Resmetirom

Abstract

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Generic Name: RESMETIROM

Proprietary Name: Rezdiffra (Madrigal Pharmaceuticals, Inc.)

Approval Rating: 1P

Therapeutic Class: Thyroid Hormone Receptor-Beta Agonist

Similar Drugs: None

Sound-/Look-Alike Names: Differin, Ramelteon, Rezafungin

Indications

Resmetirom is approved by the Food and Drug Administration (FDA) for the treatment of adults with noncirrhotic metabolic dysfunction–associated steatohepatitis (MASH; formerly nonalcoholic steatohepatitis [NASH]) with moderate to advanced liver fibrosis (consistent with stages F2-F3 fibrosis), for use in conjunction with diet and exercise. ¹ Use of resmetirom should be avoided in patients with decompensated cirrhosis. Safety and efficacy have not been established in patients with MASH cirrhosis. ¹

The indication received accelerated approval based on improvement in MASH and fibrosis in clinical trials. Continued approval is contingent upon verification of clinical benefit in confirmatory trials.^1,2

MASH is a condition characterized by macrovesicular hepatic steatosis accompanied by inflammation and cellular injury, with or without fibrosis, leading to cirrhosis. Stage F2 or higher fibrosis is clinically significant, with patients with MASH and at least F2 fibrosis having a higher risk of liver-related morbidity and mortality. ³

The terminology describing this disease state and the diagnostic criteria has undergone revision. The American Association for the Study of Liver Diseases (AASLD), European Association for the Study of the Liver (EASL), and the Fundacion Clinica Medica Sur, A.C. published a joint statement replacing the term “nonalcoholic fatty liver disease (NAFLD)” with “metabolic dysfunction–associated steatotic liver disease (MASLD),” referring to disease defined by the presence of at least 1 of 5 cardiometabolic risk factors. “Metabolic dysfunction-associated steatohepatitis (MASH)” was selected as the replacement term for NASH. Those with no metabolic parameters and no known cause of disease were deemed to have cryptogenic steatotic liver disease. The new term “metabolic and alcohol–related/associated liver disease (MetALD)” was selected to describe those with metabolic dysfunction–associated steatotic liver disease who consume alcohol (140-350 g/week for females and 210-420 g/week for males). Retention of the clinical definition of steatohepatitis allows data from earlier studies in NASH to be generalizable to individuals classified as MASLD or MASH under the new nomenclature.^4,5 The term “MASH” for metabolic dysfunction—associated steatohepatitis will be used in this monograph, consistent with the described terminology revisions.

Clinical Pharmacology

Resmetirom is a thyroid hormone receptor (THR)-beta partial agonist. It produced 83.8% of the maximum response compared to triiodothyronine (T3) in an in vitro functional assay for THR-beta activation, while producing 48.6% efficacy for resmetirom relative to T3 for THR-alpha agonism. ¹ In another in vitro assay, resmetirom was 28-fold selective for THR-beta over THR-alpha. ⁶ THR-beta is the major form of THR in the liver; stimulation of THR-beta reduces intrahepatic triglycerides. The actions of thyroid hormone outside the liver are primarily mediated by THR-alpha. ¹ The hepatic thyromimetic action of resmetirom is due to hepatocyte-specific transport by OATP1B1. ⁷

Originally developed as a treatment for dyslipidemia, resmetirom at doses ranging from 50 to 200 mg reduced LDL cholesterol up to 30% and triglycerides up to 60% in healthy volunteers with mild LDL cholesterol elevations.^6,8

In a mouse model of MASH, resmetirom reversed gray hepatization, liver fibrosis, and inflammation, and increased macrophage infiltration. Resmetirom appeared to recover expression of RGS5 (a member of the regulators of G protein signaling family that regulates inflammation), influence activation of Toll-like receptors, and inactivate Jak-STAT3 and NF-κB signaling pathways. ⁹

Resmetirom decreases liver fat content in humans. As measured by magnetic resonance imaging-proton density fat fraction (MRI-PDFF), reductions in liver fat were observed at 16 and 52 weeks of resmetirom treatment. When measured by controlled attenuation parameter, reductions in liver fat were observed at 52 weeks of treatment. ¹

A decrease in prohormone free T4 was associated with resmetirom therapy, with minimal changes in active hormone T3 or in thyroid-stimulating hormone. At 12 months, free T4 was reduced by a mean of 13% in patients treated with resmetirom 80 mg once daily, 17% in patients treated with resmetirom 100 mg once daily, and 2% in patients treated with placebo. There were no clinical findings associated with free T4 decreases. ¹

Increased concentrations of sex hormone binding globulin were observed during resmetirom treatment. The clinical significance of these changes is not known. ¹

At 2 times the maximum recommended dose, resmetirom does not prolong the QT interval to a clinically relevant extent. ¹

