OP0008 SAFETY AND EFFICACY OF ISCALIMAB IN PATIENTS WITH SJÖGREN’S DISEASE: 48-WEEK RESULTS FROM A RANDOMISED, PLACEBO-CONTROLLED, PHASE 2B DOSE-RANGING TRIAL
Authors: X. Mariette, B. Fisher, A. Papas, T. Grader-Beck, H. Bootsma, W. F. Ng, P. L. Van Daele, S. Finzel, S. Elgueta, J. Hermann, S. S. Mccoy, A. Bookman, M. Sopala, E. Hua, L. Chen, C. Scheurer, W. Hueber
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Sjögren's disease (SjD) is a chronic autoimmune disease with no approved targeted therapies. TWINSS is a phase 2b dose-ranging trial assessing the safety and efficacy of multiple doses of iscalimab, an Fc silenced fully human anti-CD40 mAb, in two SjD patient populations. Primary Week (Wk) 24 results were reported previously.[1] <h3>Objectives:</h3> To report Wk 48 results, further evaluating the safety and efficacy of iscalimab in SjD patients. <h3>Methods:</h3> Patients fulfilling the ACR/EULAR 2016 criteria, who were seropositive for anti-Ro/SSA antibodies and had a stimulated salivary flow rate of ≥0.1 mL/min were included. In cohort 1 (C1), patients with EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) ≥5 and EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) ≥5 were randomised (1:1:1:1) to placebo (PBO) or iscalimab 150, 300 or 600 mg. In cohort 2 (C2), patients with ESSDAI &lt;5, ESSPRI (dryness or fatigue) ≥5 and Impact of Dry Eye on Everyday Life (IDEEL) score ≥30 were randomised (1:1) to PBO or iscalimab 600 mg. At Wk 24, PBO-treated patients switched to iscalimab 600 mg (C1) and 300 mg (C2), following a loading dose similar to Treatment Period (TP) 1 (Wk 0-24), and patients originally assigned to iscalimab arms in both cohorts continued their initially randomised dose. Due to the lack of PBO control in the TP2 (Wk 24-48), descriptive analysis was performed for ESSDAI, ESSPRI, other patient-reported outcomes (PROs) and salivary flow. Safety was assessed during the entire study period. <h3>Results:</h3> Overall, 163 of 173 patients in C1 and 93 of 100 patients in C2 continued to TP2. In C1, change from baseline in ESSDAI observed at Wk 24 further improved by Wk 48 in patients who continued their initially randomised iscalimab dose of 150, 300 and 600 mg (LS mean change from baseline [Δ]: -7.6, -5.7 and -7.9, respectively). PBO-treated patients who switched to iscalimab 600 mg also showed meaningful improvements in ESSDAI (Δ: -6.7) at Wk 48 (<b>Figure 1A</b>). Consistent trends for improvement were observed for all PROs on all iscalimab doses, including the change from baseline on ESSPRI, Sjögren's Syndrome Symptom Diary (SSSD), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and IDEEL (<b>Figure 1B</b>). At Wk 48, PBO-iscalimab 600 mg and iscalimab 150, 300 and 600 mg showed trends for improvement in unstimulated (Δ: 0.03, 0.08, 0.03 and 0.02 mL/min, respectively) and stimulated (Δ: 0.07, 0.24, 0.16 and 0.15 mL/min, respectively) salivary flow rates comparable to Wk 24. In C2, improvements in ESSPRI were observed in both PBO-iscalimab 300 mg and iscalimab 600 mg (Δ: -2.14 and -2.29, respectively) at Wk 48 and were consistent with C1. Dryness and fatigue subscales contributed to overall ESSPRI improvements (<b>Figure 2A</b>). Both stimulated and unstimulated salivary flow rates improved with iscalimab. At Wk 48, PBO-iscalimab 300 mg and iscalimab 600 mg arms demonstrated improvements in unstimulated (Δ: 0.02 and 0.08 mL/min, respectively) and stimulated (Δ: 0.06 and 0.23 mL/min, respectively) salivary flow rate (<b>Figure 2B</b>). In C1, no dose-dependent increases in adverse events (AEs) and serious AEs (SAEs) were observed. SAEs occurred in 4.9%, 11.4%, 14.3% and 11.4% patients in PBO-iscalimab 600 mg, iscalimab 150, 300, and 600 mg groups, respectively. In C2, the incidence of SAEs was comparable between PBO-iscalimab 300 mg and iscalimab 600 mg (11.4% and 12.0%, respectively). Two deaths occurred: (i) in C1 on iscalimab 300 mg due to <i>Pneumocystis jiroveci</i> pneumonia in a 72-year-old patient with multiple comorbidities, severe SjD (ESSDAI score 28) at entry and background treatment with several immunosuppressive medicines, suspected to be related to treatment; (ii) in C2 on iscalimab 600 mg in a patient with pre-existing chronic cardiac conditions, and who was diagnosed with congestive cardiac failure 10 days prior to death, considered unrelated to treatment. <h3>Conclusion:</h3> By Wk 48, all iscalimab doses showed further improvements in disease activity outcomes and PROs, corroborating the results seen at Wk 24 in two distinct groups of patients with active SjD. Iscalimab's benefit-risk warrants further evaluation. <h3>REFERENCES:</h3> [1] Fisher BA, et al. Arthritis Rheumatol. 2023;75(suppl 9):1634. <h3>Acknowledgements:</h3> <b>NIL.</b> <h3>Disclosure of Interests:</h3> Xavier Mariette Consultant of BMS, Galapagos, GSK, Novartis, Pfizer, and Servier., Benjamin Fisher Consultant of Novartis, Roche, BMS, Galapagos, Janssen, Servier, UCB and Sanofi., Grant/research support from Janssen, Celgene, Galapagos, Servier (Funding to institution for collaborative research)., Athena Papas Consultant of Novartis., Grant/research support from Novartis, Viela Bio, and Exosome Dx., Thomas Grader-Beck Consultant of Novartis., Hendrika Bootsma: None declared, Wan-Fai Ng Consultant of Novartis, Abbvie, BMS, Sanofi, Argenx, Janssen, Resolve Therapeutics, Bain Capitals and UCB., Paul LA van Daele: None declared, Stephanie Finzel Sponsored talks/courses of Abbvie, Chugai, Galapagos, Novartis, UCB., Consultant of AstraZeneca, Novartis., Grant/research support from Novartis., Sergio Elgueta: None declared, Josef Hermann Honoraria for lectures from Lilly, MSD, AbbVie, Novartis, Astro Pharma., Grant/research support Novartis (Institution received study fees)., Sara S. McCoy Consultant for Novartis, BMS, Otsuka, Visterra, Target RDW, Horizon, Kinksa, and iCell., Arthur Bookman: None declared, Monika Sopala Shareholder of Novartis., Employee of Novartis., Eva Hua Shareholder of Novartis., Employee of Novartis., Li Chen Shareholder of Novartis., Employee of Novartis., Cornelia Scheurer Shareholder of Novartis., Employee of Novartis., Wolfgang Hueber Shareholder of Novartis., Employee of Novartis.