01 March 2017 by James Klinger

The relationship between nitric oxide pathway biomarkers and response to riociguat in the RESPITE study of patients with pulmonary arterial hypertension (PAH) not reaching treatment goals with phosphodiesterase 5 inhibitors (PDE5i)


A proportion of patients with PAH treated with PDE5i do not reach/maintain treatment goals. RESPITE investigated whether it is safe, feasible, and beneficial to replace PDE5i with riociguat in patients with an insufficient response to PDE5i. This analysis explored the relationship between nitric oxide signaling biomarkers and response to riociguat.


RESPITE (NCT02007629) was a 24-week, open-label, single-arm, Phase IIIb trial in PAH patients in WHO FC III, with 6MWD 165–440 m and cardiac index <3.0 L/min/m2, despite PDE5i treatment for ≥90 days. Patients underwent a PDE5i-free treatment period before receiving riociguat up to 2.5 mg tid. Concomitant ERAs were permitted. Exploratory endpoints included change from baseline to Week 24 in 6MWD, WHO FC, NT-proBNP, biomarkers, and clinical worsening.


Of 61 patients enrolled, 50 (82%) were receiving concomitant ERAs at baseline. Fifty one patients (84%) completed the study. At Week 24, 6MWD and WHO FC were improved, plasma cGMP had increased, and NT-proBNP decreased (Table 1). Levels of cGMP and NT-proBNP correlated with PH severity at baseline and Week 24.  At Week 24, 31 % of patients achieved a combined responder endpoint (no clinical worsening, FC I/II, and ≥30 m increase in 6MWD); responders had lower NT-proBNP and cGMP at baseline compared with non-responders.


RESPITE provided preliminary evidence that switching from PDE5i to riociguat may be beneficial in PAH patients with insufficient response to PDE5i. Further studies are needed to confirm if biomarker levels could identify patients that may benefit from switching to riociguat.

Key Contributors

James R Klinger,1 Raymond L Benza,2 Paul A Corris,3 David Langleben,4 Robert Naeije,5 Gérald Simonneau,6 Christian Meier,7 Pablo Colorado,8 MiKyung Chang,7 Dennis Busse,9 Marius M Hoeper10 1Division of Pulmonary, Sleep, and Critical Care Medicine, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI, USA; 2Cardiovascular Institute, Allegheny General Hospital, Pittsburgh, PA, USA; 3Institute of Cellular Medicine, Newcastle University, Newcastle, UK; 4Center for Pulmonary Vascular Disease and Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Canada; 5Department of Cardiology, Erasme University Hospital, Brussels, Belgium; 6Assistance Publique–Hôpitaux de Paris, Service de Pneumologie, Hôpital Bicêtre, Université Paris-Sud, Laboratoire d’Excellence en Recherche sur le Médicament et Innovation Thérapeutique, and INSERM Unité 999, Le Kremlin–Bicêtre, France; 7Global Clinical Development, Bayer Pharma AG, Berlin, Germany; 8Global Clinical Development, Bayer HealthCare Pharmaceuticals, Barcelona, Spain; 9Chrestos Concept GmbH & Co.KG, Essen, Germany; 10Clinic for Respiratory Medicine, Hannover Medical School, Hannover, Germany, member of the German Center for Lung Research (DZL).

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