Biomarker analysis from the phase 2b randomized placebo-controlled trial of riociguat in early diffuse cutaneous systemic sclerosis

Dinesh Khanna; Frank Kramer; Josef Höfler; Mercedeh Ghadessi; Peter Sandner; Yannick Allanore; Christopher P Denton; Masataka Kuwana; Marco Matucci-Cerinic; Janet E Pope; Tatsuya Atsumi; Radim Bečvář; László Czirják; Ellen De Langhe; Eric Hachulla; Tomonori Ishii; Osamu Ishikawa; Sindhu R Johnson; Valeria Riccieri; Elena Schiopu; Richard M Silver; Vanessa Smith; Chiara Stagnaro; Virginia Steen; Wendy Stevens; Gabriella Szücs; Marie-Elise Truchetet; Melanie Wosnitza; Oliver Distler

doi:10.1093/rheumatology/keae150

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. doi: 10.1093/rheumatology/keae150.

Authors

Dinesh Khanna¹, Frank Kramer², Josef Höfler³, Mercedeh Ghadessi², Peter Sandner², Yannick Allanore⁴, Christopher P Denton⁵, Masataka Kuwana⁶, Marco Matucci-Cerinic^{7

8}, Janet E Pope⁹, Tatsuya Atsumi¹⁰, Radim Bečvář¹¹, László Czirják¹², Ellen De Langhe¹³, Eric Hachulla¹⁴, Tomonori Ishii¹⁵, Osamu Ishikawa¹⁶, Sindhu R Johnson¹⁷, Valeria Riccieri¹⁸, Elena Schiopu¹⁹, Richard M Silver²⁰, Vanessa Smith²¹, Chiara Stagnaro²², Virginia Steen²³, Wendy Stevens²⁴, Gabriella Szücs²⁵, Marie-Elise Truchetet²⁶, Melanie Wosnitza², Oliver Distler²⁷

Affiliations

¹ Division of Rheumatology, University of Michigan, Ann Arbor, MI, USA.
² Research and Development, Pharmaceuticals, Bayer AG, Wuppertal, Germany.
³ Staburo GmbH, Munich, Germany.
⁴ Rheumatology A Department, Cochin Hospital, APAP, Paris Descartes University, Paris, France.
⁵ Division of Medicine, Centre for Rheumatology, University College London, London, UK.
⁶ Department of Allergy and Rheumatology, Nippon Medical School Graduate School of Medicine, Tokyo, Japan.
⁷ Division of Rheumatology, Department of Experimental and Clinical Medicine, University of Firenze, Florence, Italy.
⁸ Unit of Immunology, Rheumatology, Allergy and Rare Diseases, IRCCS San Raffaele Hospital, Milan, Italy.
⁹ Division of Rheumatology, Schulich School of Medicine, University of Western Ontario, London, ON, Canada.
¹⁰ Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
¹¹ Institute of Rheumatology, Department of Rheumatology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic.
¹² Department of Rheumatology and Immunology, Medical School, University of Pécs, Pécs, Hungary.
¹³ Laboratory of Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Center, Division of Rheumatology, Department of Development and Regeneration, KU Leuven, University Hospitals Leuven, Leuven, Belgium.
¹⁴ Department of Internal Medicine and Clinical Immunology, Referral Centre for Centre for Rare Systemic Autoimmune Diseases North and North-West of France, CHU Lille, University of Lille, Inserm, U1286 - INFINITE-Institute for Translational Research in Inflammation, Lille, France.
¹⁵ Clinical Research, Innovation and Education Center, Tohoku University, Sendai, Japan.
¹⁶ Department of Dermatology, Gunma University Postgraduate School of Medicine, Maebashi, Japan.
¹⁷ Division of Rheumatology, Department of Medicine, Toronto Western Hospital, University Health Network, Mount Sinai Hospital, University of Toronto, Toronto Scleroderma Research Program, Toronto, ON, Canada.
¹⁸ Department of Clinical, Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy.
¹⁹ Division of Rheumatology, Medical College of Georgia at Augusta University, Augusta, GA, USA.
²⁰ Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, SC, USA.
²¹ Department of Internal Medicine, Ghent University, Belgium and Department of Rheumatology, Ghent University Hospital, Belgium, and Unit for Molecular Immunology and Inflammation, VIB Inflammation Research Center, Ghent, Belgium.
²² Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
²³ Division of Rheumatology, Department of Medicine, Georgetown University Medical Center, Washington, DC, USA.
²⁴ Department of Rheumatology, St Vincent's Hospital Melbourne, Melbourne, VIC, Australia.
²⁵ Department of Rheumatology, University of Debrecen, Debrecen, Hungary.
²⁶ Department of Rheumatology, CHU Bordeaux, Bordeaux, France.
²⁷ Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

Abstract

Objective: To examine disease and target engagement biomarkers in the RISE-SSc trial of riociguat in early diffuse cutaneous systemic sclerosis and their potential to predict the response to treatment.

Methods: Patients were randomized to riociguat (n = 60) or placebo (n = 61) for 52 weeks. Skin biopsies and plasma/serum samples were obtained at baseline and week 14. Plasma cyclic guanosine monophosphate (cGMP) was assessed using radio-immunoassay. α-Smooth muscle actin (αSMA) and skin thickness were determined by immunohistochemistry, mRNA markers of fibrosis by qRT-PCR in skin biopsies, and serum CXC motif chemokine ligand 4 (CXCL-4) and soluble platelet endothelial cell adhesion molecule-1 (sPECAM-1) by enzyme-linked immunosorbent assay.

Results: By week 14, cGMP increased by 94 (78)% with riociguat and 10 (39)% with placebo (P < 0.001, riociguat vs placebo). Serum sPECAM-1 and CXCL-4 decreased with riociguat vs placebo (P = 0.004 and P = 0.008, respectively). There were no differences in skin collagen markers between the two groups. Higher baseline serum sPECAM-1 or the detection of αSMA-positive cells in baseline skin biopsies was associated with a larger reduction of modified Rodnan skin score from baseline at week 52 with riociguat vs placebo (interaction P-values 0.004 and 0.02, respectively).

Conclusion: Plasma cGMP increased with riociguat, suggesting engagement with the nitric oxide-soluble guanylate cyclase-cGMP pathway. Riociguat was associated with a significant reduction in sPECAM-1 (an angiogenic biomarker) vs placebo. Elevated sPECAM-1 and the presence of αSMA-positive skin cells may help to identify patients who could benefit from riociguat in terms of skin fibrosis.

Trial registration: Clinicaltrials.gov, NCT02283762.

Keywords: biomarkers; diffuse cutaneous systemic sclerosis; riociguat; soluble guanylate cyclase stimulators.

Publication types

Randomized Controlled Trial
Clinical Trial, Phase II

MeSH terms

Adult
Biomarkers* / blood
Biopsy
Cyclic GMP / blood
Cyclic GMP / metabolism
Double-Blind Method
Female
Fibrosis / drug therapy
Humans
Male
Middle Aged
Pyrazoles* / therapeutic use
Pyrimidines* / therapeutic use
Scleroderma, Diffuse* / drug therapy
Scleroderma, Diffuse* / pathology
Skin* / drug effects
Skin* / metabolism
Skin* / pathology
Treatment Outcome

Substances

riociguat
Pyrimidines
Pyrazoles
Biomarkers
Cyclic GMP

Associated data

ClinicalTrials.gov/NCT02283762

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding