Resmetirom

Resmetirom (MGL-3196, VIA-3196; marketed as Rezdiffra) is a first-in-class, orally administered, small-molecule, liver-directed partial agonist of the thyroid hormone receptor beta (THR-beta) that received accelerated approval from the United States Food and Drug Administration on March 14, 2024, for the treatment of adults with noncirrhotic metabolic dysfunction-associated steatohepatitis (MASH, formerly nonalcoholic steatohepatitis or NASH) with moderate to advanced liver fibrosis (stages F2 to F3), in conjunction with diet and exercise. Resmetirom is distinguished from earlier thyromimetic compounds by approximately 28-fold functional selectivity for THR-beta over THR-alpha, hepatocyte-directed uptake mediated by organic anion transporting polypeptide 1B1 (OATP1B1), and a liver-to-plasma concentration ratio of approximately 8:1, properties that collectively minimize the extrahepatic thyrotoxic effects (tachycardia, bone loss, skeletal muscle wasting) that terminated development of prior thyroid hormone receptor agonists including eprotirome and sobetirome. The molecular mechanism involves activation of THR-beta in hepatocytes, promoting fatty acid beta-oxidation, mitochondrial biogenesis, mitophagy, and autophagy while inhibiting de novo lipogenesis; these effects reduce intrahepatic triglyceride accumulation and attenuate the inflammatory and fibrotic cascades characteristic of progressive steatohepatitis. In the pivotal Phase 3 MAESTRO-NASH trial (n = 888, biopsy-confirmed noncirrhotic MASH with F2 to F3 fibrosis), resmetirom at 100 mg daily achieved MASH resolution without fibrosis worsening in 36 percent of patients versus 13 percent on placebo at 52 weeks, and fibrosis improvement by at least one stage without worsening of MASH activity in 28 percent versus 15 percent on placebo, both co-primary endpoints reaching statistical significance. Secondary endpoints demonstrated reductions in low-density lipoprotein cholesterol (16.3 percent), apolipoprotein B (16.5 percent), and triglycerides (23.4 percent), consistent with the hepatic metabolic mechanism. Pharmacokinetics are characterized by oral absorption with a median time to peak concentration of approximately 4 hours, greater than 99 percent plasma protein binding, a median terminal half-life of 4.5 hours, metabolism predominantly through cytochrome P450 2C8 (CYP2C8), and elimination principally via feces (67 percent) with a minor renal component (24 percent). The principal adverse events are diarrhea and nausea, which are generally mild to moderate and self-limiting. Clinically significant drug interactions include inhibition of organic anion transporting polypeptide transporters (elevating statin exposures) and CYP2C8-mediated metabolic interactions. This monograph reviews the chemistry, synthesis, and structural pharmacology of resmetirom; the thyroid hormone receptor biology and mechanism of action in detail; the comprehensive human pharmacokinetic record; the preclinical pharmacology; the clinical evidence base across the MAESTRO trial program; sourcing and quality verification for research-grade material; reconstitution and handling; stack-interaction considerations; adverse-event signal and safety profile; and a comparative assessment of five alternative MASH pharmacotherapy candidates against resmetirom on five competency standards.