By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco. Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
The U.S. Food and Drug Administration (FDA) has approved the first drug and first-in-class for the treatment of metabolic dysfunction-associated steatohepatitis (MASH, formerly known as nonalcoholic steatohepatitis [NASH]). Resmetirom is a selective thyroid hormone receptor-beta (THR-β) partial agonist and was granted an accelerated approval. Continued approval for this indication may be contingent on verification and description of clinical benefit in confirmatory trials.1 It is distributed by Madrigal Pharmaceuticals, Inc. as Rezdiffra.
INDICATIONS
Resmetirom is indicated in conjunction with diet and exercise for the treatment of adults with noncirrhotic nonalcoholic steatohepatitis with moderate to advanced liver fibrosis (consistent with F2 to F3 fibrosis stages).1
DOSAGE
The recommended dose is 80 mg once daily for patients with actual body weight less than 100 kg and 100 mg once daily for patients ≥ 100 kg.1 For patients on a moderate CYP2C8 inhibitor, the dose is reduced to 60 mg and 80 mg, respectively. Resmetirom can be taken without regard to meals. Resmetirom is available as 60 mg, 80 mg, and 100 mg tablets.
POTENTIAL ADVANTAGES
Resmetirom is the first drug approved for MASH and has been shown to reduce hepatic fat content and improve noninvasive markers of liver fibrogenesis.1-3 There was no previously approved treatment for MASH.
POTENTIAL DISADVANTAGES
Hepatotoxicity, cholelithiasis, cholecystitis, and obstructive pancreatitis (gallstone) have been observed with resmetirom treatment.1 Use in patients with moderate to severe hepatic impairment should be avoided. Concomitant use with strong CYP2C8 inhibitors, and with OATP1B1 and OATP1B3 inhibitors, is not recommended.1 Most common adverse reactions include diarrhea, nausea, and pruritus.1 Numerically, higher incidences of adverse drug reactions were observed in patients ≥ 65 years of age compared to younger adults.1
COMMENTS
THR-β is the main receptor for thyroid hormones in the liver promoting lipophagy, mitochondrial biogenesis, and mitophagy while reducing intrahepatic triglycerides.1,2 The accelerated approval was based on the efficacy analysis at month 12 of a 54-month, Phase III, randomized, double-blind, placebo-controlled trial (MAESTRO-NASH).1,2 Study participants had metabolic risk factors and a baseline or recent liver biopsy showing NASH with fibrosis state 2 or 3 and a nonalcoholic fatty liver disease (NAFLD) Activity Score of at least 4. Participants were randomized to resmetirom 80 mg or 100 mg or placebo. Efficacy determination was resolution of steatohepatitis without worsening of fibrosis (criterion one) and one stage improvement in fibrosis without worsening of steatohepatitis on liver biopsies at month 12 (criterion two).
The analysis included resmetirom 80 mg (n = 298), 100 mg (n = 296), and placebo (n = 294). At baseline, 63% had fibrosis stage F3 and 37% had fibrosis stage F2. Sixty-eight percent had type 2 diabetes, 79% had hypertension, and 71% had dyslipidemia. The median body mass index was 35 (31 to 40) kg/m2 and 89% were white. Results were assessed by two independent expert pathologists (A and B) after 12 months of treatment. For the first criterion, pathologist A scored 13% for placebo, 27% for the 80 mg dose, and 36% for the 100 mg dose. Pathologist B scored 9%, 26%, and 24%, respectively. For criterion two, percentages were 15%, 23%, and 28%, respectively, for pathologist A and 13%, 23%, and 24%, respectively, for pathologist B.
Other secondary benefits included significant reduction in atherogenic lipid levels compared to placebo (low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, apolipoprotein B, and triglycerides [those > 150 mg/dL at baseline]).2 There was a trend of greater reduction (month 3 through month 12) with resmetirom vs. placebo from baseline in average alanine transaminase and aspartate aminotransferase values. In another Phase III trial (MAESTRO-NAFLD-1) in participants with NAFLD and presumed NASH (n = 972), resmetirom 80 mg and 100 mg showed the drug was well tolerated and significantly reduced liver stiffness and hepatic fat compared to placebo.3
CLINICAL IMPLICATIONS
MASH is a progressive liver disease characterized by hepatic steatosis, inflammation, hepatocellular injury, and progressive liver fibrosis. It is a severe form of NAFLD.4,5 It is the most common chronic liver condition in the Western population. It is caused by reduced conversion of T4 to the active hormone T3 and increased production of the inactive metabolite rT3 and resultant impaired THR-β signaling.3 Resmetirom is a liver-targeted THR-β agonist that restores thyroid function in the liver and reduces rT3 levels.3 It is the first FDA-approved treatment for this common condition. The cost for resmetirom was not available at the time of this review.
REFERENCES
- Rezdiffra prescribing information. Madrigal Pharmaceuticals, Inc. March 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/217785s000lbl.pdf
- Harrison SA, Bedossa P, Guy CD, et al. A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis. N Engl J Med 2024;390:497-509.
- Harrison SA, Taub R, Neff GW, et al. Resmetirom for nonalcoholic fatty liver disease: A randomized, double-blind, placebo-controlled phase 3 trial. Nat Med 2023;29:2919-2928.
- Karim G, Bansal MB. Resmetirom: An orally administered, smallmolecule, liver-directed, β-selective THR agonist for the treatment of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. touchREV Endocrinol 2023;19:60-70.
- Fraile JM, Palliyil S, Barelle C, et al. Non-alcoholic steatohepatitis (NASH) – a review of a crowded clinical landscape, driven by a complex disease. Drug Des Devel Ther 2023;15:3997-4009.
