It is also the only potential therapy that has been evaluated against an active comparator in a phase III trial for HFpEF. The sNDA is primarily supported by data from the multicenter, double-blind, parallel-group, active-controlled phase I PARAGON-HF trial that compared the long-term efficacy and safety of sacubitril/valsartan with valsartan in 4,822 patients with HFpEF. Patients were randomized to receive a target dose of sacubitril/valsartan 97 mg/103 mg or valsartan 160 mg twice a day after meeting the safety criteria from a single blind run-in period of 3 to 8 weeks. The primary endpoint was the composite of cardiovascular (CV) death and total (first and recurrent) HF hospitalizations.
The trial did not demonstrate statistical significance for its composite primary endpoint (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 HF hospitalizations and CV death was observed to be greatest among HFpEF patients screened during or within 30 days of hospitalization.
In exploratory secondary endpoint analyses, sacubitril/valsartan-treated patients reported less deterioration in quality of life based on Kansas City Cardiomyopathy Questionnaire Clinical Summary Score at 8 months compared with valsartan, along with a decrease in the risk of worsening renal function. The sacubitril/valsartan treatment arm also experienced a more favorable change in the New York Heart Association class compared with valsartan. There was no difference in all-cause mortality between both treatment arms. Moreover, sacubitril/valsartan was found to be safe and well tolerated with a safety profile consistent with that observed in earlier reported data.
The FDA is expected to make a decision on the sNDA application for this indication in the first half of 2021.
« Click here to return to Cardiology Update.