SAT0279\u2005MULTICENTER DOUBLE-BLIND, PROOF-OF-CONCEPT, RANDOMIZED PLACEBO-CONTROLLED TRIAL OF RIOCIGUAT IN SYSTEMIC SCLEROSIS-ASSOCIATED DIGITAL ULCERS (RESCUE)

Abstract

Background The soluble guanylate cyclase stimulator riociguat (RIO) is a vasodilator and has antifibrotic effects in animal models and efficacy in patients with pulmonary arterial hypertension associated with connective tissue diseases. Objectives We present results from a randomized placebo-controlled trial (NCT02915835), which evaluated the efficacy and safety of RIO in patients with systemic sclerosis-associated digital ulcers (SSc-DU). Methods Eligible subjects (with active or painful indeterminate DUs) were randomized in 1:1 ratio to either placebo (PLA, n = 8) or RIO (n = 9) in individualized doses (maximum of 2.5 mg three time daily) during an 8-week titration period, followed by an 8-week stable dosing period. PDE5 inhibitors were not allowed. The primary end point was the change from baseline to week 16 in net ulcer burden (NUB), analyzed using an ANCOVA model, accounting for baseline NUB. Other outcome measures included change from baseline to week 16 in the Raynaud’s Condition Score (RCS), RP attack number, symptom severity during RP attack, patient global assessment, and proportion of subjects with treatment-emergent adverse events (AEs). Eleven plasma biomarkers were measured by ELISA and changes were tested using ANCOVA, after testing for normality. Results We randomized 17 participants with SSc-DUs between January 2017 and March 2018. Baseline characteristics were comparable between treatment groups, except participants randomized to PLA were older (mean 61 vs. 43 yrs) and had longer disease duration (mean 17.5 vs. 7.1 yrs). At baseline, the mean (SD) NUB was 2.5 (2.0) in the PLA and 2.4 (1.4) in the RIO. No significant difference was observed between RIO and PLA in change from baseline to 16 weeks in NUB [p=0.70; Table]. No significant treatment effect was observed in the secondary outcome measures. All 17 participants reported ≥1 adverse event, with the vast majority being mild or moderate. There were 4 SAEs, 3 in RIO (worsening DU, NSTEMI, and non-Hodgkin’s lymphoma) and 1 in PLA (digital ischemia; none of SAE’s were related to the study medication). Statistically significant elevation of cGMP was observed at 16 weeks [p=0.05]; no other biomarkers showed statistically significant changes. Placebo (N=8) Riociguat (N=9) Treatment Difference (95% CI) p-value Net Ulcer Burden, mean*# -0.98 -1.22 -0.24 (-1.46 to 0.99) 0.70 Patient assessment, mean*# Severity of RP (0-10) -1.41 -3.47 -2.06 (-4.63 to 0.51) 0.11 Severity of DU (0-10) -4.00 -4.63 -0.63 (-3.68 to 2.41) 0.66 Pain during RP attack (0-100) -7.01 -0.30 6.71 (-14.01 to 27.43) 0.49 Numbness during RP attack, mean (SD) (0-100) -15.44 -19.73 -4.28 (-33.44 to 24.87) 0.75 Tingling during RP attack, mean (SD) (0-100) -7.49 1.18 8.67 (-13.75 to 31.09) 0.41 Raynaud’s Condition Score, mean (SD) (0-10) -0.82 -1.15 -0.33 (-2.60 to 1.94) 0.76 Number of Raynaud’s attacks per day, mean -0.96 -1.24 -0.28 (-1.36 to 0.79) 0.57 Plasma Biomarkers, mean* cGMP nM 41.2 198.5 157.3 (3.1 to 311.5) 0.046 *A higher number denotes worse symptoms Conclusion In participants with SSc-DU, treatment with RIO did not reduce the number of NUB compared with PLA. The safety profile of RIO was similar to that previously reported. There is evidence of target engagement. The negative results may reflect small number of patients, low number of NUB at baseline, moderate-to-severe vasculopathy with long term disease, and difficulty to recruit patients in the era of widespread use of PDE5 inhibitors. Acknowledgement The trial was funded by Bayer, Inc as an investigator-initiated trial to the University of Michigan Disclosure of Interests 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, Cathie Spino: None declared, Vivek Nagaraja: None declared, Robin Domsic Consultant for: Eicos Sciences Inc/Civi Biopharma and Boehringer-Ingelheim., Robert Lafyatis: None declared, Viginia Steen Consultant for: CSL Behring, Corbus and Bayer, Paid instructor for: Advisory Board: CSL Behring, Roach, Bayer and Reata, Jessica Gordon Grant/research support from: Corbus Pharmaceuticals Cumberland Pharmaceuticals, Tracy Frech: None declared, Pei-Suen Tsou: None declared