Entresto Wins First FDA Nod in Hard-to-Treat Type of Heart Failure

FDA on Tuesday granted Entresto, a combination of sacubitril and valsartan, an indication to treat patients with heart failure (HF) with preserved ejection fraction (HFpEF), the first time a therapy has been approved for this population.

The approval could offer a new treatment choice for up to 2 million people with chronic heart failure, who until now have only had drugs to manage symptoms and comorbidities. According to a statement from Novartis, the maker of Entresto, up to 5 million of the of 6 million US patients with chronic heart failure could be candidates for the drug.

Patients with heart failure cannot adequately pump blood through the body, causing fatigue, persistent cough, weakness or other symptoms. These patients have long hospital stays, and when they are discharged, they often return. Most have other health problems, diabetes being among the most common. Half of patients with heart failure will die within 5 years of showing symptoms, so finding better treatments has long been a concern to payers and health systems alike.

Heart failure with reduced ejection fraction, also called systolic heart failure, occurs when the heart’s left ventricle becomes enlarged and fails to push blood out into the circulatory system properly. Entresto is already approved for this type of heart failure and after several years on the market has slowly become the first treatment choice.

Some patients, however, have HFpEF: The left ventricle has enough pumping power but the heart is stiff, so the chamber doesn’t fill up with enough blood. Until today, no therapies have been approved for this type of HF.

Always a cost driver, heart failure hospitalization promises to be even more so without new treatments. A 2020 review found that the number of people in the United States with HF is expected to reach 8.5 million by 2030, and that 30% to 40% will require hospitalization at current rates. Without improved outcomes, the total US cost of care in HF would reach $69.7 billion by 2030.

In the market for HF with reduced ejection fraction, Entresto faces competition from other drugs and other classes, including sodium glucose co-transporter 2 inhibitors (SGLT2s), a treatment group first developed to treat type 2 diabetes that can reduce heart failure hospitalization through an entirely different mechanism. In fact, some believe the future of care for patients with HFpEF will involve treatment with both Entresto and SGLT2 inhibitors.

But today, Entresto’s odyssey ends with an FDA indication, more than a year after a highly anticipated study fell just short of hitting its primary end point. However, in December 2020, FDA’s Cardiovascular and Renal Drugs Advisory Committee found that Entresto was worthy of some indication based on the PARAGON-HF trial, which studied patients with left ventricular ejection fraction (LVEF) of ≥45%. The panel discussed the fact that HFpEF is something of a misnomer and that LVEF above 40% but below 57% may constitute its own range.

The language in the announcement reflected that discussion. Novartis stated that FDA had approved an expanded indication “to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure,” and that, “Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal.”

The announcement further states, “The label also states LVEF is a variable measure and clinical judgment should be used in deciding whom to treat.”

“This approval is a significant advancement, providing a treatment to many patients who were not eligible for treatment before because their ejection fraction was above the region we normally considered reduced. Until now, treatment for these patients was largely empiric,” Scott Solomon, MD, professor of medicine at Harvard Medical School and Brigham and Women's Hospital, and PARAGON-HF Executive Committee co-chair, said in the announcement. “We can now offer a treatment to a wider range of patients who have an LVEF below normal.”