improve concentration of natriuretic peptide and bradykinin, to dilate blood vessels, increase cardiac output, reduce aldosterone level, inhibit RASS (renin-angiotensin-aldosterone system), reduce cardiac preload and afterload, delay myocardial remodeling, and improve cardiac functions of heart failure patients.

Natriuretic peptide cannot be directly applied clinically due to high price and short half-life, etc., though it is conductive to treating hypertension and CHF. However, research has found that natriuretic peptide can slow down own metabolism through decomposing and inhibiting NEP, thereby functioning as treating hypertension, CHF and other cardiovascular diseases. One of the ingredient of Entresto® is NEP inhibitor precursor Sacubitril which splits into NEP inhibitor LBQ657 under the action of its specific enzyme, and LBQ657 functions as vasodilation and promoting natriuresis, etc. through inhibiting NEP.

III. Clinical advantages of Entresto®

According to data of the large-scale PARADIGM-HF: Phase 3 clinical trial of Entresto® that recruited the largest number of heart failure patients (n=8,442), Entresto® was significantly superior to the standard heart failure drug ACE inhibitor: enalapril in many key endpoints. Across the treatment groups, Entresto® had showed sustainable treatment benefits in the early stage of treatment: reduced the risk for death from cardiovascular causes by 20%, reduced the risk for hospitalization for heart failure by 21%, and reduced the risk of all-cause mortality by 16%; overall there was a 20% risk reduction on the primary endpoint, a composite measure of cardiovascular death or time to first heart failure hospitalization.

The clinical study results also showed that the antihypertensive effect of Entresto® was better than that of valsartan, and Entresto® showed a good tolerance.

Most of the present anti-heart-failure drugs treat patients through drug combination and shall be conducted dose adjustment, with poor patient compliance, however, Entresto® can inhibit both NEP and angiotensin receptor, is not required to treat patients in combination with ACE inhibitor or ARB drug, and requires taking twice every day. Entresto® dose not only facilitate patients’ use, it also improves patients’ compliance with the product.

The biggest clinical benefit of Entresto® is that it is the first and only drug with efficacy significantly surpassing that of the standard drug enalapril in clinical trial, and it showed higher safety.

By Biodiscover.com

Authored by Yunqing

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