Pharmacokinetics

Following multiple daily oral doses of resmetirom 80 or 100 mg, the median T_max is approximately 4 hours. Food does not have a significant impact on absorption, reducing C_max by 33%, reducing AUC by 11%, and delaying median T_max by about 2 hours compared to administration in the fasted state. Steady state is reached within 3 to 6 days of once-daily dosing. Steady-state exposure increases in a dose-proportional manner between doses of 40 and 100 mg and in a greater than dose-proportional manner between doses of 100 and 200 mg (by about 5.6-fold). Resmetirom exposure is similar in patients with MASH with F2 stage fibrosis and those with F3 stage fibrosis. ¹

The apparent volume of distribution at steady state is 68 L. Resmetirom is greater than 99% plasma protein bound. ¹

The median terminal plasma half-life is 4.5 hours and steady-state apparent clearance is 17.5 L/h. Resmetirom is metabolized by CYP2C8. The major metabolite, MGL-3623, has 28-times lower potency for THR-beta than resmetirom and represents 33% to 51% of resmetirom AUC at steady state following administration of resmetirom 100 mg orally once daily. The dose is primarily eliminated as metabolites in the feces and urine; following a radiolabeled dose, 67% was recovered in the feces and 24% in the urine. ¹

No clinically important differences in resmetirom pharmacokinetics were observed based on age (18-83 years), sex, race (White, Black, or Asian), ABCG2 genotype (BCRP p.Gln141Lys, p.Val12Met), or mild to moderate renal impairment (estimated glomerular filtration rate [eGFR] 30 to 89 mL/minute/1.73 m²). The effects of severe renal impairment (eGFR less than 30 mL/min/1.73 m²) on resmetirom pharmacokinetics is unknown. Resmetirom AUC was 1.3-fold, 2.7-fold, and 19-fold higher and C_max was 1.2-fold, 1.7-fold, and 8.1-fold higher in patients with mild, moderate, and severe hepatic impairment, respectively, compared to subjects with normal hepatic function. The AUC of the major metabolite was 1.3-fold, 2-fold, and 5.8-fold higher in patients with mild, moderate, and severe hepatic impairment, respectively, compared to subjects with normal hepatic function. ¹

A clinically important difference in resmetirom exposure was not observed with the recommended weight-based dosage; however, the apparent volume of distribution and apparent clearance increase with increasing body weight, resulting in lower resmetirom exposure in patients with higher body weight receiving the same dosage as lower-weight patients. ¹

Comparative Efficacy

Indication: Noncirrhotic Metabolic Dysfunction—Associated Steatohepatitis with Fibrosis

Guidelines

Guideline: American Association for the Study of Liver Diseases practice guidance on the clinical assessment and management of nonalcoholic fatty liver disease

Reference: American Association for the Study of Liver Diseases, 2023 ³

Comments: Management of MASH and fibrosis may include weight loss, changes in dietary composition, exercise, and bariatric surgery. Pharmacologic therapies have included vitamin E, pioglitazone, glucagonlike peptide 1 (GLP-1) receptor agonists, and sodium glucose cotransporter 2 inhibitors. The current guidance acknowledged a lack of FDA-approved medications specific for the condition but considers use of several medications to treat MASH and associated comorbidities. Semaglutide may be considered for treatment of type 2 diabetes and/or obesity in patients with MASH, as it offers cardiovascular benefit an improves MASH. Pioglitazone may be considered for patients with MASH and type 2 diabetes. Vitamin E may be considered in select patients without diabetes. None of these therapies have demonstrated an antifibrotic benefit. Resmetirom was not approved at the time the guideline was published and was not mentioned.

Guideline: American Association of Clinical Endocrinology clinical practice guideline for the diagnosis and management of nonalcoholic fatty liver disease in primary care and endocrinology clinical settings: Co-sponsored by the American Association for the Study of Liver Diseases

Reference: American Association of Clinical Endocrinology, 2022 ¹⁰

Comments: In addition to dietary intervention and exercise, the guideline identifies a number of medications for the treatment of liver disease and cardiometabolic conditions associated with MASLD or MASH. Pioglitazone and GLP-1 receptor agonists are recommended for patients with type 2 diabetes and biopsy-proven MASH, and these agents must be considered for diabetes management when there is an elevated probability of MASH. Vitamin E may be considered for the treatment of MASH in patients without diabetes. Semaglutide or liraglutide are recommended as adjunctive therapy to lifestyle modification in individuals with obesity and MASLD or MASH. Resmetirom was not approved at the time the guideline was published and was not mentioned.

