What are the latest updates and guideline recommendations in MASLD/MASH?

Background
Occurring in 25 to 30% of individuals in the general population, non-alcoholic fatty liver disease (NAFLD) has been renamed as metabolic dysfunction-associated steatotic liver disease (MASLD) and non-alcoholic steatohepatitis (NASH) as metabolic-associated steatohepatitis (MASH).^1-5 The nomenclature update by the American Association for the Study of Liver Diseases (AASLD) is reported to provide a near total overlap (99%) between populations based on MASLD and NAFLD definitions, with previous recommendations from the AASLD on clinical assessment and management still considered applicable.^4,5

The first medication for the treatment of MASH was recently approved by the Food and Drug Administration (FDA).⁶ Resmetirom (Rezdiffra^®), a thyroid hormone receptor beta agonist, received accelerated approval from the FDA in March 2024 for the treatment of metabolic-associated steatohepatitis (MASH) in noncirrhotic moderate to advanced liver fibrosis (stages F2 to F3) based on 12 -liver biopsy findings.^6,7 The approval of resmetirom was based on clinical data from the MAESTRO NASH trial with safety data from the MAESTRO-NAFLD-1 trial.^6,8 Based on this approval, the AASLD has issued new guidance on resmetirom therapy, which serves as an update to the 2023 AASLD practice guidance.^6,9 This FAQ aims to summarize this recent guidance and the MAESTRO NASH trial that led to resmetirom’s approval.

Practice Recommendations
General recommendations for management of MASLD/MASH involve optimizing the management of comorbid conditions (e.g., hypertension, hyperlipidemia, obesity, cardiovascular disease, type 2 diabetes mellitus), and incorporating lifestyle modifications.^6,9,10 For pharmacologic treatment of MASLD/MASH, previous guidance from the AASLD acknowledged that in the absence of approved therapies for MASLD/MASH, medications with liver benefits such as vitamin E, pioglitazone, liraglutide, semaglutide, tirzepatide, and sodium glucose cotransporter 2 (SGLT2) inhibitors could be considered for off-label use in appropriate patients.^6,9 With the approval of resmetirom, the AASLD has issued updated guidance on whom to treat, and how to monitor treatment response and safety.⁶

Although resmetirom was studied in the MAESTRO-NASH trial in patients with biopsy-confirmed MASH, the labeling for resmetirom does not require liver biopy to confirm fibrosis before initiating therapy.^6,8 In light of this, the AASLD states that patient eligibility criteria for resmetirom should include evidence of F2 to F3 fibrosis either from either noninvasive liver disease testing (preferably using imaging), or biopsy without evidence of concomitant, histologically active autoimmune liver disease.⁶ Upon initiation of resmetirom, the recommended dosage is 100 mg/day in patients weighing ≥100 kg, or 80 mg/day in patients weighing <100 kg. Dosage adjustments are recommended in patients receiving concomitant treatment with a cytochrome P450 (CYP) isoenzyme 2C8 inhibitor (e.g., clopidogrel). Resmetirom can be used concomitantly with statin therapy; however, there are maximum daily dose recommendations for statins during resmetirom therapy (e.g., atorvastatin 40 mg/daily, pravastatin 40 mg/daily, rosuvastatin 20 mg/daily, simvastatin 20 mg/daily).

Before initiating resmetirom, the AASLD recommends assessing thyroid function, and correcting hyperthyroidism or hypothyroidism before starting treatment.⁶ Resmetirom use should be avoided in patients with compensated/decompensated cirrhosis, concomitant uncontrolled active liver disease (e.g, autoimmune hepatitis, primary biliary cholangitis), in patients with ongoing alcohol consumption (>20 g/day for women or >30 g/day for men), or in patients with symptomatic gallstone-related conditions such as acute cholecystitis. Hepatic function should be monitored during treatment, and thyroid function in patients with known thyroid disease. The drug should be discontinued if hepatotoxicity occurs.

Because the MAESTRO NASH trial is ongoing and efficacy data for resmetirom are based on 12-month liver biopsy findings, the AASLD states that the decision to continue treatment beyond 12 months should be based on improvement, worsening, or stabilization of disease.^6,8 The AASLD recommends continuing resmetirom beyond 12 months in patients with significant fibrosis improvement.⁶ In patients who met initial treatment criteria using liver stiffness measurements (LSM), repeat LSM at 12 months are recommended; a vibration-controlled transient elastography (VCTE) improvement of ≥ 25% or magnetic resonance elastography (MRE) improvement of ≥ 20% from baseline represents clinically meaningful disease improvement. Remestirom discontinuation should be considered in patients with worsening of liver disease at 12 months. For patients without clear improvement or disease worsening, a more holistic assessment is warranted, taking into account the baseline fibrosis status, potential benefit of slowing or stabilizing fibrosis, comorbid conditions, concomitant therapy, changes in noninvasive liver disease assessments (NILDA) and liver function tests, and adverse effects.

