First-in-Class Drug Approved for Heart Failure
Novartis announced that the Food and Drug Administration (FDA) has approved Entresto (sacubitril/valsartan), a first-in-class drug for the treatment of heart failure. Specifically, Entresto is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction.
The FDA approval was based on results from the PARADIGM-HF study of 8,442 patients, which was the largest clinical trial ever conducted on heart failure. Entresto demonstrated clinically relevant and statistically significant superiority to enalapril and met the primary endpoint of a reduced risk of cardiovascular death or heart failure hospitalization by 20% at a median follow-up of 27 months. It also improved overall survival by 16% compared to enalapril due to a lower incidence of cardiovascular death in the Entresto arm. PARADIGM-HF was halted early based on recommendations from the Data Monitoring Committee (DMC) after the primary endpoint was met. Previously Entresto was granted Priority Review and Fast Track Designation by the FDA.
Entresto is the first in a new class of medicines called Angiotensin Receptor Neprilysin Inhibitors (ARNI), which act in multiple ways on the neurohormonal systems of the heart. Entresto inhibits neprilysin (neutral endopeptidase; NEP) via LBQ657, the active metabolite of the prodrug sacubitril, and blocks the angiotensin II type-1 (AT1) receptor via valsartan. The cardiovascular and renal effects of Entresto in heart failure patients are attributed to the increased levels of peptides that are degraded by neprilysin, such as natriuretic peptides, by LBQ657, and the simultaneous inhibition of the effects of angiotensin II by valsartan. Valsartan inhibits the effects of angiotensin II by selectively blocking the AT1 receptor, and also inhibits angiotensin II-dependent aldosterone release.
The most common side effects in clinical trial participants being treated with Entresto were hypotension, hyperkalemia, and renal impairment. Angioedema was also reported with Entresto; black patients and patients with a prior history of angioedema have a higher risk. Health care professionals should advise patients not to use Entresto with any drug from the ACE inhibitor class because the risk of angioedema is increased. When switching between Entresto and an ACE inhibitor, use of the two drugs should be separated by 36 hours.
Entresto will be available in three tablet strengths: 24/26mg, 49/51mg, and 97/103mg.
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