Studies

Drug: Resmetirom versus Placebo

Reference: Harrison et al.,^1,11,12 (MAESTRO-NASH trial; MGL-3196-11 trial; NCT03900429)

Study Design: Phase 3, randomized, double-blind, multicenter study

Study Funding: Madrigal Pharmaceuticals

Patients: 966 patients 18 years of age or older with MASH and fibrosis stage F1, F2, or F3. Patients had at least 3 of 5 metabolic risk factors (according to the International Diabetes Foundation criteria for metabolic syndrome) and had undergone prescreening vibration-controlled transient elastography (within the past 3 months) showing a controlled attenuation parameter of 280 dB/m or more and a liver-stiffness measurement of 8.5 kPa or more, or had a recent liver biopsy showing MASH with fibrosis stage F2 or F3. Other inclusion criteria included histologic evidence of MASH and a NAFLD activity score of at least 4 (on a scale of 0-8, with higher scores indicating more severe disease), with a score of 1 or more for each component (steatosis, lobular inflammation, and hepatocellular ballooning). Weight and doses of GLP-1 agonists were required to be stable for at least 6 months before biopsy. Key exclusion criteria were alcohol consumption of more than 20 g/day for females and more than 30 g/day for males; HbA_1c level greater than 9% at screening; active hyperthyroidism; history of bariatric surgery; regular use of drugs historically associated with MASLD such as amiodarone, methotrexate, systemic oral glucocorticoids, tetracyclines, tamoxifen, high-dose estrogen, and valproic acid; and causes of chronic liver disease other than noncirrhotic MASH. Mean patient age was 56.6 years; 56% were female; approximately 21% were Hispanic; and approximately 89% were White, 3% were Asian, and 2% were Black. Mean baseline body mass index was 35.7 kg/m². Fibrosis stage was F2 in 33% and F3 in 61.9%; 67% had type 2 diabetes, 78.1% had hypertension, and 71.3% had dyslipidemia; and 49% were receiving statins and 14% were receiving thyroxine.

Intervention: Patients were randomized (1:1:1) to resmetirom 80 mg orally once daily (n = 322), resmetirom 100 mg orally once daily (n = 323), or placebo (n = 321), in addition to lifestyle counseling on nutrition and exercise. Randomization was stratified according to presence or absence of type 2 diabetes and fibrosis stage (F1, F2, or F3). Patients were maintained on stable doses of medications for diabetes, dyslipidemia, and hypertension.

Results: Two pathologists (A and B) independently read the liver biopsies for each patient and separately assessed for end points. The published article reports on 966 patients in the primary analysis population; 11 patients had a delay in their week 52 biopsy due to COVID-19 and were removed from the primary biopsy analysis population, resulting in data analysis for 955 patients (316 patients in the resmetirom 80 mg group, 321 patients in the resmetirom 100 mg group, and 318 patients in the placebo group). Study results are provided in the prescribing information for 888 patients with F2 or F3 fibrosis at baseline (298 in the resmetirom 80 mg group, 296 in the resmetirom 100 mg group, and 294 in the placebo group).

Primary End Point(s):

• • Percentage of patients with resolution of MASH (achievement of a hepatocellular ballooning score of 0, a lobular inflammation score of 0 or 1, and a reduction in NAFLD activity score of at least 2 points) and no worsening of liver fibrosis at week 52: 25.9% with resmetirom 80 mg (P < .001 vs placebo), 29.9% with resmetirom 100 mg (P < .001 vs placebo), and 9.7% with placebo.

  • ○ Results reported in the prescribing information (assessed by pathologist A): 27% with resmetirom 80 mg (placebo-adjusted difference, 14%; 95% CI: 8%-20%); 36% with resmetirom 100 mg (placebo-adjusted difference, 23%; 95% CI: 16%-30%), and 13% with placebo.
  • ○ Results reported in the prescribing information (assessed by pathologist B): 26% with resmetirom 80 mg (placebo-adjusted difference, 17%; 95% CI: 11%-23%), 24% with resmetirom 100 mg (placebo-adjusted difference, 15%; 95% CI: 9%-21%), and 9% with placebo.
  • ○ Percentage of patients with at least 1-stage improvement in liver fibrosis and no worsening of NAFLD activity score at week 52: 24.2% with resmetirom 80 mg (P < .001 vs placebo), 25.9% with resmetirom 100 mg (P < .001 vs placebo), and 14.2% with placebo.
  • ○ Results reported in the prescribing information (assessed by pathologist A): 23% with resmetirom 80 mg (placebo-adjusted difference, 8%; 95% CI: 2%-14%), 28% with resmetirom 100 mg (placebo-adjusted difference, 13%; 95% CI: 7%-20%), and 15% with placebo.
  • ○ Results reported in the prescribing information (assessed by pathologist B): 23% with resmetirom 80 mg (placebo-adjusted difference, 11%; 95% CI: 5%-17%), 24% with resmetirom 100 mg (placebo-adjusted difference, 11%; 95% CI: 5%-17%), and 13% with placebo.

Secondary End Point(s):

• Percent change from baseline in LDL cholesterol level at week 24: −13.6% with resmetirom 80 mg (P < .001 vs placebo), −16.3% with resmetirom 100 mg (P < .001 vs placebo), and 0.1% with placebo.

