Vaskuläres Anti- und Reverse-Remodelling bei pharmakologischer Aktivierung der löslichen Guanylatzyklase bei pulmonaler Hypertonie

• Applicant: Professor Dr. Friedrich Grimminger
• Subject Area: Pneumology, Thoracic Surgery
• Term: from 2010 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 165239704

• Final Report Year: 2014

Final Report Abstract

Impaired nitric oxide (NO) bioavailability, soluble guanylate cyclase (sGC) activity and cGMP production have been implicated in the pathogenesis of pulmonary hypertension (PH). The focus of this project was centered on the role of sGC in pulmonary vascular remodeling and the development of therapeutic strategies focusing on pharmacological sGC activation. Within the project, we performed preclinical studies addressing the role of the sGC-signaling pathway in PH. We have demonstrated the localization of the sGC-subunits in healthy and hypertensive lungs. In several animal models of PH, we demonstrated the effects of sGC stimulators on hemodynamics, pulmonary vascular and RV remodeling. Further, we locally delivered a sGC stimulator to the lung and demonstrated regression of PH. Early clinical trials addressing safety and efficacy of the sGC stimulator riociguat in patients with pulmonary arterial hypertension (PAH) and non-operable chronic thromboembolic pulmonary hypertension (CTEPH) were followed by two phase 3 trials in PAH and CTEPH. These randomized controlled trials demonstrated efficacy of this compound in both PH forms and led to the approval of riociguat for the treatment of PAH and CTEPH.

Publications

• First acute haemodynamic study of soluble guanylate cyclase stimulator riociguat in pulmonary hypertension. Eur Respir J. 2009; 33(4):785-792
  Grimminger F, Weimann G, Frey R, Voswinckel R, Thamm M, Bölkow D, Weissmann N, Mück W, Unger S, Wensing G, Schermuly RT, Ghofrani HA
  
• Soluble guanylate cyclase stimulation: an emerging option in pulmonary hypertension therapy. Eur Respir Rev. 2009; 18(111):35-41
  Ghofrani HA, Grimminger F
  
• Riociguat for chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension: a phase II study. Eur Respir J. 2010;36(4):792-799
  Ghofrani HA, Hoeper MM, Halank M, Meyer FJ, Staehler G, Behr J, Ewert R, Weimann G, Grimminger F
  
• Riociguat for pulmonary hypertension. Future Cardiol. 2010; 6(2):155-166
  Ghofrani HA, Voswinckel R, Gall H, Schermuly R, Weissmann N, Seeger W, Grimminger F
  
• Riociguat for the treatment of pulmonary hypertension. Expert Opin Investig Drugs. 2011; 20(4):567-576
  Schermuly RT, Janssen W, Weissmann N, Stasch JP, Grimminger F, Ghofrani HA
  
• The soluble guanylate cyclase stimulator riociguat ameliorates pulmonary hypertension induced by hypoxia and SU5416 in rats. PLoS One. 2012; 7(8):e43433
  Lang M, Kojonazarov B, Tian X, Kalymbetov A, Weissmann N, Grimminger F, Kretschmer A, Stasch JP, Seeger W, Ghofrani HA, Schermuly RT
  
• New trial designs and potential therapies for pulmonary artery hypertension. J Am Coll Cardiol. 2013;62(25 Suppl):D82-91
  Gomberg-Maitland M, Bull TM, Saggar R, Barst RJ, Elgazayerly A, Fleming TR, Grimminger F, Rainisio M, Stewart DJ, Stockbridge N, Ventura C, Ghofrani AH, Rubin LJ
  
• Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med. 2013;369(4):319-329
  Ghofrani HA, D'Armini AM, Grimminger F, Hoeper MM, Jansa P, Kim NH, Mayer E, Simonneau G, Wilkins MR, Fritsch A, Neuser D, Weimann G, Wang C
  
• Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013; 369(4):330-340
  Ghofrani HA, Galiè N, Grimminger F, Grünig E, Humbert M, Jing ZC, Keogh AM, Langleben D, Kilama MO, Fritsch A, Neuser D, Rubin LJ
  
• Novel and Emerging Therapies for Pulmonary Hypertension. Am J Respir Crit Care Med. 2014; 189(4): 394-400
  Pullamsetti SS, Schermuly R, Ghofrani A, Weissmann N, Grimminger F, Seeger W