A Novel Anti-CD40 Monoclonal Antibody, Iscalimab, for Control of Graves Hyperthyroidism-A Proof-of-Concept Trial

  • J Clin Endocrinol Metab. 2020 Mar 1;105(3):dgz013. doi: 10.1210/clinem/dgz013.
George J Kahaly  1 ,  Marius Nicolae Stan  2 ,  Lara Frommer  1 ,  Peter Gergely  3 ,  Laurence Colin  4 ,  Ahmed Amer  5 ,  Imelda Schuhmann  3 ,  Pascal Espie  3 ,  James S Rush  3 ,  Craig Basson  4 ,  Yanling He  4
Affiliations
  • 1. Department of Medicine I, Johannes Gutenberg University (JGU) Medical Center, Mainz, Germany.
  • 2. Division of Endocrinology, Diabetes & Metabolism, Mayo Clinic, Rochester, Minnesota.
  • 3. Novartis, Basel, Switzerland.
  • 4. Novartis Institute for Biomedical Research, Massachusetts.
  • 5. One Health Plaza, East Hanover, New Jersey.
PMID: 31512728 DOI: 10.1210/clinem/dgz013
Abstract

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

Objective: Evaluate efficacy and safety of a human, blocking, nondepleting 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 5 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 7 of 15 (47%) patients. Free and total triiodothyronine and thyroxine normalized in 7 patients who did not receive any rescue medication with antithyroid drugs (ATD), and 2/15 (13.3%) showed normal thyrotropin. Six (40%) patients required ATD. Four of 7 responders relapsed after treatment completion. Serum concentrations of thyrotropin receptor autoantibodies (TSH-R-Ab) significantly declined in all patients (mean 15.3 IU/L vs 4.0 IU/L, 66% reduction; P < 0.001) and TSH-R-Ab levels normalized in 4 (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 1 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.

Keywords
Graves hyperthyroidism; anti-CD40; iscalimab; monoclonal antibody.
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