Drug Name (Brand / Generic)
Company / Licensee
Angiotensin receptor neprilysin inhibitor (ARNI)
Approved in the US
Entresto (sacubitril/valsartan) is an angiotensin II receptor blocker indicated to treat chronic heart failure, found to reduce the risk of cardiovascular death and hospitalisation related to heart failure.
Discovered and developed by Novartis, Entresto is the first and only medicine to show significant mortality benefit compared to Enalapril, a widely used ACE inhibitor.
Novartis submitted the new drug application (NDA) for the drug under FDA’s fast track programme and was granted priority review designation in February 2015.
Entresto was approved by the US Food and Drug Administration (FDA) in July 2015 to reduce the risk of death and hospitalisation in heart patients classified under The New York Heart Association (NYHA) class II-IV, approved to decrease the risk of heart failure in those with reduced ejection fraction (outbound pumping of blood by heart).
NYHA functional classifications are based on the extent of heart failure in heart disease patients. The classifications II-IV range from mild symptoms with ordinary activities to severe limitations characterised by the occurrence of symptoms even at rest.
Europe’s Committee for Medicinal Products for Human Use (CHMP) granted accelerated assessment to the drug in November 2014 and approved the drug in November 2015.
Swissmedic approved Entresto for heart failure in September 2015, while Health Canada approved the drug for treating heart failure with reduced ejection fraction (HFrEF) in October 2015.
Entresto received FDA approval for an extended indication of heart failure in paediatric patients aged one year and older with systemic left ventricular systolic dysfunction in October 2019.
Heart failure and its prevalence in the US
Heart failure occurs when the heart fails to pump a sufficient amount of blood to other parts of the body due to the weakening of its muscles. People suffering from the condition are at a high risk of death and frequent hospitalisations and experience symptoms including breathlessness, fatigue and fluid retention.
Heart failure is estimated to affect approximately six million people in the US, half of who have reduced ejection fraction form. Approximately 2.2 million people with heart failure are classified as NYHA II-IV.
Entresto’s mechanism of action
Entresto is the first-in-class angiotensin receptor neprilysin inhibitor (ARNI) that reduces strain on the failing heart. It contains two active components, sacubitril, a neprilysin inhibitor and valsartan, an angiotensin receptor blocker.
The sacubitril/valsartan drug inhibits neprilysin and blocks angiotensin II type-I receptor, increasing the levels of peptides degraded by neprilysin.
Valsartan inhibits the effects of angiotensin II by blocking the AT1 receptor and by inhibiting the release of angiotensin II-dependent aldosterone.
Clinical trials on Entresto
FDA approval of Entresto was based on results from a randomised, double-blind, phase three clinical trial known as Paradigm-HF, conducted to determine the safety and efficacy of the drug.
It was the biggest heart failure study ever conducted and was completed before schedule as the drug showed significant results in reducing the cardiovascular death risk.
Paradigm-HF enrolled 8,442 patients with HFrE and NYHA Class II-IV heart failure. The study compared Entresto with another ACE inhibitor, Enalapril, and was designed to find out whether it is superior to Enalapril in decreasing cardiovascular mortality by at least 15%.
During the study, subjects discontinued their existing ACE inhibitor or other therapies and entered a sequential single-blind trial in which they received Enalapril 10mg twice daily followed by Entresto 100mg twice a day, increasing to 200mg.
Upon completing the run-in periods, they were randomised to receive either Entresto 200mg or Enalapril 10mg twice a day.
The study was carried out for more than three years. Its primary endpoint was the composite of time of the first occurrence of either heart failure-related hospitalisation or cardiovascular death.
Secondary endpoints were the difference in the clinical summary score for heart failure symptoms.
In March 2014, the Data Monitoring Committee confirmed that subjects treated with Entresto are less likely to die from cardiovascular complications. The drug reduced the risk of death from these causes by 20%, heart failure-related hospitalisations by 21% and the risk of all-cause mortality by 16% during the study.
The gross risk reduction on the primary endpoint was 16%.
Common adverse reactions observed during the study were angioedema (swelling of skin), hypotension, impaired renal function and hyperkalemia (high levels of potassium).
PANORAMA-HF clinical study in paediatric patients
FDA approval for paediatric heart failure indication was based on analysis of data at 12 weeks in 110 patients from the ongoing PANORAMA-HF study.
The clinical trial is being conducted in two parts and will enrol a total of 390 patients aged one month to less than 18 years with heart failure (NYHA/Ross Class II-IV) due to systemic left ventricular systolic dysfunction (LVEF <40%).
Part one is an open-label dose determination study, while part two is a 52-week randomised, double-blind analysis, which will compare Entresto with Enalapril.
The trial is underway in 39 countries and 129 clinical sites across Europe, North America, Latin America and Asia and is scheduled to end in 2021.
The primary endpoint of the trial changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP) plasma from baseline to 12 weeks between the two groups. The analysis of the data from 12 weeks showed that the NT-proBNP was 44% for Entresto and 33% for Enalapril.
Safety and tolerability of Entresto in paediatric patients were consistent with that seen in adult patients.
PARAGON-HF clinical trial in HFpEF patients
PARAGON-HF is the largest clinical trial in HFpEF patients performed to date. The double-blind, randomised, active-controlled parallel-group, phase three, two-arm trial compared Entresto’s long-term effectiveness and safety to valsartan in 4,822 HFpEF patients.
The trial showed a 13% relative decrease in the primary composite endpoint of cardiovascular death and total (first and recurrent) cardiac failure hospitalisations but missed statistical significance.
The secondary outcome demonstrated that patients treated with Entresto reported less decline in quality of life than patients treated with valsartan based on the KCCQ Clinical Summary Rating (CSS).
Entresto, however, demonstrated larger declines in hospitalisation in patients with cardiac failure compared to valsartan. This greater benefit was seen in women with HFpEF, and patients who were recently hospitalised for heart failure with HFpEF.
Entresto (sacubitril/valsartan) was approved six weeks prior to the FDA’s priority review action date, enabling the company to make the drug available to US patients more quickly. It is estimated to achieve peak sales of $5bn upon being approved by all health authorities.