OR19-6 A Novel Anti-CD40 Monoclonal Antibody, Iscalimab, Successfully Treats Graves’ Hyperthyroidism

Objective: Graves’ disease (GD) is an autoimmune disorder characterized by thyrotropin receptor autoantibody (TSHR-Ab)-mediated pathology, leading to hyperthyroidism. To date there is no pharmacotherapy that addresses the underlying pathogenesis. The CD40-CD154 (CD40L) co-stimulatory pathway plays an important role in the pathogenesis of GD by promoting auto-reactive B cell activation and intrathyroidal ectopic lymphoid structure formation and function. Iscalimab (CFZ533) is a fully human, blocking and non-depleting anti-CD40 monoclonal antibody. The purpose of this study was to investigate the efficacy and safety of Iscalimab in patients with Graves’ hyperthyroidism. Methods: In total, fifteen patients with Graves’ hyperthyroidism were enrolled in an open label Phase I proof-of concept study and all completed the trial. Each patient received five doses of Iscalimab at 10 mg/kg IV over 12 weeks. We assessed the effects of Iscalimab on thyroid-related hormones (baseline TSH, free and total T3/T4) and autoantibodies (TSHR-Ab) over 36 weeks following the first dose of Iscalimab. Safety, pharmacokinetics, soluble CD40 levels in plasma, free CD40 on whole blood CD19-positive B cells, and CXCL13 were also assessed. Results: Based on the CD40 occupancy and plasma levels of soluble CD40, the intervention resulted in full CD40 engagement for up to 20 weeks (12-week treatment + 8 week follow up). A clinical response and biochemical euthyroidism was observed in seven out of 15 (46.7%) by Day 211. Free T3/T4 normalized in seven (46.7%) patients who did not received any rescue medication with anti-thyroid drugs. Two further patients (13.3%) did not normalize but did not require rescue medication. In contrast, six (40%) patients required rescue medication with anti-thyroid drugs by Day 141. No patients achieved normalization of TSH by Day 85, however, two out of 15 patients (13.3%) showed normal TSH by Day 169. The levels of free thyroid hormones and TSHR-Ab levels declined over time up to Day 211. The mean levels of TSHR-Ab declined from 15.3 IU/L (baseline) to 9.4 IU/L at Day 85 (35% reduction, P<0.001), then further decreased to 4.0 IU/L at day 141 (66% reduction, P<0.001). The TSHR-Ab levels fell in normal range in four out of 15 patients (26.7%). Treatment with Iscalimab was associated with a rapid and significant reduction in the serum levels of CXCL13 (94.1 pg/mL at baseline to 68.5 pg/mL at Day 15) and remained at similar levels during the 12 week treatment period. Twelve patients reported at least one adverse event. Most events were mild in nature (34 in 8 patients, 53.3%) and few were moderate (5 in 4 patients, 26.7%). Conclusions: Iscalimab was generally safe and clinically effective in a subgroup of patients with Graves’ hyperthyroidism. These encouraging results suggest that Iscalimab may be an attractive strategy as the immunomodulation treatment for GD.