Treatment with linsitinib, an IGF-1 receptor inhibitor, attenuates disease development and progression in an experimental model of Graves’ Orbitopathy

Abstract

Abstract Study objective: The activity of linsitinib, a small molecule inhibitor of the insulin-like growth factor 1 receptor (IGF-1R), was assessed in a mouse model of Graves’ orbitopathy (GO). GO is the most common extra-thyroidal manifestation of Graves’ disease (GD), which is caused by autoantibodies against the thyroid stimulating hormone receptor (TSHR). Methods: GD was induced in mice by immunization with a human TSHR A-subunit encoding plasmid. Linsitinib was administered orally for four weeks either in parallel to or after disease induction. Endocrine orbitopathy and inflammation were determined by histology and MRI. Results: Immunization with the TSHR A-subunit induced hyperthyroidism, as well as CD3+ T-cell infiltration and macrophage infiltration into orbital muscle/adipose tissue. Linsitinib reduced these effects by up to 80% whether given prophylactically or after disease induction. In addition, linsitinib reduced the formation of brown adipose tissue in the orbit and displayed an additional effect on the immune system. An MRI using F19 imaging confirmed marked orbital inflammation, significant muscle edema and formation of brown fat in experimental GO, events that were abrogated upon application of linsitinib. Linsitinib’s pharmacologic effects were observed at a dose that did not impact the concentration of plasma glucose. Conclusion: Linsitinib improved GO-related endpoints in a TSHR autoantibody dependent mouse model of Graves’ disease. Both prophylactic and therapeutic intervention with linsitinib improved clinically relevant endpoints in the orbita and thyroid gland. Our results are consistent with the therapeutic hypothesis being evaluated in an ongoing Phase 2b clinical study (NCT05276063). This work was funded by Sling Therapeutics, Inc.