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 >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 (
Key safety endpoints and selected efficacy endpoints
AEs – safety population |
PBO
| BEL/RTX (N=24 ) |
BEL
|
RTX
|
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