Thyroid Hormone Analogs: Recent Developments

Background: Thyroid hormone exerts its function on virtually all tissues in the human body through binding to the thyroid hormone receptor (TR), making it an interesting vehicle for therapeutic intervention in nonthyroid conditions with metabolic consequences, as well as genetic thyroid hormone signaling disorders. Since the 1990s, several thyroid hormone analogs have been developed that have tissue specificity. Given the recent approval of two thyroid hormone analogs, the aim of this review is to give an update on developments in the field since 2020. Summary: Although initial therapeutic use of thyroid hormone analogs for nonthyroid conditions with metabolic consequences focused on cardiovascular disease and dyslipidemia, nowadays the primary focus is on the treatment of metabolic dysfunction-associated steatohepatitis (MASH). Clinical trials with MGL-3196 (resmetirom) showed significant improvement on hepatic steatosis, fibrosis, and lipids, which led to approval by the U.S. Food and Drug Administration in 2024 for the treatment of MASH. Results are currently awaited for prodrug VK2809, exerting organ specificity through prodrug conversion in the liver, ultimately targeting MASH. For the treatment of genetic thyroid hormone signaling disorders (resistance to thyroid hormone β [RTHβ] and monocarboxylate transporter 8 [MCT8] deficiency), different thyroid hormone analogs have been tested. 3,5,3'-triiodothyroacetic acid (Triac), an endogenous thyroid hormone analog, has been prescribed on a compassionate use basis for RTHβ. In MCT8 deficiency, 3,5-diiodothyropropionic acid has been explored in patients, and Sob-AM2, a prodrug of which the active compound accumulates in the brain, has been investigated in preclinical studies. Recently, the European Medicines Agency has granted market authorization for Triac, being the first approved medicine for this rare disease. Conclusions: Ongoing strategies to enhance organ specificity of thyroid hormone analogs should include not only TR specificity but also other determinants of tissue selectivity, such as tissue-specific transporters or enzymes that activate the prodrug. This, together with the recent approval of two thyroid hormone analogs, may ensure a promising future for the development and application of thyroid hormone analogs.