A Novel Anti-Cd40 Monoclonal Antibody, Iscalimab, for Control of Graves' Hyperthyroidism - A Proof-Of-Concept Trial.

CONTEXT: The CD40-CD154 co-stimulatory pathway plays an important role in the pathogenesis of Graves' disease (GD) by promoting auto-reactive B cell activation.

OBJECTIVE: Evaluate efficacy and safety of a human, blocking, non-depleting anti-CD40 monoclonal antibody, iscalimab, in hyperthyroid patients with GD.

DESIGN: Open label, phase II proof-of-concept study.

SETTING: Multicenter.

PATIENTS: Fifteen with GD.

INTERVENTION: Patients received five doses of iscalimab at 10 mg/kg intravenously over 12 weeks.

MAIN OUTCOME MEASURES: Thyroid-related hormones and autoantibodies, plasma soluble CD40, free CD40 on B cells, soluble CXCL13, pharmacokinetics, and safety were assessed.

RESULTS: 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 and total T3 and T4 normalized in seven patients who did not receive any rescue medication with anti-thyroid drugs (ATD), and 2/15 (13.3%) showed normal TSH. Six (40%) patients required ATD. Four of seven responders relapsed after treatment completion. 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<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 (P<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.

CONCLUSION: Iscalimab was generally safe and clinically effective in a subgroup of hyperthyroid GD patients. The potential therapeutic benefit of Iscalimab should be further tested.