MAESTO-NASH Clinical Trial
The MAESTRO-NASH trial is an ongoing randomized, double-blind, placebo-controlled trial that reported on MASH resolution and fibrosis improvement in 966 patients at 52-weeks.⁸ At 54 months, the study will also report on the time to a composite clinical outcome event, consisting of all-cause mortality, liver transplant, and significant hepatic events, including hepatic decompensation events.¹¹ Patients in MAESTRO-NASH were randomized to remetirom 100 mg daily (n=323), resmetirom 80 mg daily (n=322), or placebo therapy (n=321).⁸ Eligibility criteria for MAESTRO-NASH included ≥ 3 of 5 metabolic risk factors and stage 1b, 2, or 3 liver fibrosis and biopsy-confirmed MASH. Patients could not have a history of bariatric or intestinal surgery within 5 years, had to have a stable weight ( 20 g/day for women or > 30 g/day for men), HbA1c of > 9%, and other causes of chronic liver disease besides MASH. Baseline patient characteristics were similar across treatment groups; the majority of patients had concomitant hypertension (78.1%), dyslipidemia (71.3%), and type 2 diabetes mellitus (67%). At baseline, biopsies indicated that 83.5% of patients had an NAFLD activity score ≥ 5, 5.1% had F1B fibrosis, 33% had F2, and 61.9% had F3.

The 2 primary endpoints were MASH resolution (achieving a hepatocellular ballooning score of 0 or 1, lobular inflammation score of 0 or 1, and reduction in NAFLD activity score by ≥ 2 points) with no worsening of fibrosis, and fibrosis improvement ≥ 1 stage with no worsening of the NAFLD activity score at 52 weeks.⁸ At 52 weeks, MASH resolution with no worsening of fibrosis was achieved in a greater proportion of patients receiving resmetirom versus placebo (25.9% in the 80-mg group, 29.9% in the 100-mg group, and 9.7% in the placebo group; p<0.001 each placebo comparison). At 52 weeks, fibrosis was also improved by ≥ 1 stage with no worsening of the NAFLD activity score in a greater proportion of patients receiving resmetirom versus placebo (24.2% in the 80-mg group, 29.9% in the 100-mg group, and 14.2% in the placebo group; p<0.001 each placebo comparison). Levels of low-density lipoprotein (LDL) cholesterol levels were also decreased from baseline by 24 weeks in patients who received resmetirom (-13.6% in the 80-mg group and -16.3% in the 100-mg group), and were not decreased in patients who received placebo (0.1%; p<0.001 for each resmetirom comparison).

Diarrhea and nausea were the most common adverse events in MAESTRO-NASH, which occurred with initiation of resmetirom.⁸ Diarrhea occurred for a median of 15 to 20 days. About half of the cases of diarrhea were considered worsening cases, or intermittent/loose stools. No cases of drug-induced liver injury were reported. By week 52, 6.8% of patients in the 100 mg resmetirom group had discontinued therapy due to adverse events, 1.9% in the 80 mg group, and 2.2% in the placebo group.

Conclusion

Resmetirom has recently become FDA-approved for the treatment of adults with noncirrhotic MASH with moderate to advanced liver fibrosis (stages F2 to F3), in conjunction with diet and exercise. With this new drug approval, the AASLD has issued new practice guidance on resmetirom therapy for MASLD, which serves as an update to the 2023 AASLD practice guidance on the clinical assessment and management of NAFLD. Additional evidence may warrant future changes in these recommendations as more data on resmetirom becomes available.

References

1. Browning JD, Szczepaniak LS, Dobbins R, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology. 2004;40(6):1387-1395. doi:10.1002/hep.20466
2. Younossi ZM, Koenig AB, Abdelatif D, et al. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64(1):73-84. doi:10.1002/hep.28431
3. Le MH, Devaki P, Ha NB, et al. Prevalence of non-alcoholic fatty liver disease and risk factors for advanced fibrosis and mortality in the United States. PLoS One. 2017;12(3):e0173499. Published 2017 Mar 27. doi:10.1371/journal.pone.0173499
4. Rinella ME, Lazarus JV, Ratziu V, et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. Ann Hepatol. 2024;29(1):101133. doi:10.1016/j.aohep.2023.101133
5. Kanwal F, Neuschwander-Tetri BA, Loomba R, et al. Metabolic dysfunction-associated steatotic liver disease: Update and impact of new nomenclature on the American Association for the Study of Liver Diseases practice guidance on nonalcoholic fatty liver disease. Hepatology. 2024;79(5):1212-1219. doi:10.1097/HEP.0000000000000670
6. Chen VL, Morgan TR, Rotman Y, et al. Resmetirom therapy for metabolic dysfunction-associated steatotic liver disease: October 2024 updates to AASLD Practice Guidance. Hepatology. Published online October 18, 2024. doi:10.1097/HEP.0000000000001112
7. Rezdiffra [package insert]. West Conshohocken, PA: Madrigal Pharmaceuticals; 2024.
8. 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(6):497-509. doi:10.1056/NEJMoa2309008
9. Rinella ME, Neuschwander-Tetri BA, Siddiqui MS, et al. AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology. 2023;77(5):1797-1835. doi:10.1097/HEP.0000000000000323
10. Cusi K, Isaacs S, Barb D, et al. 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 (AASLD). Endocr Pract. 2022;28(5):528-562. doi:10.1016/j.eprac.2022.03.010
11. Clinicaltrials.gov. National Institutes of Health; 2024. Accessed October 18, 2024. https://clinicaltrials.gov/

Prepared by:
Christie Denton, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

October 2024

The information presented is current as October 18, 2024. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.