• Proportion of patients achieving at least a 2-point improvement in NAFLD activity score with at least a 1-point improvement in hepatocellular ballooning or lobular inflammation with no worsening of fibrosis: 41.3% with resmetirom 80 mg (difference from placebo, 20.2%; 95% CI: 13.8%-26.5%), 44.9% with resmetirom 100 mg (difference from placebo, 23.8%; 95% CI: 17.4%-30.2%), and 21.2% with placebo.

• Proportion of patients achieving at least a 2-point improvement in NAFLD activity score with at least 1-point improvement in hepatocellular ballooning or lobular inflammation and at least 1-point improvement in fibrosis: 18.8% with resmetirom 80 mg (difference from placebo, 10.5%; 95% CI: 5.8%-15.3%), 21.2% with resmetirom 100 mg (difference from placebo, 13%; 95% CI: 8.3%-17.7%), and 8.5% with placebo.

• Improvement in each component of the NAFLD activity score was achieved in 23.3% with resmetirom 80 mg (difference from placebo, 16.1%; 95% CI: 11.1%-21%), 27.9% with resmetirom 100 mg (difference from placebo, 20.9%; 95% CI: 15.8%-25.9%), and 7.2% with placebo.

• Improvement of fibrosis by 2 stages or more was achieved in 8.3% with resmetirom 80 mg (difference from placebo, 5.6%; 95% CI: 2.5%-8.7%), 10.1% with resmetirom 100 mg (difference from placebo, 7.4%; 95% CI: 3.9%-10.8%), and 2.8% with placebo.

• MASH resolution and fibrosis improvement by at least 1 stage was achieved in 14.2% with resmetirom 80 mg (difference from placebo, 9.5%; 95% CI: 5.4%-13.6%), 16% with resmetirom 100 mg (difference from placebo, 11.6%; 95% CI: 7.5%-15.8%), and 4.9% with placebo.

• Greater reductions of the following parameters from baseline were observed with both doses of resmetirom compared with placebo: Apolipoprotein B, triglycerides and lipoprotein(a) at week 24; MRI-PDFF at week 52; and ALT, AST, and gamma-glutamyltransferase at week 48.

Comments: The study was conducted at 245 sites in 15 countries including Austria, Belgium, France, Germany, Hungary, Israel, Italy, Spain, Switzerland, United Kingdom, and the United States. The majority of patients were from the United States. Week 52 results provided the basis for approval (the trial is ongoing with a planned duration of 54 months). At week 52, adherence to the trial regimen was greater than 80% in 92% of patients.

Completion of this trial to demonstrate clinical benefit on the composite end point of progression to cirrhosis, hepatic decompensation events, liver transplant, and mortality is a requirement for continued approval. The trial completion date is August 2028, with a final report submission date of March 2029. ² A second pivotal outcomes trial evaluating resmetirom 80 mg once daily in adults with well-compensated MASH cirrhosis (MAESTRO-NASH-OUTCOMES trial; NCT05500222) is also underway, with completion anticipated in January 2027.^12,13

Limitations: A limitation of the MAESTRO-NASH trial is the lack of clinical outcomes data to correlate with histologic data. The safety of long-term use of resmetirom has not been assessed.

Reference: Harrison et al., ¹² (MAESTRO-NAFLD-1 trial; NCT04197479) ¹⁴

Study Design: Phase 3 randomized, double-blind, multicenter study

Study Funding: Madrigal Pharmaceuticals

Patients: 972 adults (at least 18 years of age) with at least 3 metabolic risk factors and suspected or confirmed MASLD/MASH diagnosed either using noninvasive biomarkers and imaging (FibroScan with kPa of at least 5.5 and less than 8.5; continuous attenuation parameter of at least 280 dB/m or magnetic resonance elastography [MRE] at least 2 and less than 4; MRI-PDFF with at least 8% liver fat consistent with steatosis and fibrosis stage of at least F1 and less than F4) or by recent liver biopsy documenting MASH/MASLD with steatosis. Subjects were required to be maintained on stable therapy for dyslipidemia for at least 30 days before randomization and during the trial. Exclusion criteria included significant alcohol consumption defined as 2 or more alcoholic drinks per day for males and 1.5 alcoholic drinks per day for females; use of drugs associated with MASLD; active hyperthyroidism or untreated clinical hypothyroidism; active autoimmune disease; history of bariatric surgery; weight gain or loss of 5% or more of total body weight within 12 weeks of randomization; HbA_1c greater than 9%; or the presence of cirrhosis, hepatic decompensation, or other chronic liver disease. Mean patient age was 56 years; 57% were female; 88% were White; and 34% were Hispanic. Common metabolic risk factors included obesity (mean BMI, 35 kg/m²), type 2 diabetes (49%), dyslipidemia (88%), and hypertension (75%). Statins were used by 46% of patients to manage dyslipidemia at baseline.

