POS0815 CD40L BLOCKADE WITH DAZODALIBEP (VIB4920/HZN4920) REDUCES BLOOD BIOMARKERS OF T AND B CELL COSTIMULATION IN SUBJECTS WITH SYSTEMIC SJÖGREN’S SYNDROME

Background Dazodalibep (DAZ) is a non-antibody biologic antagonist of CD40L. In several autoimmune diseases, the CD40/CD40L pathway is activated on a variety of cell types, including T cells, B Cells, antigen-presenting cells, and activated epithelial cells. DAZ blocks costimulatory signals between T cells and CD40-expressing B cells, disrupting the development of germinal centers, pathogenic B cells, plasma cells, and autoantibodies that are hallmarks of Sjögren’s Syndrome (SS). Objectives To evaluate the impact of DAZ on blood biomarkers of B and T cell costimulation in adult SS subjects with moderate-to-high systemic disease activity. Methods This was a randomized, double-blind, placebo-controlled, crossover study to evaluate DAZ therapy in adult SS subjects with moderate-to-high systemic disease activity, as defined by a EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) score ≥ 5. Subjects were randomized 1:1 to receive intravenous DAZ 1500 mg or placebo (PBO) Q2W x 3 doses, then Q4W x 4 additional doses (Stage 1). Starting on Day 169, subjects initially randomized to DAZ received PBO Q4W x 5 doses and subjects initially randomized to PBO received DAZ Q4W x 5 doses and were then followed for 12 weeks (Stage 2). B cell subsets downstream of T cell stimulation (Ki67+CD27+ memory, CD27 high CD38 high plasmablasts, and CD11c high atypical memory cells) were assayed via FACS throughout the study period. Serum CXCL13 concentrations, a chemokine essential for GC formation produced by activated follicular T cells, and rheumatoid factor (RF) autoantibodies were also measured. Results Concomitant with DAZ-related reductions in ESSDAI observed at Stage 1, significant and rapid reductions were observed in Ki67+CD27+ memory B cells, plasmablasts, CD11chigh memory B cells, CXCL13 and RF antibodies from day 15 onwards in subjects who received DAZ as compared to PBO. In Stage 2, similar reductions were found in these biomarkers when PBO-treated subjects were transitioned to DAZ treatment. In DAZ-treated subjects who were transitioned to PBO in stage 2, these biomarkers returned to baseline values while sustained reductions were observed in ESSDAI from baseline through the duration of stage 2. Conclusion CD40-CD40L blockade with DAZ in patients with SS reduces systemic disease activity by inhibiting T and B cell costimulation, as evidenced by treatment related reductions in blood biomarkers downstream of these pathways. Acknowledgements Funded by Horizon Therapeutics. Medical writing support provided by Brendan Lujan, PhD, an employee of Horizon Therapeutics. Disclosure of Interests Michael Smith Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Nanette Mittereder Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Michele Gunsior Shareholder of: Horizon Therapeutics plc, Employee of: Former employee of Horizon Therapeutics plc, Jodi Karnell Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Fanny Legrand Consultant of: Horizon Therapeutics plc, Kenneth Der Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Claire Emson Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, William Rees Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Ilias Alevizos Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, E. William St. Clair Consultant of: Horizon Therapeutics plc, Bristol Myers Squibb, CSL Behring, Resolve Therapeutics, Sonoma Biotherapeutics, and receives royalties from UpToDate.