Riociguat: Mode of Action and Clinical Development in Pulmonary Hypertension

Article ID	Journal	Published Year	Pages	File Type
5600410	Chest	2017	41 Pages	PDF

Abstract

Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are progressive and debilitating diseases characterized by gradual obstruction of the pulmonary vasculature, leading to elevated pulmonary artery pressure (PAP) and increased pulmonary vascular resistance (PVR). If untreated, they can result in death due to right-sided heart failure. Riociguat is a novel soluble guanylate cyclase (sGC) stimulator that is approved for the treatment of PAH and CTEPH. We describe in detail the role of the nitric oxide-sGC-cyclic guanosine monophosphate (cGMP) signaling pathway in the pathogenesis of PAH and CTEPH and the mode of action of riociguat. We also review the preclinical data associated with the development of riociguat, along with the efficacy and safety data of riociguat from initial clinical trials and pivotal phase III randomized clinical trials in PAH and CTEPH.

Keywords

6MWD SvO2 PAP PKG PDE5 BH4 tetrahydrobiopterin EQ-5D ADMA SGC NT-proBNP SAE mPAP CTEPH HFpEF N-terminal prohormone of brain natriuretic peptide LPH QOL SVR PAH NADPH eNOS PEA NOS cGMP Quality of life 6-minute walking distance ILD endothelin receptor antagonist pulmonary endarterectomy Cardiac output Right ventricular Interstitial lung disease asymmetric dimethylarginine World Health Organization endothelial nitric oxide synthase Soluble guanylate cyclase PVR Heart rate adverse event ERA Serious adverse event Phosphodiesterase 5 Pulmonary arterial hypertension Pulmonary artery pressure mean pulmonary artery pressure Chronic thromboembolic pulmonary hypertension mixed venous oxygen saturation Systemic vascular resistance Pulmonary vascular resistance cyclic guanosine monophosphate Heart failure with preserved ejection fraction Nitric oxide nitric oxide synthase nicotinamide adenine dinucleotide phosphate Pulmonary hypertension cGMP-dependent protein kinase functional class Least squares WHO