FDA Approves Sacubitril/Valsartan for Pediatric Heart Failure

The US Food and Drug Administration (FDA) has approved sacubitril/valsartan (Entresto) for the treatment of pediatric symptomatic heart failure with systemic left ventricular systolic dysfunction in patients aged 1 year and older.

The approval was based on the findings through week 12, from the 52-week PANORAMA-HF trial, in which cardiac biomarker NT-proBNP was reduced among pediatric patients with heart failure due to systemic left ventricular dysfunction.

Because sacubitril/valsartan was shown to improve cardiovascular outcomes and reduced NT-proBNP among adult patients in the PARADIGM-HF trial as well, the observed effect of the drug on NT-proBNP was deemed a reasonable based to improve similar outcomes in pediatric patients.

Reductions in NT-proBNP with therapy from baseline (44%) and the active comparator enalapril (33%) were similar to or greater than those observed in adults. However, the disparity between effect in the treatment groups was not statistically significant.

The safety and tolerability of sacubitril/valsartan in pediatric patients was consistent with that observed in adult patients.

It is estimated that about half of all children with systolic heart failure require a heart transplant before reaching age 5, and that almost one-third die or require a transplant within another year.

Though the clinical data for sacubitril/valsartan’s benefit in pediatric systolic heart failure is limited, Novartis intends to complete 52-week follow-up assessments from the full study population from PANORAMA-HF, David Soergel, MD, global head of Cardiovascular, Renal and Metabolic Drug Developments, said.

“We remain committed to trial completion to generate further evidence on how Entresto impacts the clinical course of pediatric HF and are grateful for the ongoing collaboration with the investigators, as well as the patients and their families,” Soergel said in a statement.

Sacubitril/valsartan was initially approved in the US in 2015 for the reduced risk of cardiovascular death or heart failure hospitalization in adult patients with chronic heart failure and reduced ejection fraction (HFrEF)—the subtype which affects approximately half of all adult heart failure patients.

In an interview with MD Magazine® while at the Heart Failure Society of America (HFSA) 2019 Scientific Sessions last month, study author James Januzzi, MD, professor of medicine at Harvard Medical School, and of the Cardiology Division at Massachusetts General Hospital, explained the promising findings from sacubitril/valsartan profile studies such as PARADIGM-HF and PROVE-HF give clinicians more confidence in prescribing it.

“The bottom line is that the trial really provides useful information to reassure our clinicians that this drug exerts a rather profound reverse cardiac remodeling effect—more so than any other drug that we have studied, together with obvious safety,” he said.

In previewing follow-up assessments for at least PROVE-HF, Januzzi highlight the significance of subgroup analyses, including those for older patients, women, and people of color. There’s also interest in observing sacubitril/valsartan’s benefit in other outcomes.

“We have a very robust prior repository from which we'll be looking at the effects of sacubitril/valsartan on a wide range of biomarkers, to help us better understand mechanism of action and mechanism of benefit, and quality of life measures to see how the drug affected symptoms and quality of life across the whole year of management,” Januzzi said.