Intervention: Patients were randomized (1:1:1:1) to 3 double-blind arms (resmetirom 80 mg [n = 327], resmetirom 100 mg [n = 325], or placebo [n = 320]), or to an open-label resmetirom 100 mg arm (n = 171); randomization to the open-label arm was discontinued after the target number of subjects was achieved. Each treatment was administered once daily for 52 weeks. Randomization was stratified by presence or absence of type 2 diabetes and by history of documented atherosclerotic cardiovascular disease. Patients with hypothyroidism and on thyroxine doses greater than 75 µg were initially enrolled in the open-label resmetirom 100 mg arm to allow for comparison with patients not on thyroxine; however, after a protocol amendment allowed patients on thyroxine to be enrolled in the double-blind phase, 44.4% of patients in the open-label 100 mg arm were on thyroxine at baseline compared to 10.5% to 11.9% in the double-blind arms.

Results:

Primary End Point(s):

• • Treatment-emergent adverse events over 52 weeks occurred in 86.5% of patients in the open-label resmetirom 100 mg arm, 86.1% of patients in the double-blind resmetirom 100 mg arm, 88.4% with double-blind resmetirom 80 mg, and 81.8% of placebo-treated patients.

  • ○ Adverse events occurring more frequently with resmetirom than placebo included mild or moderate diarrhea (23.5%-31.2% in the resmetirom arms compared with 13.8% in the placebo arm) and nausea (11.9%-18.2% in the resmetirom arms vs 7.9% in the placebo arm).

Secondary End Point(s):

• • Least squares (LS) mean change in LDL cholesterol from baseline to week 24: LDL cholesterol was reduced by 19.4% with open-label resmetirom 100 mg, by 13.9% with double-blind resmetirom 100 mg (P < .001 vs placebo), by 12.4% with double-blind resmetirom 80 mg (P < .001 vs placebo), and by 1.3% with placebo; LS mean difference from placebo was −12.6% (97.5% CI: −16.7% to −8.6%; P < .001 for double-blind resmetirom 100 mg and −11.1% (97.5% CI: −15% to −7.2%; P < .001) for double-blind resmetirom 80 mg.

  • ○ Similar results were observed at week 48 (P < .001 for double-blind resmetirom 100 and 80 mg groups vs placebo).
• • LS mean change in apolipoprotein B from baseline to week 24: Apolipoprotein B was reduced by 21.3% with open-label resmetirom 100 mg, by 16.5% with double-blind resmetirom 100 mg (P < .001 vs placebo), by 14.3% with double-blind resmetirom 80 mg (P < .001 vs placebo), and was unchanged with placebo; LS mean difference from placebo was −16.5% (97.5% CI: −19.5% to −13.4%; P < .001) for double-blind resmetirom 100 mg and −14.3% (97.5% CI: −17.4% to −11.3%; P < .001) for double-blind resmetirom 80 mg.

  • ○ Similar results were observed at week 48 (P < .001 vs placebo for both comparisons).
• • LS mean change in triglycerides from baseline to week 24: In patients with baseline triglycerides greater than 150 mg/dL, triglycerides were reduced by 27.5% with open-label resmetirom 100 mg, by 23.4% with double-blind resmetirom 100 mg (P < .001 vs placebo), by 18.4% with double-blind resmetirom 80 mg (P < .001 vs placebo), and by 3% with placebo; LS mean difference from placebo was −20.4% (97.5% CI: −30.2% to −10.6%; P < .001) for double-blind resmetirom 100 mg and −15.4% (97.5% CI: −24.9% to −5.9%; P < .001) for double-blind resmetirom 80 mg.

  • ○ Similar results were observed at week 48 (P < .001 vs placebo for both comparisons).
• • LS mean change in hepatic fat, assessed by MRI-PDFF percent fat fraction, from baseline to week 16: Hepatic fat was reduced by 47.8% with open-label resmetirom 100 mg, by 44.8% with double-blind resmetirom 100 mg, by 34.9% with double-blind resmetirom 80 mg, and by 6.2% with placebo; LS mean difference from placebo was −38.6% (97.5% CI: −44.6% to −32.6%; P < .001) for double-blind resmetirom 100 mg and −34.9% (97.5% CI: −41 to −28.9%; P < .001) for double-blind resmetirom 80 mg.

  • ○ Similar results were observed at week 52 (P < .001 vs placebo for both comparisons).
  • ○ Week 52 hepatic fat as estimated by continuous attenuation parameter was reduced from baseline by 46% with open-label resmetirom 100 mg, by 42.8% with double-blind resmetirom 100 mg (P < .001 vs placebo), by 36.7% with double-blind resmetirom 80 mg (P < .001 vs placebo), and by 18.4% with placebo.

• • Liver enzymes (ALT, AST, and GGT) were reduced to a greater extent from baseline to week 52 in each resmetirom group compared to placebo.

• • MASH biomarkers (CK-18/M30, adiponectin, and reverse T3) were improved to a greater extent from baseline to week 52 in each resmetirom group compared to placebo.

Comments: This study was conducted at approximately 80 sites in the United States. COVID-19 delayed medication delivery such that 86% to 88% of subjects in the double-blind arms missed study visits. In the open-label arm, which used bottles of tablets, only 19% of subjects missed study visits. Overall, adherence was 81.2% in the open-label arm and 76.4% across the 3 double-blind arms.

