Safety and Efficacy of the Soluble Guanylate Cyclase Stimulator Praliciguat in Patients with Heart Failure with Preserved Ejection Fraction (Capacity HFpEF): A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 2 Trial

Abstract

Introduction Heart failure with preserved ejection fraction (HFpEF) is associated with poor quality of life and increased mortality with exercise intolerance being the main symptom. Hypothesis The soluble guanylate cyclase (sGC) stimulator praliciguat (PRL) may help restore deficient NO-sGC-cGMP signaling and improve exercise capacity. Methods CAPACITY HFpEF was a phase 2, multicenter, randomized, double-blind, placebo-controlled trial to evaluate the safety and efficacy of PRL over 12 weeks in patients with HFpEF and at least 2 of 4 conditions potentially associated with NO deficiency (diabetes, hypertension, obesity, age >70 years). Patients were randomized to PRL or placebo. The primary endpoints were change from baseline to week 12 in peak oxygen consumption (pVO2) by cardiopulmonary exercise testing and treatment-emergent adverse events (TEAEs). Secondary endpoints included the change in 6-minute walk distance (6MWD), ventilatory efficiency (VE/VCO2 slope), and the proportion of pVO2 responders (change ≥1.5 mL/kg/min). Health status was assessed using the Kansas City Cardiomyopathy Questionnaire (KCCQ). Results Among 196 patients randomized (mean age 70.3 years, 57% men), 169 completed. For the evaluable population (completed 8 weeks of dosing with no dose reduction), mean baseline pVO2 was 13.3 and 12.8 mL O2/kg/min in PRL 40 mg (N=65) and placebo (N=78) groups, respectively. Placebo-adjusted least squares mean changes from baseline to week 12 [95% CI] were pVO2 (-0.30 mL O2/kg/min [-0.95, 0.35] p=0.37), 6MWD (-16.7 m [-47.4, 13.9]) and VE/VCO2 slope (-0.30 [-1.59, 1.00]). The odds ratio for pVO2 response [95% CI] was 0.91 [0.40, 2.1]. KCCQ overall and domain scores did not improve in the PRL group versus the placebo group. PRL was generally well tolerated; headache, dizziness, and hypotension TEAEs were reported more frequently in the PRL group. The frequency of serious TEAEs was similar between groups. Conclusion In a population selected to enrich for the metabolic/NO-deficient profile of HFpEF, PRL was well tolerated but did not affect pVO2, 6MWD, VE/VCO2 slope, proportion of pVO2 responders or KCCQ scores over 12 weeks compared to placebo.