MON-589 A Novel, Oral Small Molecule Antagonist Targeting TSHR Improves Hyperthyroidism in an in vivo Model of Graves’ Disease

Abstract J. Zhang: Employee; Self; Septerna, Inc. K. Alvarez: Employee; Self; Septerna, Inc.. I. Gomez: None. H. Banie: Employee; Self; Septerna, Inc. K. Nguyen: Employee; Self; Septerna, Inc. V. Wu: Employee; Self; Septerna, Inc.. S. McKerrall: None. A.M. Mirza: Employee; Self; Septerna, Inc. In the United States, more than a million people are affected by Graves’ Disease (GD) with approximately 70,000 new cases per year. GD is a complex autoimmune disorder characterized by the production of autoantibodies against the Thyroid Stimulating Hormone Receptor (TSHR), a G protein-coupled receptor. These activating autoantibodies bind to TSHR, stimulating its activity, and lead to the overproduction of thyroid hormones Triiodothyronine (T3) and Thyroxine (T4). Sustained activation of TSHR leads to hyperthyroidism and increased metabolism, causing symptoms such as weight loss, hand tremors, and tachycardia. Treatments for GD include anti-thyroid drugs, radioactive iodine, or thyroidectomy surgery. Currently, there are no oral small molecule therapies targeting activated TSHR function to directly treat GD. Here we describe proof-of-concept data for a novel, potent, and selective orally bioavailable small molecule TSHR antagonist that directly targets TSHR function and could be used to treat the manifestations of GD including its ophthalmic manifestations. In vitro pharmacological effects of the small molecule compound SP-1351 were determined using primary mouse thyrocytes. It was shown that TSH as well as patient-derived autoantibodies such as M22 and K1-18 have stimulatory effects on functional gene expression in primary thyrocytes. SP-1351 was shown to inhibit both TSH- and M22-mediated expression of genes such as thyroglobulin in a dose dependent manner. Furthermore, an in vivo murine model of hyperthyroidism was established with chronic administration of activating autoantibodies. In this model, the levels of T3 and T4 are dysregulated and the gross size of the thyroid significantly increased mirroring the effects of GD. Oral administration of SP-1351 showed rapid onset of inhibitory activity reducing T4 levels within 24 hours. Sustained treatment reduced the overall size of the thyroid and improved the histological parameters of GD such as follicular hyperplasia, intracellular colloid droplets, cell scalloping, follicular colloid, and patchy lymphocytic infiltration. In addition, exposure of circulating PBMCs to stimulating autoantibodies increased B cell markers such as CD69, CD5, and CD27. These were subsequently reduced with SP-1351 treatment suggesting treatment could have effects on important immune parameters for GD. SP-1351 is an investigational novel, oral small molecule TSHR antagonist that blocks the stimulating effects of autoantibodies known to drive GD. The study described here provides proof-of-concept that potent small molecules directly targeting TSHR function could ameliorate the effects of hyperthyroidism and GD and thus improve the lives of patients. Monday, June 3, 2024