RESMETIROM (REZDIFFRA®)

• Thyroid hormone receptor-beta (THR-β) partial agonist
• Resmetirom (Rezdiffra®)

• Thyroid hormone receptor (THR) beta (β), the primary THR in the liver, stimulates triglyceride metabolism when bound by T3. In NASH, its function is impaired, leading to reduced mitochondrial activity, diminished fatty acid oxidation, and fibrosis. Resmetirom is a THR-β partial agonist that promotes triglyceride metabolism and reduces hepatic adiposity through THR-β activation. [1,2]

• Resmetirom is indicated in conjunction with diet and exercise for the treatment of adults with noncirrhotic nonalcoholic steatohepatitis (NASH) with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis).

• Overview
• The effects of resmetirom on NASH were evaluated in the ongoing MAESTRO-NASH study below

• Professional recommendations
• See AASLD NASH treatment recommendations

• Summary
• Interim results from the MAESTRO-NASH trial showed that one year of resmetirom 100 mg resolved NASH in 30% of patients and improved fibrosis in 26%. Based on these findings, resmetirom became the first drug approved to treat NASH under the FDA's accelerated pathway. The full trial is planned for 54 months, where its effects on clinical outcomes, including mortality, hepatic decompensation (e.g., ascites, hepatic encephalopathy, variceal bleeding), and liver transplant, are being evaluated.
• For primary care doctors, selecting appropriate candidates for resmetirom may follow the following sequence: (1) Calculate a FIB-4 score; (2) If FIB-4 is > 1.3, order an ELF test; (3) If ELF is > 7.7, order a liver biopsy; (4) if F2 or F3 fibrosis is present, start resmetirom.

• Hepatotoxicity
• In resmetirom trials, one subject experienced severe elevations in AST, ALT, and total bilirubin that required hospitalization. Immunoglobulin G (IgG) levels were also elevated, suggesting drug-induced autoimmune hepatitis. Liver tests returned to normal after resmetirom discontinuation.
• Monitor patients for liver enzyme increases and signs of hepatotoxicity (e.g., jaundice, fatigue, nausea, vomiting, rash, eosinophilia > 5%). Discontinue resmetirom if liver toxicity is suspected.

• Elevated AST / ALT
• In trials, mean AST and ALT levels increased in resmetirom-treated patients at four weeks of therapy. Increases were less than 1.5 times the upper limit of normal, and values returned to baseline around eight weeks. Over 52 weeks, incidences of LFT elevations > 3X ULN were similar between resmetirom and placebo.

• Gallbladder events
• In trials, gallbladder events, including cholelithiasis, acute cholecystitis, and obstructive pancreatitis, were more common in resmetirom-treated patients than placebo. However, the overall incidence of these events was less than 1%/year in all treatment arms.

• Hypersensitivity reactions
• In trials, urticaria and rash were observed more frequently in resmetirom-treated patients, with incidences of 1.5%/year and 5%/year, respectively, in patients receiving 100 mg daily.

• Thyroid hormone
• In trials, free T4 levels decreased by 13% and 17% at 12 months in patients treated with resmetirom 80 mg and 100 mg, respectively. TSH and free T3 levels were minimally changed, and hypothyroidism symptoms were not observed.

• None

• Kidney disease
• CrCl ≥ 30 ml/min: no dose adjustment necessary
• CrCl < 30 ml/min: has not been studied

• Liver disease
• Mild disease (Child-Pugh A): No dose adjustment necessary
• Moderate-to-severe disease (Child-Pugh B and C): DO NOT USE. Exposure is increased.

• NOTE: The drug interactions presented here are NOT all-inclusive. Other interactions may exist. Drug interaction checkers provide the most efficient and practical way to check for interactions among multiple medications. A free interaction checker is available from Drugs.com (see Drugs.com interactions checker).


• CYP2C8 inhibitors and substrates - resmetirom is a CYP2C8 sensitive substrate and weak inhibitor. It should not be taken with strong CYP2C8 inhibitors, and the dosage should be reduced when combined with moderate inhibitors (see Dosing below). Resmetirom may increase exposure of CYP2C8 substrates.
• OATP1B1/3 inhibitors - resmetirom is an OATP1B1 and OATP1B3 substrate and inhibitor. OATP1B1 and/or OATP1B3 inhibitors may increase its exposure, and concomitant use is not recommended. The effect of resmetirom on OATP1B1/3 substrates is unknown.
• Atorvastatin (Lipitor®) - resmetirom may increase atorvastatin exposure. Daily atorvastatin dose should not exceed 40 mg when combining.
• Pravastatin (Pravachol®) - resmetirom may increase pravastatin exposure. Daily pravastatin dose should not exceed 40 mg when combining.
• Rosuvastatin (Crestor®) - resmetirom may increase rosuvastatin exposure. Daily rosuvastatin dose should not exceed 20 mg when combining.
• Simvastatin (Zocor®) - resmetirom may increase simvastatin exposure. Daily simvastatin dose should not exceed 20 mg when combining.

• Metabolism and clearance
• CYP2C8 - sensitive substrate and weak inhibitor
• OATP1B1/3 - substrate and inhibitor
• BCRP - substrate and inhibitor
• OAT3 - inhibitor

• Dosage form (tablet)
• 60 mg
• 80 mg
• 100 mg
• No generic. 30 tablets costs >$3000.


• Dosage
• Standard
• Body weight < 220 lbs (100 kg): 80 mg once daily
• Body weight ≥ 220 lbs (100 kg): 100 mg once daily
• May take without regard to food
• With moderate CYP2C8 inhibitors
• Body weight < 220 lbs (100 kg): 60 mg once daily
• Body weight ≥ 220 lbs (100 kg): 80 mg once daily
• With strong CYP2C8 inhibitors
• DO NOT COMBINE

• 1 - Rezdiffra PI
• 2 - PMID 38324483 - A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis, NEJM (2024)