ISCALIMAB-KAHALY-SUPPLEMENTAL

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 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<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<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. Iscalimab should be tested
further to understand better its potential therapeutic benefit.