Novartis Heart Failure Drug Gains Speedy FDA Approval

Entresto, Novartis’s novel heart failure (HF) drug, gained FDA approval earlier today. The approval arrived 6 weeks ahead of the drug’s action date. Formerly known as LCZ 696, the drug had already received a fast track designation and an expedited review under the FDA’s priority review program.Novartis said the wholesale acquisition cost of Entresto will be $12.50 per day, less discounts.

According to Novartis, the label will state that Entresto is “indicated to reduce the risk of cardiovascular death and heart failure hospitalization in patients with chronic heart failure (NYHA class II-IV) and reduced ejection fraction. Entresto is usually administered in conjunction with other heart failure therapies, in place of an ACE inhibitor or other ARB.”

Entresto is the first of a new class of drugs known as Angiotensin Receptor Neprilysin Inhibitors, or ARNIs. It consists of the well-known angiotensin receptor blocker valsartan and a novel compound, the neprilysin inhibitor sacubitiril. Inhibition of neprilysin is intended to held reduce the neurohormonal activation that helps drive common heart failure (HF) processes like vasoconstriction, sodium retention, and remodeling. This specific combination was designed to avoid angioedema, a side effect which doomed a similar earlier drug, omapatrilat, which combined an ACE inhibitor and a neprilysin inhibitor.

The drug will be available in three dosage strengths: 24/26 mg, 49/51 mg and 97/103 mg (sacubitril/valsartan). The label recommends that most patients should start with the middle dose and move to the higher dose after 2-4 weeks. The lower dose may be preferred for some patients.

Excitement about Entresto began last year following the impressive results of the PARADIGM pivotal trial, in which 8,442 HF patients with reduced ejection fraction (EF) were randomized to the ACE inhibitor enalapril or Entresto. As I’ve reported previously, the study was stopped early, though enrollment in the trial had been completed, following an interim analysis performed by the data and safety monitoring committee, which found “that the prespecified stopping boundary for an overwhelming benefit had been crossed.” After a mean followup of 27 months, Entresto was superior to enalapril in most of the major outcomes. There were significant reductions in the primary endpoint (the combination of cardiovascular death or hospitalization for HF), the individual components of the endpoint, all-cause mortality, and HF symptoms.

Entresto is the first HF drug that has been shown to have a significant mortality benefit when compared to an ACE inhibitor, the current standard of treatment.

The FDA said the most common side effects in patients receiving Entresto were hypotension, hyperkalemia, and renal impairment. Black patients and patients with a history of angioedema are more likely to develop angioedema. In PARADIGM angioedema occurred in 19 Entresto patients and 10 enalapril patients. Entresto should not be used while patients are also taking an ACE inhibitor as this increases the risk of angioedema.

Although there have been previous concerns that Entresto might increase the risk of developing dementiaNovartis said there is no mention of dementia in the label.

“Despite the uncertainty and high financial risk we designed the world’s largest heart failure trial to compare Entresto to the previous gold standard. As a result millions of people diagnosed with reduced ejection fraction heart failure now have a much greater opportunity to live longer and stay out of hospital,” said David Epstein, Division Head, Novartis Pharmaceuticals, in a press release. “We recognize our responsibility to ensure Entresto reaches US patients and prescribers as soon as possible and will begin shipping in the US in the coming week.”

“The very meaningful survival advantage of Entresto seen in the PARADIGM-HF trial should persuade physicians to consider Entresto for all appropriate patients, in place of traditional ACE inhibitors or angiotensin receptor blockers,” said Dr. Milton Packer, Professor and Chair for the Department of Clinical Sciences at University of Texas Southwestern Medical Center, Texas, USA. “Entresto is expected to change the management of patients with HFrEF for years to come.”

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