Patients completing this trial were eligible to enroll in a 52-week open-label extension (MAESTRO-NAFLD-OLE trial; NCT04951219) to further assess safety; completion of the extension study is anticipated in April 2026.^12,14,15 In addition to the open-label arm in the original MAESTRO-NAFLD-1 trial, three additional open-label arms were included in this study: patients with noncirrhotic MASH enrolled after the original randomization was complete, patients with well-compensated MASH cirrhosis, and patients with moderate renal impairment. Results from these 3 open-label treatment arms are to be reported separately and are not yet available.^12,14

Results of the phase 3 trials were consistent with the results observed in a phase 2 placebo-controlled trial enrolling 125 patients with biopsy-confirmed MASH (fibrosis stages F1 through F3) and hepatic fat fraction of at least 10% at baseline as assessed by MRI-PDFF. Resmetirom 80 mg once daily was associated with a greater reduction in hepatic fat compared with placebo at week 12 (−32.9% vs −10.4%; P < .0001) and week 36 (−37.3% vs −8.9%; P < .0001). Adverse effects included a higher incidence of diarrhea and nausea with resmetirom.^16-18

Limitations: COVID-19 impacted medication adherence and evaluations. Clinical end points were not assessed. Few patients had fibrosis, so the impact in this population could not be assessed.

Contraindications, Warnings, and Precautions

Contraindications

The resmetirom prescribing information states there are no contraindications to its use. ¹ Though not stated in the product labeling, a potential contraindication is hypersensitivity to resmetirom or any of its inactive ingredients (ie, colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, mannitol, microcrystalline cellulose; tablet film coating: polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, red iron oxide [100 mg tablets], yellow iron oxide [80 mg and 100 mg tablets]).

Warnings and Precautions

Hepatotoxicity has been observed with the use of resmetirom. Patients should be monitored during treatment for elevations in liver tests and for the development of liver-related adverse reactions (eg, fatigue, nausea, vomiting, right upper quadrant pain or tenderness, jaundice, fever, rash, and/or eosinophilia). If hepatotoxicity is suspected, resmetirom therapy should be discontinued, and the patient should continue to be monitored. If laboratory values return to baseline, weigh the potential risks against the benefits of restarting therapy. If laboratory values do not return to baseline, consider drug-induced autoimmune-like hepatitis or autoimmune liver disease in the evaluation of liver test elevations. One patient treated with resmetirom 80 mg daily had normal ALT, AST, and total bilirubin at baseline, but developed substantial elevations of liver biochemistries while on treatment that resolved when treatment was interrupted. After reinitiating resmetirom, the patient had substantial elevations of ALT, AST, and total bilirubin, accompanied by elevations in immunoglobulin G levels suggestive of drug-induced autoimmune-like hepatitis. Liver tests returned to baseline following hospitalization and discontinuation of resmetirom without any therapeutic intervention. ¹

Gallbladder-related adverse reactions, including cholelithiasis, acute cholecystitis, and obstructive pancreatitis (gallstone), were observed more often in resmetirom-treated patients than in placebo-treated patients in clinical trials. If cholelithiasis is suspected, gallbladder diagnostic studies and appropriate clinical follow-up are indicated. If an acute gallbladder event is suspected, resmetirom therapy should be interrupted until the event is resolved. ¹

Increased exposure to atorvastatin, pravastatin, rosuvastatin, and simvastatin was observed when administered concomitantly with resmetirom, which may increase the risk of adverse reactions. Dosage adjustment for certain statins is recommended if administered concomitantly and patients should be monitored for statin-related adverse reactions (eg, liver tests, myopathy, rhabdomyolysis). ¹

There are no adequate and well-controlled studies of resmetirom use during pregnancy. In animal reproduction studies, adverse effects on embryofetal development occurred in pregnant rabbits at doses 3.5 times the maximum recommended dose. These effects were associated with maternal toxicity. Pregnancies should be reported to the manufacturer (Madrigal Pharmaceuticals Adverse Event reporting line, 1-800-905-0324; https://www.madrigalpharma.com/contact/). There are risks to the mother and fetus related to underlying maternal MASH with liver fibrosis, including an increased risk of gestational diabetes, hypertensive complications, preterm birth, and postpartum hemorrhage. ¹ Completion of a prospective and retrospective study of patients exposed to resmetirom during pregnancy and/or lactation to assess for risk of maternal complications, adverse effects on the developing fetus and neonate, and adverse effects on the infant is required, with infant outcomes assessed through the first year of life; the study completion date is March 2030, with the final report due by September 2030. ²

