Neprilysin inhibition for pulmonary arterial hypertension: a randomized, double‐blind, placebo‐controlled, proof‐of‐concept trial

BACKGROUND AND PURPOSE: Pulmonary arterial hypertension (PAH) is an incurable, incapacitating disorder resulting from increased pulmonary vascular resistance, pulmonary arterial remodeling and right ventricular failure. In pre-clinical models, combination of a phosphodiesterase 5 inhibitor (PDE5i) with a neprilysin inhibitor augments natriuretic peptide bioactivity, promotes cyclic GMP signaling, and reverses the structural and hemodynamic deficits that characterize PAH. Herein, we conducted a randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of repurposing the neprilysin inhibitor, racecadotril, in PAH. EXPERIMENTAL APPROACH: 21 PAH patients stable on PDE5i therapy were recruited. Acute hemodynamic and biochemical changes following a single dose of racecadotril or matching placebo were determined; this was followed by a 14 day safety and efficacy evaluation. The primary endpoint in both steps was circulating atrial natriuretic peptide (ANP) concentration (Δmax ), with secondary outcomes including pulmonary and systemic hemodynamics plus mechanistic biomarkers. KEY RESULTS: Acute administration of racecadotril (100mg) resulted in a 79% (95%CI, +6,+203) increase in the plasma ANP concentration and a 106% (+28,+229) increase in plasma cyclic GMP levels, with a concomitant 14% (-24,-3) fall in pulmonary vascular resistance. Racecadotril (100mg; tid) treatment for 14 days resulted in a 19% (-18,+72) rise in plasma ANP concentration. Neither acute (-16%,-28,+1) nor chronic (-4%, -21,+16) administration of racecadotril resulted in a significant drop in MABP or any serious adverse effects. CONCLUSIONS AND IMPLICATIONS: This Phase IIa evaluation provides proof-of-principle evidence that neprilysin inhibitors may have therapeutic utility in PAH and warrants a larger-scale prospective trial.