Riociguat: Clinical research and evolving role in therapy

Abstract

Riociguat is a first-in-class soluble guanylate cyclase stimulator, approved for the treatment of adults with pulmonary arterial hypertension (PAH), inoperable chronic thromboembolic pulmonary hypertension (CTEPH), or persistent or recurrent CTEPH after pulmonary endarterectomy. Approval was based on the results of the phase III PATENT-1 (PAH) and CHEST-1 (CTEPH) studies, with significant improvements in the primary endpoint of 6-minute walk distance vs placebo of +36 m and +46 m, respectively, as well as improvements in secondary endpoints such as pulmonary vascular resistance and World Health Organization functional class. Riociguat acts as a stimulator of cyclic guanosine monophosphate synthesis rather than as an inhibitor of cGMP metabolism. As with other approved therapies for PAH, riociguat has antifibrotic, antiproliferative and anti-inflammatory effects, in addition to vasodilatory properties. This has led to further clinical studies in patients who do not achieve a satisfactory clinical response with phosphodiesterase type-5 inhibitors. Riociguat has also been evaluated in patients with World Health Organization group 2 and 3 pulmonary hypertension, and other conditions including diffuse cutaneous systemic sclerosis, Raynaud's phenomenon and cystic fibrosis. This review evaluates the results of the original clinical trials of riociguat for the treatment of PAH and CTEPH, and summarises the body of work that has examined the safety and efficacy of riociguat for the treatment of other types of pulmonary hypertension.

Keywords: drug information; pharmacotherapy; therapeutics.

FIGURE 1

Key signalling pathways targeted by medical therapies for pulmonary hypertension (PH). Reproduced under a CC BY‐NC 4.0 license from Humbert et al. cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; ETR_A, endothelin receptor A; ETR_B, endothelin receptor B; IP, prostacyclin; NO, nitric oxide; PDE5, phosphodiesterase type 5; PKA, phosphate kinase A; PKG, cGMP‐dependent protein kinase; RV, right ventricular; sGC, soluble guanylate cyclase

FIGURE 2

Mechanism of action of riociguat. (A) Riociguat directly stimulates soluble guanylate cyclase (sGC) in a nitric oxide (NO)‐independent manner. (B) Riociguat sensitises sGC to endogenous NO by stabilising binding of the molecules. Reproduced under a CC BY 4.0 license from Benza et al. cGMP, cyclic guanylate monophosphate; GTP, guanosine triphosphate

FIGURE 3

Six‐minute walking distance (6MWD) in PATENT‐2. (A) 6MWD in the overall population, and treatment‐naïve and pretreated subgroups of PATENT‐2. Graph shows mean ± standard error of the mean. (B) Kaplan–Meier analysis showing the association of 6MWD with survival based on median value at baseline. (C) Kaplan–Meier analysis showing the association of 6MWD with survival at follow‐up. Reprinted with permission from Elsevier from Ghofrani et al.

FIGURE 4

Six‐minute walking distance (6MWD) in CHEST‐2. (A) 6MWD in the overall population, and inoperable and persistent/recurrent subgroups of CHEST‐2. Graph shows mean ± standard error of the mean. (B) Kaplan–Meier analysis showing the association of 6MWD with survival based on median value at baseline. (C) Kaplan–Meier analysis showing the association of 6MWD with survival at follow‐up. Reprinted with permission from Elsevier from Simonneau et al.