No studies have been conducted to assess the presence of resmetirom in human milk, or its effects on breastfeeding infants or milk production. The developmental and health benefits of breastfeeding should be considered along with the patient’s clinical need for resmetirom and any potential adverse effects on the breastfeeding infant from resmetirom or from the underlying maternal condition. ¹ The manufacturer is required to perform a study assessing concentrations of resmetirom in the milk of lactating patients who have received resmetirom; the study completion date is March 2027, with the final report due by September 2027. ²

Safety and effectiveness of resmetirom have not been established in pediatric patients. ¹ A postmarketing study assessing the safety, pharmacokinetics, and efficacy of resmetirom in postpubertal pediatric patients 12 to 17 years of age with MASH with stage F2 and F3 fibrosis is due to be completed by January 2028, with a final report submission date of August 2028; a study in prepubertal pediatric patients 6 to 12 years of age with MASH and stage F2 and F3 fibrosis must be completed by July 2030, with a final report submission date of February 2031. Studies in pediatric patients younger than 6 years have been waived, as the necessary studies in that age group are impractical. ²

In a clinical trial, 25% of patients treated with resmetirom were 65 years and older and 2% were 75 years and older. No differences in effectiveness were observed, but a numerically higher incidence of adverse reactions were observed in patients 65 years and older compared to younger adults. ¹

The recommended dosage of resmetirom in patients with mild to moderate renal impairment is the same as in patients with normal kidney function; resmetirom has not been studied in patients with severe renal impairment. ¹

Resmetirom use should be avoided in patients with decompensated cirrhosis (moderate to severe hepatic impairment [Child-Pugh class B or C]). Moderate or severe hepatic impairment increases resmetirom C_max and AUC, which may increase the risk of adverse reactions. No dosage adjustment is recommended for patients with mild hepatic impairment (Child-Pugh class A). The safety and effectiveness of resmetirom have not been established in patients with MASH cirrhosis. ¹

Adverse Reactions

The most common adverse reactions with resmetirom in clinical trials were diarrhea, nausea, pruritus, vomiting, constipation, abdominal pain, and dizziness; incidence rates in comparison with placebo are summarized in Table 1. Adverse reactions that occurred more frequently with resmetirom than placebo, but in fewer than 5% of patients, included decreased appetite, flatulence, abnormal feces, dysgeusia, vertigo, arrhythmia, palpitations, depression, erythema, hypoglycemia, tendinopathy, and abnormal uterine bleeding. ¹ Diarrhea and nausea both typically began early after treatment initiation and were mild to moderate in severity.^1,11 In the MAESTRO-NASH study, diarrhea occurred in 27% of patients treated with resmetirom 80 mg, 33.4% treated with resmetirom 100 mg, and 15.6% of the placebo recipients. ¹¹ Diarrhea and nausea were the most common causes of treatment discontinuation. ¹

Table 1.

Exposure-Adjusted Incidence Rates of Common Adverse Reactions in Adults With Noncirrhotic Metabolic Dysfunction–Associated Steatohepatitis (MAESTRO-NASH Trial).^1,a,b,c

Adverse reactions	Resmetirom 80 mg once daily (n = 298) d (%)	Resmetirom 100 mg once daily (n = 296) d (%)	Placebo (n = 294) d (%)
Diarrhea	23	33	14
Nausea	18	15	9
Pruritus	6	10	4
Vomiting	7	8	4
Constipation	5	8	4
Abdominal pain	5	7	4
Dizziness	4	4	1

^aPopulation includes adult patients with noncirrhotic MASH with liver fibrosis (stages F2 and F3 at eligibility).

^bMedian exposure duration was 74 weeks for resmetirom 80 mg once daily, 66 weeks for resmetirom 100 mg once daily, and 68 weeks for placebo.

^cExposure-adjusted incidence rates are per 100 person-years where total person-years were 435, 407, and 435 for resmetirom 80 mg once daily, resmetirom 100 mg once daily, and placebo arms, respectively.

^dExposure-adjusted incidence rate per 100 person-years can be interpreted as an estimated number of first occurrences of the adverse reaction of interest if 100 patients are treated for 1 year.

Hypersensitivity reactions such as urticaria and rash were observed in patients treated with resmetirom. The exposure-adjusted incidence rates for urticaria were slightly greater in the resmetirom groups than those observed in the placebo-treated subjects. ¹

In clinical trials, a higher incidence of cholelithiasis, acute cholecystitis, and obstructive pancreatitis (gallstone) was observed in the treatment arms compared to placebo. However, the exposure-adjusted incidence rates for these events were less than 1 per 100 patient-years for all treatment arms. ¹

Increases in mean ALT and AST levels were observed in the first 4 weeks after initiating resmetirom therapy; mean elevation in ALT and AST values was less than 1.5 times baseline at 4 weeks after treatment initiation and returned to baseline around 8 weeks after initiation of treatment. An increase in ALT to greater than 3 times the upper limit of normal occurred in 11% of patients treated with resmetirom 80 mg daily, 13% treated with resmetirom 100 mg daily, and 10% treated with placebo. An increase in AST to greater than 3 times the upper limit of normal occurred in 9% of patients treated with resmetirom 80 mg daily, 12% treated with resmetirom 100 mg daily, and 10% treated with placebo. ¹

