Resmetirom (Rezdiffra), a thyroid hormone receptor-beta agonist, is conditionally approved for use in adults with noncirrhotic nonalcoholic steatohepatitis (NASH) with moderate to advanced fibrosis (stages F2 to F3) to reduce liver fat accumulation and to prevent progression of and reverse fibrosis when combined with diet and exercise.¹ Resmetirom was approved using the U.S. Food and Drug Administration accelerated approval pathway on the basis of histologic data and may be granted final, traditional approval if the ongoing confirmatory trial verifies clinical outcome benefit.²

The American Association for the Study of Liver Diseases and other international liver societies have adopted new nomenclature for nonalcoholic fatty liver disease. NASH has been renamed MASH (metabolic dysfunction–associated steatohepatitis). The term NASH is used in this article to reflect consistency with the trial data and drug package labeling.

SAFETY

Resmetirom has been evaluated in 645 patients.¹ Nearly 90% of these patients were White, and safety issues may develop with wider use. The major safety concern of resmetirom is the theoretical potential for liver injury given the finding of presumed drug-induced hepatotoxicity in one patient with elevated liver function tests. The manufacturer suggests monitoring liver enzymes and for signs and symptoms of hepatotoxicity (i.e., fever, fatigue, nausea, vomiting, right upper quadrant pain, jaundice, rash, or eosinophilia [greater than 5%]). Therapy should be discontinued if hepatotoxicity is suspected. If laboratory values normalize after repeat monitoring, the risks vs. benefits of taking resmetirom should be considered before resuming treatment. Cholelithiasis, acute cholecystitis, and obstructive pancreatitis due to gallstones are observed more often in patients treated with resmetirom compared with placebo. If an acute gallbladder event is suspected, therapy should be discontinued until resolution of the event.¹

Important drug interactions should be considered when taking resmetirom. Concomitant use with moderate or strong cytochrome P450 (CYP) 2C8 inhibitors or inhibitors of OATP1B1 or OATP1B3 may increase the likelihood of adverse reactions caused by resmetirom. When used concomitantly with a moderate CYP2C8 inhibitor (e.g., clopidogrel), the dose of resmetirom should be limited to 60 mg in patients weighing less than 100 kg (220 lb) and 80 mg in patients weighing more than 100 kg. Resmetirom should not be used in patients taking strong CYP2C8 inhibitors (e.g., gemfibrozil) or with OATP1B1 or OATP1B3 inhibitors (e.g., cyclosporine). Resmetirom increases the plasma concentrations of atorvastatin, pravastatin, rosuvastatin, and simvastatin. When co-administering resmetirom, daily statin doses should be limited accordingly (20-mg maximum doses of rosuvastatin andsimvastatin; 40-mg maximum doses of pravastatin and atorvastatin). Patients with decompensated cirrhosis or moderate to severe hepatic impairment (Child-Pugh class B or C) should not take resmetirom.² There are no available data for use in children or in pregnant or lactating patients.¹

TOLERABILITY

Diarrhea and nausea are the most common adverse effects experienced during initiation of treatment with resmetirom.¹ Diarrhea, characterized as loose stools or worsening of underlying diarrhea, is reported about twice as often among patients receiving either 80 mg (27%) or 100 mg (33.4%) of resmetirom compared with those receiving placebo (15.6%), and symptoms may last up to 3 weeks. Nausea occurs in 22% of patients taking 80 mg of resmetirom and 19% of patients taking 100 mg, compared with 12.5% of patients taking placebo. Up to 7% of patients taking 100 mg daily of resmetirom will discontinue treatment due to adverse effects, compared with approximately 2% of patients receiving a lower dosage or placebo.³

EFFECTIVENESS

Resmetirom has been evaluated in one study of 966 participants with NASH and biopsy-proven liver fibrosis.³ Significantly more patients treated with resmetirom for 1 year experienced NASH resolution with no worsening of fibrosis (i.e., 25.9% of patients taking 80 mg per day; 29.9% of patients taking 100 mg per day) compared with 9.7% of patients taking placebo (number needed to treat = 6 for patients taking 80 mg; 5 for patients taking 100 mg). Significantly more patients treated with resmetirom experienced fibrosis improvement by one stage or more (24.2% in patients taking 80 mg per day for 1 year and 25.9% in patients taking 100 mg per day for 1 year) compared with 14.2% in patients taking placebo (number needed to treat = 10 for patients taking 80 mg; 9 for patients taking 100 mg). Resmetirom has not been evaluated in the setting of well-compensated NASH cirrhosis; however, this trial is presently recruiting. It is unknown whether treatment with resmetirom will decrease the likelihood of developing end-stage cirrhosis, progression to liver failure, the need for transplantation, cancer, or mortality. Resmetirom has not been compared with any other alternative treatments for NASH.

PRICE

Resmetirom costs approximately $4,000 for a 1-month supply. It may not be covered by health insurance and may require preauthorization. In comparison, off-label treatments such as pioglitazone, liraglutide (Victoza), or semaglutide (Ozempic) are less expensive ($18, $660, and $960 for a 30-day supply, respectively) and more widely accessible. No economic evaluation has been performed to determine whether resmetirom is cost-effective. Therapeutic options for weight loss or reduction of liver fat may be less expensive.

SIMPLICITY

Resmetirom is taken orally once daily. There are no monitoring requirements beyond ongoing liver function assessment. Resmetirom is available only through a limited network of seven national specialty pharmacies.

BOTTOM LINE

Resmetirom may be considered in some patients with NASH, but it has not yet been shown to impact patient-oriented outcomes. Resmetirom is more expensive than alternative treatments and is not likely to be covered by all insurance plans.