Novartis’ Entresto Becomes First FDA-Approved Treatment for Heart Failure with Preserved Ejection Fraction (HFpEF)

February 17, 2021 /BioValleyBIOON/ --Novartis(Novartis) recently announced that the U.S. Food and Drug Administration (FDA) Approved expansion of the indication for the heart failure drug Entresto (Chinese brand name: Nuo Xin Tuo; sacubitril/valsartan): to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with heart failure with preserved ejection fraction (HFpEF). Patients with left ventricular ejection fraction (LVEF) below normal values derive the most significant benefit. The Entresto label also notes that LVEF is a variable measure that can be used in clinical judgment to determine which patients should receive treatment.

Entresto is a blockbuster drug approved for the treatment of heart failure with reduced ejection fraction (HFrEF), typically defined as an ejection fraction <40%. Notably, with this approval,Entresto is the first and only therapy approved for the treatment of patients with guideline-defined heart failure, including those with heart failure with reduced ejection fraction (HFrEF) and those with heart failure with preserved ejection fraction (HFpEF).This expanded indication will provide more adult patients with heart failure and below-normal left ventricular ejection fraction (LVEF) the opportunity to receive treatment, among whom the therapeutic benefits are most pronounced.

This label expansion is based on the efficacy and safety evidence observed in the PARAGON-HF study. To date, this remains the largest and only Phase III active-controlled trial conducted in patients with guideline-defined heart failure with preserved ejection fraction (HFpEF). Although the primary endpoint did not achieve statistical significance, the overall evidence from the study indicates that Entresto provides clinically meaningful benefits in specific subgroups of patients with HFpEF. In particular, patients with left ventricular ejection fraction (LVEF) below the normal range derived the greatest benefit.

In the United States, approximately 6 million people suffer from chronic heart failure (HF), with about 3 million having heart failure with reduced ejection fraction (HFrEF). Of the remaining 3 million, approximately 2 million have heart failure with preserved ejection fraction (HFpEF) characterized by a left ventricular ejection fraction (LVEF) below the normal range. With the aging of the population, the prevalence of HF is increasing. Patients frequently experience worsening symptoms, leading to frequent hospitalizations for heart failure. Each hospitalization event contributes to a deterioration in long-term prognosis. Approximately one-quarter of patients are readmitted for heart failure, and 10% of patients may die within 30 days after discharge. The overall mortality rate for heart failure remains high, with up to half of patients dying within five years of diagnosis.

Scott D. Solomon, MD, Professor of Medicine at Harvard Medical School and Brigham and Women’s Hospital, and Co-Chair of the PARAGON-HF Executive Committee, stated, “This approval represents a significant advance, providing treatment for many patients who were previously ineligible because their ejection fraction was higher than the range typically considered reduced. Until now, therapy for these patients has been largely empirical. We can now offer treatment to a broader population of patients with left ventricular ejection fraction below normal.”

Novartis“Marie France Tschudin, President of Pharmaceuticals, stated: ‘We are proud of our goal to reimagine medicine. This commitment has enabled us to deliver treatments to millions of heart failure patients in the United States, many of whom had no approved therapeutic options until now. Without researchers,’Clinical Trial"We are deeply grateful for the tremendous dedication of patients and advocacy groups; without it, this achievement would not have been possible."

Heart Failure (Image source: slideserve.com)

Heart failure (HF) is a progressive and severe disease affecting approximately 26 million people worldwide, characterized by the heart's inability to pump sufficient blood to the body. There are two distinct types: heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF). Heart failure is typically classified as HFrEF when the ejection fraction falls below 40%. HFpEF accounts for approximately half of all heart failure cases and is more prevalent in women and older adults.

HFpEF is a distinct type of heart failure characterized by preserved myocardial contraction, but impaired ventricular relaxation during ventricular filling (or diastole). HFpEF is associated with high hospitalization rates, poor quality of life, and increased mortality, and is gradually becoming the predominant form of heart failure; previously, there were no approved therapeutic agents for this condition. In contrast, HFrEF indicates insufficient cardiac contractility, resulting in reduced blood ejection, and multiple approved treatments are already available.

Cardiology experts believe that HFpEF poses a more formidable challenge for drug development, as it is a highly heterogeneous disease likely resulting from the interplay of multiple factors, including structural changes in the heart, vasculature, or kidneys, and even the efficiency of oxygen transport by the blood.

Analysts predict that success in HFpEF will unlock a global patient pool of approximately 13 million for Entresto, a population characterized by high hospitalization rates, reduced quality of life, and elevated mortality risk.

Entresto is a dual-acting angiotensin receptor-neprilysin inhibitor (ARNI) with a unique mode of action that enhances the heart’s protective neuroendocrine system (the NP system, or natriuretic peptide system) while inhibiting the harmful system (the RAAS system, or renin-angiotensin-aldosterone system), and is believed to reduce strain on the failing heart. Entresto combinesNovartisHypertensionThe medication Diovan (generic name: valsartan) and sacubitril, the latter being a neprilysin inhibitor that blocks the mechanisms of two peptides responsible for lowering blood pressure, while valsartan is an angiotensin II receptor antagonist that improves vasodilation and stimulates the excretion of sodium and water.

Since its approval in July 2015 for the treatment of heart failure with reduced ejection fraction (HFrEF) to reduce the risk of cardiovascular death and hospitalization for heart failure, Entresto has become a preferred and foundational therapy for HFrEF. By modulating the cardiac neuroendocrine system through multiple mechanisms, Entresto is regarded as a major breakthrough in heart failure treatment over the past two decades. It was the first drug to demonstrate significantly superior efficacy compared with the standard-of-care agent enalapril in clinical trials, substantially reducing cardiovascular death and heart failure hospitalizations while exhibiting an improved safety profile. As such, it represents one of the most important advances in cardiology in the past decade.

In the Chinese market, Entresto (Novartis) was approved in July 2017 for adult patients with heart failure with reduced ejection fraction (HFrEF) to reduce the risk of cardiovascular death and hospitalization due to heart failure.

In 2020, global sales of Entresto reached $2.497 billion, representing a 44.7% increase from 2019, making the drug a key driver ofNovartisA key product driving sales growth. The company expects Entresto to reach annual peak sales of $5 billion. (Bioon.com)

Original source: Novartis Entresto® granted expanded indication in chronic heart failure byFDA