Riociguat is primarily indicated for the management of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). A recent phase 2b RISE-SSc trial, published in Rheumatology (Oxford), has shed light on the potential of riociguat in treating early diffuse cutaneous systemic sclerosis (dcSSc) by identifying biomarkers that may predict patient response to therapy.
The randomized, placebo-controlled study included 121 patients, with 60 receiving riociguat and 61 on placebo over a 52-week period. Biomarker analysis conducted at baseline and week 14 revealed a significant increase in plasma cyclic guanosine monophosphate (cGMP) levels in the riociguat group, rising by 94% compared to a modest 10% increase in the placebo group. This indicates active engagement with the nitric oxide-soluble guanylate cyclase-cGMP pathway. Additionally, key biomarkers linked to fibrosis and angiogenesis, such as serum soluble platelet endothelial cell adhesion molecule-1 (sPECAM-1) and CXC motif chemokine ligand 4 (CXCL-4), showed significant reductions in the riociguat group (P = 0.004 and P = 0.008, respectively). While there was no marked difference in skin collagen markers between the two groups, the presence of specific biomarkers at baseline appeared to correlate with better clinical outcomes. Patients with elevated baseline sPECAM-1 level or α-smooth muscle actin (αSMA)-positive cells in their skin biopsies experienced greater reductions in the modified Rodnan skin score at week 52 when treated with riociguat. This suggests these biomarkers could serve as predictors of a favorable response to riociguat in reducing skin fibrosis.
Riociguat, the first-in-class soluble guanylate cyclase (sGC) stimulator, was approved by the FDA in October 2013 and remains the only therapy approved for PAH and CTEPH. Riociguat has a dual mechanism of action: it enhances the effects of endogenous nitric oxide while also directly stimulating sGC, even in the absence of nitric oxide. This leads to increased production of cyclic guanosine monophosphate (cGMP), which promotes vasodilation and exerts antiproliferative and antifibrotic effects. The nitric oxide (NO)–soluble guanylate cyclase (sGC)–cyclic guanosine monophosphate (cGMP) pathway plays a critical role in maintaining tissue homeostasis through mechanisms that include antifibrotic and anti-inflammatory effects. Preclinical studies, both in vitro and in vivo, have demonstrated that the sGC stimulator riociguat exerts anti-inflammatory, antifibrotic, and antiproliferative effects, partly by dampening TGF-β signaling.
A previous study by Humbert et al. analyzed the results from the Pulmonary Arterial Hypertension sGC-Stimulator Trial (PATENT)-1 and PATENT-2, which evaluated the effects of riociguat in patients with PAH. Within this study, there was a subgroup of patients with PAH associated with SSc. In this subgroup, riociguat was found to be well tolerated and effectively prevented the decline in functional capacity. Additionally, a single-dose pilot study by Huntgeburth et al. found that riociguat improved digital blood flow in some patients with Raynaud’s phenomenon.
The findings highlight the potential role of riociguat in modulating pathways involved in fibrosis and vascular dysfunction in dcSSc, with biomarkers like sPECAM-1 and αSMA serving as potential tools for identifying patients most likely to benefit from this therapy. This biomarker-driven approach may pave the way for more personalized treatment strategies in managing early-stage SSc.
References
- Khanna D, Kramer F, Höfler J, Ghadessi M, Sandner P, Allanore Y, et al. Biomarker analysis from the phase 2b randomized placebo-controlled trial of riociguat in early diffuse cutaneous systemic sclerosis. Rheumatology (Oxford). 2024 Nov 1;63(11):3124-3134.
- Humbert M, Coghlan JG, Ghofrani HA, Grimminger F, He JG, Riemekasten G, Vizza CD, Boeckenhoff A, Meier C, de Oliveira Pena J, Denton CP. Riociguat for the treatment of pulmonary arterial hypertension associated with connective tissue disease: results from PATENT-1 and PATENT-2. Ann Rheum Dis. 2017 Feb;76(2):422-426.
- Huntgeburth M, Kießling J, Weimann G, Wilberg V, Saleh S, Hunzelmann N, Rosenkranz S. Riociguat for the Treatment of Raynaud’s Phenomenon: A Single-Dose, Double-Blind, Randomized, Placebo-Controlled Cross-Over Pilot Study (DIGIT). Clin Drug Investig. 2018 Nov;38(11):1061-1069.
- Kenny M, Clarke MM, Pogue KT. Overview of Riociguat and Its Role in the Treatment of Pulmonary Hypertension. J Pharm Pract. 2022 Jun;35(3):437-444.