OP0135 SAFETY AND EFFICACY OF SUBCUTANEOUS BELIMUMAB AND INTRAVENOUS RITUXIMAB COMBINATION IN PATIENTS WITH PRIMARY SJÖGREN’S SYNDROME: A PHASE 2, RANDOMISED, PLACEBO-CONTROLLED 68-WEEK STUDY
Authors: X. Mariette, C. Baldini, F. Barone, H. Bootsma, K. Clark, S. De Vita, K. Lerang, P. Mistry, F. Morin, R. Punwaney, R. Seror, P. L. Van Daele, A. Van Maurik, N. Wisniacki, D. Roth
Journal: Annals of the Rheumatic Diseases (2021)

Background: B-lymphocyte stimulator (BLyS) is increased in primary Sjögren’s syndrome (pSS) and plays a role in the B-cell hyperactivity thought to contribute to pSS. Belimumab (BEL, anti-BLyS) and rituximab (RTX, anti-CD20) target B cells through distinct and potentially complementary mechanisms. Objectives: To evaluate the safety and efficacy of subcutaneous (SC) BEL/intravenous (IV) RTX combination (BEL/RTX) in patients with pSS. Methods: This Phase 2, double-blind study (GSK Study 201842; NCT02631538 ) randomised 86 adults with active pSS to 4 treatment arms stratified for baseline EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) scores 5-12 or &gt;12: placebo (PBO; N=13), BEL/RTX (N=24; BEL 200 mg SC weekly to Week [Wk] 24 followed by weekly PBO SC to Wk 52 + RTX 1000 mg IV, Wk 8 + 10), BEL monotherapy (N=24; BEL 200 mg SC weekly to Wk 52) or RTX monotherapy (N=25; RTX 1000 mg IV, Wk 8 + 10). Follow-up was at Wk 68. Safety to Wk 68 was the primary endpoint (safety population; patients received ≥1 dose of study treatment). Secondary/other endpoints (completer population; patients completed treatment and follow-up phase) were ESSDAI score, stimulated salivary flow, CD20+ B-cell count within salivary gland biopsies, patient-reported oral dryness, and EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) score. Results: Baseline demographics and disease characteristics were similar among arms. Adverse events (AEs) were balanced across arms. Serious AEs were infrequent but occurred only in active treatment arms (Table). No unexpected safety issues were identified with BEL/RTX relative to BEL or RTX. Treatment phase and follow-up were completed by 60/86 patients. ESSDAI reductions with BEL/RTX were numerically greater over time than PBO, with greatest difference at Wk 68 (Table), but were not differentiated from monotherapy. Stimulated salivary flow showed a trend favouring BEL/RTX vs PBO over later time points (Table). In contrast with PBO, BEL, and RTX, salivary gland biopsies from BEL/RTX showed almost complete B-cell depletion (Wk 24). There was no clear evidence for a positive effect of BEL/RTX on patient-reported oral dryness or ESSPRI score. Table 1. Key safety endpoints and selected efficacy endpoints AEs – safety population PBO (N=13 ) BEL/RTX (N=24 ) BEL (N=24 ) RTX (N=25 ) AEs, n (%) 13 (100) 24 (100) 23 (96) 24 (96) Drug-related AEs, n (%) 10 (77) 17 (71) 16 (67) 14 (56) AEs leading to discontinuation/withdrawal, n (%) 1 (8) 5 (21) 3 (13) 5 (20) SAEs, n (%) 0 3 (13) 2 (8) 4 (16) Number of SAEs 0 4 2 7 Deaths, n (%) 0 1 (4)* 0 0 Infections and Infestations, n (%) † 11 (85) 19 (79) 21 (88) 18 (72) Efficacy – completer population PBO (N=8 ) BEL/RTX (N=17 ) BEL (N=19 ) RTX (N=16 ) ESSDAI change, LS mean (SE) from BL over time ‡ Wk 12 -2.00 (1.449) -4.85 (0.996) -3.87 (0.949) -4.22 (1.048) § Wk 24 -2.87 (1.324) -5.32 (0.911) -3.87 (0.869) -5.25 (0.940) Wk 52 -2.87 (1.294) -5.67 (0.890) -4.76 (0.850) -4.32 (0.919) Wk 68 -1.75 (1.400) -5.73 (0.962) -3.87 (0.918) -4.38 (0.994) Stimulated salivary flow (ml/min), mean (SD) BL 0.47 (0.247) 0.71 (0.629) 0.43 (0.329) 0.62 (0.621) Wk 12 0.49 (0.205) 0.75 (0.834) 0.49 (0.373) 0.58 (0.527) Wk 24 0.55 (0.305) 0.78 (0.790) 0.45 (0.411) 0.72 (0.890) Wk 52 0.53 (0.378) 1.00 (1.146) 0.58 (0.608) 0.69 (0.781) Wk 68 0.36 (0.163) 0.88 (0.817) 0.52 (0.450) 0.73 (0.785) § *Aspiration (n=1); not considered related to treatment; patient died of food aspiration; † System organ class with the highest percent of AEs; ‡ Analysis was performed using mixed model repeated measures; § n=15. BL, baseline; LS, Least square; SAEs, serious AEs; SD, standard deviation; SE, standard error Conclusion: No unexpected safety issues were identified with BEL/RTX relative to BEL or RTX. BEL/RTX showed a trend towards improvement in ESSDAI and stimulated salivary flow over time, which was sustained post treatment. BEL/RTX depleted B cells in minor salivary gland biopsies. Funding: GSK Acknowledgements: Medical writing assistance was provided by Katalin Bartus, PhD, Fishawack Indicia Ltd., UK, part of Fishawack Health, and was funded by GSK. Disclosure of Interests: Xavier Mariette Consultant of: BMS, Galapagos, Gilead, GSK, Janssen, Novartis, Pfizer, Servier, UCB, Grant/research support from: Servier, Chiara Baldini: None declared, Francesca Barone Consultant of: GSK, UCB, Roche, Actelion, Grant/research support from: GSK, UCB, Roche, Actelion, Employee of: Kintai therapeutics, Candel Therapeutics, Hendrika Bootsma Speakers bureau: BMS, Novartis, Consultant of: BMS, Roche, Novartis, MedImmune, UCB, Servier, Grant/research support from: BMS, Roche, Ken Clark Shareholder of: GSK, Employee of: GSK, Salvatore De Vita Consultant of: GSK, Roche, Karoline Lerang: None declared, Prafull Mistry Shareholder of: GSK, Employee of: GSK, Frederic Morin: None declared, Rajesh Punwaney Shareholder of: GSK, Employee of: GSK, Raphaèle Seror Consultant of: GSK, BMS, Fresenius Kabi, Boehringer, Jansen, Amgen, Pfizer, Roche, Paul LA van Daele: None declared, Andre van Maurik Shareholder of: GSK, Employee of: GSK, Nicolas Wisniacki Shareholder of: GSK, Employee of: GSK, David Roth Shareholder of: GSK, Employee of: GSK