Riociguat

Riociguat

Riociguat is a soluble guanylate cyclase stimulator useful in the treatment of chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH). CHEST-1 trial was a phase 3, multicenter, randomized, double blind, placebo controlled study [1]. 261 patients with inoperable chronic thromboembolic pulmonary hypertension or persistent or recurrent pulmonary hypertension after pulmonary endarterectomy were randomly assigned to receive either placebo or riociguat. Primary end point of the study was the change in 6 minute walk distance from baseline to the end of 16th week. Secondary end points were change in pulmonary vascular resistance, NT-proBNP level, WHO functional class, time to clinical worsening, Borg dyspnea score, quality of life variables and safety.

6 minute walk distance increased by a mean of 39 m in the riociguat group as compared to a mean decrease of 6 m in the placebo group. Pulmonary vascular resistance decreased by 226 dyn·sec·cm^–5 in the riociguat group while it increased by 23 dyn·sec·cm^–5 in the placebo group. Significant improvements were noted in NT-proBNP level and WHO functional class. Serious adverse events were similar in both groups.

CHEST-2 was an open-label extension of CHEST-1 study, which evaluated the long-term safety and efficacy of riociguat [2]. 237 patients entered CHEST-2 and 211 (89%) were ongoing at the interim analysis in March 2013. There were no new safety signals noted in CHEST-2. Improvements in 6 minute walk distance and WHO functional class persisted at 1 year. 

In CHEST-2 two year overall survival was 93% and clinical worsening free survival was 82% [3]. A significant association with overall survival was noted for 6 minute walk distance and NT-proBNP concentration. Change of 6 minute walk distance from baseline was also significantly associated with survival. WHO functional class at baseline and follow up was not associated with overall survival. But it was associated with clinical worsening free survival. Serious adverse events were noted in 54% of patients, but only 6% discontinued riociguat therapy because of adverse events.

Right heart size and function by echocardiography on riociguat treatment was assessed in RIVER study [4]. 71 patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTPEH) were included in the study. After 12 months of treatment, patients on riociguat showed significant reduction in right atrial and right ventricular area and right ventricular thickness. Significant increase in tricuspid annular plane systolic excursion (TAPSE) and right ventricular fractional area change were also documented.

EXPosurE Registry RiociguaT in patients with pulmonary hypertension (EXPERT) study evaluated the long-term safety of riociguat in clinical practice [5]. It was an international, multicenter, prospective uncontrolled study of patients treated with riociguat. Patients were followed up for a minimum of 1 year and up to 4 years from enrollment or until 30 days after stopping riociguat treatment. 326 patients with pulmonary arterial hypertension (PAH) were analyzed. The final data report from EXPERT was that safety in clinical practice was consistent with clinical trials. No new safety concerns were identified.

References

1. 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; CHEST-1 Study Group. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med. 2013 Jul 25;369(4):319-29.
2. Simonneau G, D’Armini AM, Ghofrani HA, Grimminger F, Hoeper MM, Jansa P, Kim NH, Wang C, Wilkins MR, Fritsch A, Davie N, Colorado P, Mayer E. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension: a long-term extension study (CHEST-2). Eur Respir J. 2015 May;45(5):1293-302.
3. Simonneau G, D’Armini AM, Ghofrani HA, Grimminger F, Jansa P, Kim NH, Mayer E, Pulido T, Wang C, Colorado P, Fritsch A, Meier C, Nikkho S, Hoeper MM. Predictors of long-term outcomes in patients treated with riociguat for chronic thromboembolic pulmonary hypertension: data from the CHEST-2 open-label, randomised, long-term extension trial. Lancet Respir Med. 2016 May;4(5):372-80. 
4. Marra AM, Halank M, Benjamin N, Bossone E, Cittadini A, Eichstaedt CA, Egenlauf B, Harutyunova S, Fischer C, Gall H, Ghofrani HA, Hoeper MM, Lange TJ, Olsson KM, Klose H, Grünig E. Right ventricular size and function under riociguat in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension (the RIVER study). Respir Res. 2018 Dec 19;19(1):258. 
5. Hoeper MM, Gomez Sanchez MA, Humbert M, Pittrow D, Simonneau G, Gall H, Grünig E, Klose H, Halank M, Langleben D, Snijder RJ, Escribano Subias P, Mielniczuk LM, Lange TJ, Vachiéry JL, Wirtz H, Helmersen DS, Tsangaris I, Barberà JA, Pepke-Zaba J, Boonstra A, Rosenkranz S, Ulrich S, Steringer-Mascherbauer R, Delcroix M, Jansa P, Šimková I, Giannakoulas G, Klotsche J, Williams E, Meier C, Ghofrani HA; Collaborators list. Riociguat treatment in patients with pulmonary arterial hypertension: Final safety data from the EXPERT registry. Respir Med. 2020 Dec 3;177:106241.