Novartis had hoped Entresto could find itself yet another niche, this time in patients who’d had a heart attack. But in late April, a large study found the heart failure drug couldn’t quite top widely used ACE inhibitor ramipril in those patients, at least in a statistically significant way.
But that doesn’t mean the company isn’t sifting the data for nuggets of good news—and, Saturday, it revealed details at the American College of Cardiology's virtual scientific session.
In the 5,669-patient Paradise-MI trial, heart attack patients on Entresto were 10% less likely than those on ramipril to be hospitalized for heart failure, die of cardiovascular causes or develop symptomatic heart failure. The drug needed to hit 15% for the win to be statistically significant.
It's "not the outcome [Novartis] hoped for," but the company plans "additional analyses to understand the data fully in the context of Entresto’s clinical profile,” a Novartis spokesperson said via email.
An approval in post-heart attack patients wouldn’t be a blockbuster for Entresto. Jefferies analyst Peter Welford noted last year that these patients only made up $525 million of the $5.1 billion global peak sales Jefferies had estimated for the drug—unlike the $1 billion approval the drug won in February in a new group of heart failure patients.
In the Paradise-MI trial, a symptomatic heart failure diagnosis or hospitalization, or death from cardiovascular causes, cropped up in Entresto patients at a rate of 6.7 per 100 patient years, or 11.9%, the spokesperson said. Ramipril charted a 13.2% event rate, or 7.4 per 100 patient years.
Peeling back those results, the rate of cardiovascular death for Entresto patients was 5.9% versus ramipril's 6.7%. There was a 6% rate of heart failure hospitalizations in the Entresto arm, versus 6.9% in the ACE inhibitor cohort. And 1.4% of Entresto patients developed outpatient heart failure compared to 2% in subjects who received ramipril.
One possible silver lining? “Although we did not significantly reduce our primary endpoint, there were consistent findings that sacubitril/valsartan could represent an incremental improvement over ramipril,” lead study author Marc Pfeffer, M.D., Ph.D., said in a release. He called the results “encouraging,” particularly in the context of “recurrent heart failure events,” rather than just the first.
“We did notice several aspects of heart failure development that were lessened with sacubitril/valsartan but to investigate these observations would require further evaluations,” he added.
Specifically, an exploratory analysis of the total burden of heart failure, which included recurrent events, showed a 21% reduction in patients on Entresto versus ramipril.
Side effect rates were consistent across both treatment arms, Novartis said. Patients on Entresto did show a slightly higher rate of low blood pressure, while those on ramipril were slightly more likely to report coughing. While the results “may not change guidelines,” they “should make physicians even more comfortable” prescribing the drug for vulnerable heart failure patients, Pfeffer said.
With plans to dig deeper into the data, Novartis is keeping its regulatory ambitions close to the vest. “We will provide an update on any potential health authority interactions at the appropriate time,” the company’s spokesperson said.
Despite the trial flop, Entresto's star is rising. The FDA in February approved the drug in a key new patient group—those with heart failure with preserved ejection fraction, provided their left ventricular ejection fraction is below normal. Thanks to its existing nod in patients with chronic heart failure and reduced ejection fraction, Entresto is now the only drug with with a green light in both conditions.
During the first three months of the year, Entresto sales jetted upward by 39% to $789 million. It also joined the triumvirate of Novartis' top-selling drugs last year, generating $2.5 billion in 2020 sales.