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

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