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Neprilysin inhibition for pulmonary arterial hypertension: a randomized, double‐blind, placebo‐controlled, proof‐of‐concept trial
Author(s) -
Hobbs Adrian J.,
Moyes Amie J.,
Baliga Reshma S.,
Ghedia Dipa,
Ochiel Rachel,
Sylvestre Yvonne,
Doré Caroline J.,
Chowdhury Kashfia,
Maclagan Kate,
Quartly Harriet L.,
Sofat Reecha,
Smit Angelique,
Schreiber Benjamin E.,
Coghlan Gerry J.,
MacAllister Raymond J.
Publication year - 2019
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.14621
Subject(s) - medicine , neprilysin , vascular resistance , natriuretic peptide , atrial natriuretic peptide , placebo , clinical endpoint , hemodynamics , cardiology , heart failure , pulmonary hypertension , pharmacology , randomized controlled trial , pathology , chemistry , biochemistry , alternative medicine , enzyme
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.