Biomarker Analysis from the Phase 2b Randomized Placebo-controlled Trial of Riociguat in Early Diffuse Cutaneous Systemic Sclerosis

Overview

Journal Rheumatology (Oxford)

Publisher Oxford University Press

Specialty Rheumatology

Date 2024 Mar 9

PMID 38460548

Authors

Dinesh Khanna

Frank Kramer

Josef Hofler

Mercedeh Ghadessi

Peter Sandner

Yannick Allanore

Christopher P Denton

Masataka Kuwana

Marco Matucci-Cerinic

Janet E Pope

Tatsuya Atsumi

Radim Becvar

Laszlo Czirjak

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 Szucs

Marie-Elise Truchetet

Melanie Wosnitza

Oliver Distler

Affiliations

Soon will be listed here.

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.

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