Riociguat 
Endothelium-derived NO regulates vascular homeostasis through pulmonary arteries SMC relaxation via the activation of the second messenger cGMP. The clinical benefits associated with the PDE-5 inhibitor class has led to interest in testing whether other agents that modulate NO signaling might be similarly beneficial in PAH. Riociguat is a first-in-class drug that augments cGMP biosynthesis through direct stimulation of the enzyme soluble guanylate cyclase (sGC) promoting vasodilatation by direct stimulation of sGC in an NO-independent fashion, and by sensitization of sGC to low endogenous NO levels [250].
A phase I randomized placebo-controlled study in 58 healthy male subjects were given riociguat orally was designed to test the safety profile, pharmacokinetics and pharmacodynamics of single oral doses of riociguat (0.25–5 mg). A proof-of-concept study was conducted to investigate oral riociguat in patients with moderate to severe PH in a two-part, non-randomized, open-label, single center trial [251]. Riociguat was well tolerated in doses up to 2.5 mg, whereas 5 mg caused asymptomatic hypotension in one patient. Therefore the 2.5 mg dose was used in the second part of the trial to demonstrate efficacy. Riociguat significantly reduced mPAP, PVR and systemic vascular resistance and increased cardiac index [251]. Results from a multicenter, open-label, uncontrolled phase II trial involving 75 patients with PAH (n = 33) and chronic thrombo-embolic PH (n = 42) showed that 12 weeks of oral riociguat given 3 times daily conferred improvements in symptoms, NYHA FC, exercise capacity, NT-proBNP level, and pulmonary hemodynamics [252]. Riociguat is also under investigation in other form of PH as PH associated with chronic obstructive pulmonary disease, with interstitial lung disease or with left ventricular dysfunction [253-255].
The Phase III, double-blind, randomized, placebo-controlled PATENT-1 study investigated the efficacy and safety of riociguat in patients with symptomatic PAH [256]. Treatment-naïve patients and patients pre-treated with ERAs or prostacyclin analogues were eligible. Riociguat was titrated from a starting dose of 1 mg three times daily (t.i.d.) [range 0.5–2.5 mg t.i.d.]. The primary outcome was the change from baseline in 6-MWD at week 12. Secondary endpoints included the change from baseline in pulmonary vascular resistance (PVR), NT-proBNP, NYHA FC, clinical worsening, living with PH questionnaire and Borg dyspnea score. A total of 445 patients were randomized. Preliminary analysis showed a significant increase in 6-MWD from baseline of 35.8 m with riociguat versus placebo (95% CI 20.1–51.5 m, p < 0.0001). Predefined exploratory analyses indicated that riociguat improved 6-MWD in pretreated patients (+35.7 m [95% CI 15.0–56.3 m]) as well as treatment naïve patients (+38.4 m [95% CI 14.5–62.3 m]). Significant improvements were also seen in PVR (p < 0.0001), NT-proBNP (p < 0.0001), functional class (p = 0.003), clinical worsening (p = 0.0046), living with PH questionnaire (p = 0.002) and Borg dyspnea score (p = 0.002). Riociguat was well tolerated and had a favorable safety profile. Thus, riociguat may represent a new treatment option for patients with PAH. An open-label extension study (PATENT-2) will evaluate the long-term safety of riociguat in patients with PAH.