ISCALIMAB-KAHALY-SUPPLEMENTAL

<b>Context</b> The CD40-CD154 co-stimulatory pathway plays an important role in the pathogenesis of Graves’ disease (GD) by promoting auto-reactive B cell activation. <b>Objective</b> Evaluate efficacy and safety of a human, blocking, non-depleting anti-CD40 monoclonal antibody, iscalimab, in hyperthyroid patients with GD <b>Design</b> Open label, phase II proof-of-concept study <b>Setting </b>Multicenter <b>Patients </b>Fifteen with GD <b>Intervention</b> Patients received five doses of iscalimab at 10 mg/kg intravenously over 12 weeks. <b>Main outcome measures</b> Thyroid-related hormones and autoantibodies, plasma soluble CD40, free CD40 on B cells, soluble CXCL13, pharmacokinetics, and safety were assessed. <b>Results: </b>The iscalimab intervention resulted in complete CD40 engagement for up to 20 weeks. A clinical response and biochemical euthyroidism was observed in seven of 15 (47%) patients, free T3 and T4 normalized in seven patients who did not received any rescue medication with anti-thyroid drugs (ATD), and 2/15 (13.3%) showed normal TSH. Six (40%) patients required ATD. Serum concentrations of thyrotropin receptor autoantibodies (TSH-R-Ab) significantly declined in all patients (mean 15.3 IU/L versus 4.0 IU/L, 66% reduction, P&lt;0.001) and TSH-R-Ab levels normalized in four (27%). Thyroperoxidase and thyroglobulin autoantibodies significantly decreased in responders. Iscalimab rapidly reduced serum CXCL13 concentrations (94.1 pg./mL at baseline, 68.5 pg./mL, day 15, P&lt;0.001). Twelve (80.0%) patients reported at least one adverse event (AE). All treatment-related AE were mild or moderate and resolved by end of the study. <b>Conclusion</b>: Iscalimab was generally safe and clinically effective in a subgroup of hyperthyroid GD patients. Iscalimab should be tested further to understand better its potential therapeutic benefit.