FRI0303 THE EFFECTS OF RIOCIGUAT ON RAYNAUD’S PHENOMENON AND DIGITAL ULCERS IN PATIENTS WITH DIFFUSE SYSTEMIC SCLEROSIS: RESULTS FROM THE PHASE IIB RISE-SSC STUDY
Authors: Dinesh Khanna, Yannick Allanore, Christopher Denton, Masataka Kuwana, Marco Matucci-Cerinic, Janet Pope, Janethe de Oliveria Pena, Kaisa Laapas, Zhen Yao, Melanie Hemmrich, Oliver Distler
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Riociguat is a soluble guanylate cyclase stimulator approved for treatment of pulmonary arterial hypertension associated with connective tissue disease. Through its vasodilatory and anti-remodeling properties, it was predicted that riociguat might relieve Raynaud's phenomenon (RP) attacks and reduce net digital ulcer (DU) burden in patients with diffuse cutaneous systemic sclerosis (dcSSc). <h3>Objectives</h3> We present exploratory endpoints from the RISE-SSc study (NCT02283762) on the effects of riociguat on RP and DUs in early dcSSc patients. <h3>Methods</h3> RISE-SSc was a Phase IIb, multicenter, randomized, double-blind, placebo-controlled study. Inclusion criteria were: SSc fulfilling ACR/EULAR criteria, diffuse cutaneous involvement, disease duration ≤18 months, and modified Rodnan skin score 10−22 units. Patients were assigned to placebo or riociguat individually adjusted from 0.5 mg up to 2.5 mg, 3 times daily. Exploratory efficacy endpoints included 1) change in Raynaud's attacks from baseline to Week 14, assessed by: Raynaud's condition score; patient/physician assessment of RP; attack symptoms, attack duration, and average number of attacks per day; and 2) change in net DU burden from baseline to Week 52, assessed by ulcer count, ulcer burden, and visual analog score for patient-reported severity. Blood samples for exploratory evaluation of biomarkers were taken on Day 0, Week 14 and for discontinuation before Week 14. <h3>Results</h3> 60 patients were treated with riociguat and 61 with placebo. None of the effects of riociguat on RP or DUs were statistically significant vs placebo. However, there was a greater relative reduction in attack duration, attack frequency, pain, numbness, tingling, and patient/physician global assessment in the riociguat group vs placebo, from baseline to Week 14. Reductions in net DU burden were –0.09±0.50 for riociguat and –0.08±1.47 for placebo (estimated treatment difference: –0.11 [95% CI: –0.38, 0.17; p=0.44]) at Week 52. At Week 14, 2 patients in the riociguat group and 6 in the placebo group had developed new DUs. At Week 52, 5 and 12 patients, respectively, had developed new DUs. The total numbers of new DUs were 4 and 6 with riociguat and placebo, respectively, at Week 14, and 12 and 65, respectively, at Week 52 (Figure). Riociguat was associated with reductions vs placebo in serum sPECAM-1 (p=0.004) and CXCL-4 (p=0.008), potentially indicating anti-vasculopathy properties of riociguat. <h3>Conclusion</h3> Riociguat did not produce statistically significant changes in DUs. Riociguat may reduce the development of new DUs in patients with early dcSSc and may favourably improve cytokine vasculopathy. Left: Number of patients with new digital ulcers Right: Total number of new digital ulcers New digital ulcers are defined as ulcers not existing at baseline. <h3>Acknowledgement</h3> Adelphi Communications Ltd, Bollington, UK provided medical writing support. <h3>Disclosure of Interests</h3> Dinesh Khanna Shareholder of: Eicos Sciences, Inc, Grant/research support from: Bayer, BMS, Pfizer, Horizon, Consultant for: Actelion Acceleron, Arena, Bayer, BI, BMS, CSL Behring, Corbus, Cytori, GSK, Genentech/Roche, Galapagos, Employee of: Elcos Sciences, Inc, Yannick Allanore Grant/research support from: Inventiva, F Hoffman La-Roche, Sanofi, BMS, Pfizer, Consultant for: Actelion, Bayer, BMS, Boehringer, Roche, Sanofi, Christopher Denton Grant/research support from: GlaxoSmithKline, Inventiva, CSF Behring, Consultant for: Roche-Genentech, Actelion, GlaxoSmithKline, Sanofi Aventis, Inventiva, CSL Behring, Boehringer Ingelheim, Bayer, Masataka Kuwana Grant/research support from: Actelion, Consultant for: Chugai, Reata, GlaxoSmithKline, Bayer, Boehringer-Ingelheim, Corpus, CSL-Berling, Mochida, Speakers bureau: Actelion, Pfizer, Bayer, Nippon Shinyaku, Chugai, Marco Matucci-Cerinic Grant/research support from: Actelion, MSD, Pfizer, BMS, Chemomab, Sanipedia, Speakers bureau: Actelion, BMS; MSD, Janssen, Janet Pope Consultant for: Eli Lilly and Company, Janethe de Oliveria Pena Employee of: Bayer, Kaisa Laapas Employee of: StatFinn Oy, partly insourced to Bayer, Zhen Yao Employee of: Bayer, Melanie Hemmrich Employee of: Bayer AG, Oliver Distler Grant/research support from: Prof. Distler received research funding from Actelion, Bayer, Boehringer Ingelheim and Mitsubishi Tanabe to investigate potential treatments of scleroderma and its complications, Consultant for: Prof. Distler has/had consultancy relationship within the last 3 years with Actelion, AnaMar, Bayer, Boehringer Ingelheim, ChemomAb, espeRare foundation, Genentech/Roche, GSK, Inventiva, Italfarmaco, iQvia, Lilly, medac, MedImmune, Mitsubishi Tanabe Pharma, Pharmacyclics, Novartis, Pfizer, Sanofi, Serodapharm and UCB in the area of potential treatments of scleroderma and its complications. In addition, he had/has consultancy relationship within the last 3 years with A. Menarini, Amgen, Abbvie, GSK, Mepha, MSD, Pfizer and UCB in the field of arthritides and related disorders