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

Abstract

Background and purpose: Pulmonary arterial hypertension (PAH) is an incurable, incapacitating disorder resulting from increased pulmonary vascular resistance, pulmonary arterial remodelling, and right ventricular failure. In preclinical models, the combination of a PDE5 inhibitor (PDE5i) with a neprilysin inhibitor augments natriuretic peptide bioactivity, promotes cGMP signalling, and reverses the structural and haemodynamic 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: Twenty-one PAH patients stable on PDE5i therapy were recruited. Acute haemodynamic 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 the maximum change in circulating atrial natriuretic peptide (ANP) concentration (Δ_max ), with secondary outcomes including pulmonary and systemic haemodynamics plus mechanistic biomarkers.

Key results: Acute administration of racecadotril (100 mg) resulted in a 79% increase in the plasma ANP concentration and a 106% increase in plasma cGMP levels, with a concomitant 14% fall in pulmonary vascular resistance. Racecadotril (100 mg; t.i.d.) treatment for 14 days resulted in a 19% rise in plasma ANP concentration. Neither acute nor chronic administration of racecadotril resulted in a significant drop in mean arterial BP 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.

Figure 1

CONSORT flow chart for Step 1 (left panel) and Step 2 (right panel)

Figure 2

Time course (left panel), absolute change (middle panels), and maximum percentage change from baseline (right panel) in plasma atrial natriuretic peptide concentration ([ANP]); (a) or cGMP concentration; (b) in PAH patients receiving racecadotril (100 mg) or matching placebo. Data are represented as geometric mean ± 95% CI. n = 4 (placebo) and n = 9 (racecadotril). Data were analysed by paired t test for absolute intrapatient change (i.e., before and after treatment) and by unpaired t test for intergroup comparison (i.e., placebo vs. racecadotril) of Δ_max (%). Correlation between maximum percentage change in PVR and maximum percentage change in plasma [ANP] or plasma [cGMP] (c). n = 4 (placebo) and n = 8 (racecadotril). Data were analysed by Pearson correlation. In all cases, P < 0.05 was considered statistically significant

Figure 3

Time course (left panel), absolute change (middle panels), and maximum percentage change from baseline (right panel) in pulmonary vascular resistance (PVR; (a) or pulmonary capillary wedge pressure (PCWP); (b) in PAH patients receiving racecadotril (100 mg) or matching placebo. Data are presented as geometric mean ± 95% CI. n = 4 (placebo) and n = 8 (racecadotril). Data were analysed by paired t test for absolute intrapatient change (i.e., before and after treatment) and by unpaired t test for intergroup comparison (i.e., placebo vs. racecadotril) of Δ_max (%). P < 0.05 was considered statistically significant

Figure 4

Time course (left panel), absolute change (middle panels), and maximum percentage change from baseline (right panel) in mean pulmonary artery pressure (mPAP; (a) or mean arterial BP (MABP); (b) in PAH patients receiving racecadotril (100 mg) or matching placebo. Data are presented as geometric mean ± 95% CI. n = 4 (placebo) and n = 9 (racecadotril). Data were analysed by paired t test for absolute intrapatient change (i.e., before and after treatment) and by unpaired t test for intergroup comparison (i.e., placebo vs. racecadotril) of Δ_max (%). P < 0.05 was considered statistically significant

Figure 5

Time course (left panel), absolute change (middle panels), and maximum percentage change from baseline (right panel) in plasma endothelin‐1 concentration ([ET‐1]; (a) or N‐terminal‐pro‐brain natriuretic peptide concentration [NT‐proBNP]; (b) in PAH patients receiving racecadotril (100 mg) or matching placebo. Data are presented as geometric mean ± 95% CI. n = 4 (placebo) and n = 9 (racecadotril). Data were analysed by paired t test for absolute intrapatient change (i.e., before and after treatment) and by unpaired t test for intergroup comparison (i.e., placebo vs. racecadotril) of Δ_max (%). P < 0.05 was considered statistically significant

Figure 6

Absolute change (left and middle panels) and maximum percentage change from baseline (right panel) in mean arterial BP (MABP); (a) or plasma atrial natriuretic peptide concentration [ANP]; (b) in PAH patients receiving racecadotril (100 mg; t.i.d.; 14 days) or matching placebo. Data are presented as geometric mean ± 95% CI. n = 3 (placebo) and n = 5 (racecadotril). Data were analysed by paired t test for absolute intrapatient change (i.e., before and after treatment) and by unpaired t test for intergroup comparison (i.e., placebo vs. racecadotril) of Δ_max (%). P < 0.05 was considered statistically significant