The Food and Drug Administration (FDA) has accepted for review the supplemental New Drug Application (sNDA) for sacubitril/valsartan (Entresto; Novartis) in the treatment of heart failure with preserved ejection fraction (HFpEF).

The treatment combines sacubitril, a neprilysin inhibitor, with valsartan, an angiotensin II receptor blocker. The sNDA is primarily supported by data from the multicenter, double-blind, parallel-group, active-controlled phase 3 PARAGON-HF trial that compared the long-term efficacy and safety of sacubitril/valsartan to valsartan in 4822 patients with HFpEF. Patients were randomized to receive a target dose of sacubitril/valsartan 97mg/103mg or valsartan 160mg twice a day after meeting the safety criteria from a single blind run-in period of 3-8 weeks. The primary end point was the composite of cardiovascular (CV) death and total (first and recurrent) heart failure (HF) hospitalizations.

The trial missed statistical significance for its composite primary end point (rate ratio [RR] 0.87; 95% CI, 0.75-1.01; P =.06), however a greater benefit was observed in certain predefined subgroups. Subgroup analyses showed a 22% relative reduction (RR 0.78; 95% CI, 0.64-0.95) in patients with an ejection fraction ≤57% (median) and a 27% relative reduction (RR 0.73; 95% CI, 0.59-0.90) in women. In a separate post-hoc analysis, the treatment effect of sacubitril/valsartan on total heart failure hospitalizations and cardiovascular death was observed to be greatest among HFpEF patients screened during or within 30 days of hospitalization.

In exploratory secondary end point analyses, sacubitril/valsartan-treated patients reported less worsening in quality of life based on Kansas City Cardiomyopathy Questionnaire Clinical Summary Score at 8 months compared with valsartan, along with a reduction in the risk of worsening renal function. The sacubitril/valsartan treatment arm also experienced a more favorable change in the New York Heart Association (NYHA) class compared with valsartan. There was no difference in all-cause mortality between both treatment arms.

Additionally, sacubitril/valsartan was found to be safe and well tolerated with a safety profile consistent with that observed in previously reported data. 

The FDA is expected to complete its review in the first half of 2021.

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Entresto is currently indicated for use as first-line treatment to reduce the risk of CV death and hospitalization for HF in patients with chronic HF (NYHA Class II-IV) and reduced ejection fraction. It is also approved for the treatment of symptomatic HF with systemic left ventricular systolic dysfunction in children aged ≥1 year.

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