Drug Interactions

Resmetirom is a CYP2C8 substrate. Concomitant use with a strong or moderate CYP2C8 inhibitor increased the resmetirom C_max and AUC and may increase the risk of resmetirom adverse reactions. Administration with clopidogrel, a moderate CYP2C8 inhibitor, increased resmetirom C_max 1.3-fold and increased AUC 1.7-fold. Reduce the dose of resmetirom if used with a moderate CYP2C8 inhibitor (eg, clopidogrel). Concomitant use of resmetirom with strong CYP2C8 inhibitors (eg, gemfibrozil) is not recommended ¹

Resmetirom is a weak CYP2C8 inhibitor and increases exposure of CYP2C8 substrates, which may increase the risk of adverse reactions related to these substrates. Monitor patients for adverse reactions more frequently if resmetirom is administered concomitantly with CYP2C8 substrates where minimal concentration changes may lead to serious adverse reactions. ¹

Resmetirom is an OATP1B1 and OATP1B3 substrate. Concomitant use with OATP1B1 and OATP1B3 inhibitors may increase resmetirom C_max and AUC, which may increase the risk of resmetirom adverse reactions. Concomitant use of resmetirom with OATP1B1 or OATP1B3 inhibitors (eg, cyclosporine) is not recommended. ¹

Increased exposure to atorvastatin, pravastatin, rosuvastatin, and simvastatin was observed when administered concomitantly with resmetirom, which may increase the risk of adverse reactions related to those drugs. Rosuvastatin C_max was increased 2.9-fold and the AUC 1.8-fold with concomitant administration with resmetirom; lesser increases were observed with atorvastatin, pravastatin, and simvastatin. Dosage adjustments for these statins are recommended: Limit rosuvastatin and simvastatin daily doses to 20 mg and atorvastatin and pravastatin daily doses to 40 mg. Patients should be monitored for statin-related adverse reactions (eg, liver tests, myopathy, rhabdomyolysis). ¹

In vitro, resmetirom is an inhibitor of CYP2C8, UGT1A4, UGT1A9, OATP1B1, OATP1B3, BCRP, OAT3, and BSEP, and is a substrate for OATP1B1, OATP1B3, and BCRP. ¹

Recommended Monitoring

Evaluate liver biochemistries and signs or symptoms associated with liver (eg, fatigue, nausea, vomiting, right upper quadrant pain or tenderness, jaundice, fever, rash, eosinophilia) or gallbladder injury. Monitor for myopathy and rhabdomyolysis if concurrently used with HMG-CoA reductase inhibitors. ¹

Liver biopsy, ALT, FIB-4 Index, MASLD fibrosis score, and noninvasive tests including ultrasound (eg, FibroScan), computed tomography, MRI, and MRE are used to diagnose and monitor for progression of steatohepatitis and fibrosis. ¹⁹

Dosing

The recommended resmetirom dosage is based on actual body weight. For patients weighing less than 100 kg, the recommended dosage is 80 mg orally once daily. For patients weighing 100 kg or more, the recommended dosage is 100 mg orally once daily. Resmetirom may be administered with or without food. ¹

Concomitant use of resmetirom with strong CYP2C8 inhibitors (eg, gemfibrozil) is not recommended. A resmetirom dosage reduction is recommended if resmetirom is used concomitantly with a moderate CYP2C8 inhibitor (eg, clopidogrel). For patients weighing less than 100 kg, reduce the resmetirom dosage to 60 mg once daily. For patients weighing 100 kg or more, reduce the resmetirom dosage to 80 mg once daily. ¹

No dosage adjustment is necessary in patients with mild or moderate renal impairment; resmetirom has not been studied in patients with severe renal impairment. No dosage adjustment is recommended for patients with mild hepatic impairment. Use should be avoided in patients with decompensated cirrhosis (consistent with moderate to severe hepatic impairment). ¹

Product Availability and Storage

Resmetirom was FDA approved on March 14, 2024. ² Resmetirom is available as 60 mg tablets in bottles of 30, and as 80 and 100 mg tablets in bottles of 30 and 90. ¹

Store resmetirom tablets at 20°C to 25°C (68°F-77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). ¹

Drug Safety/REMS

No REMS is required for resmetirom.

Conclusion

Resmetirom, a THR-beta partial agonist, is indicated for the treatment of adults with noncirrhotic MASH with moderate to advanced liver fibrosis (consistent with stages F2-F3 fibrosis), for use in conjunction with diet and exercise. Resmetirom is the first FDA-approved therapy for this indication. Studies demonstrated improvements in steatohepatitis and fibrosis. Therapy has been well tolerated, with mild to moderate diarrhea and nausea most commonly observed upon initiation of therapy. Ongoing trials are evaluating long-term outcomes (including liver disease progression, liver transplant, and all-cause mortality) and long-term safety and tolerability.