Effective Date

Date of Origin 

01-01-2025            

03-01-2024

Rezdiffra™

(resmetirom)

Tablet

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). This indication is approved under accelerated approval based on improvement of NASH and fibrosis. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Limitations of Use: Avoid use of Rezdiffra in patients with decompensated cirrhosis.

1

Metabolic dysfunction-associated steatotic liver disease (MASLD)/Metabolic dysfunction-associated steatohepatitis (MASH)

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously termed non-alcoholic fatty liver disease (NAFLD), is defined as steatotic liver disease (SLD) in the presence of one or more cardiometabolic risk factor(s) and the absence of harmful alcohol intake. SLD occurs when your body begins storing fat in your liver. Some fat in your liver is normal, but when more than 5 to 10% of the liver's weight is fat, it is classified as steatosis. MASLD and alcoholic liver disease (ALD), (alcohol intake >50 g/day for females and >60 g/day for males) comprise the most common causes of SLD. A new category, requiring further characterization, termed MetALD, describes those with MASLD who consume greater amounts of alcohol (20-50 g/day for females and 30-60 g/day for males, respectively), but do not meet the criteria for ALD. The history of alcohol consumption is an important factor as the current drinking pattern may not necessarily reflect previous drinking behavior. Importantly, despite sharing the same prevalence of cardiometabolic risk factors, MetALD is associated with a higher risk of all-cause mortality, underpinning MetALD as a distinct subclass of SLD with poorer prognosis. Therefore, diagnostic and treatment recommendations provided for MASLD cannot be extended to the MetALD population.(2,5,10,12)

The spectrum of MASLD includes steatosis, metabolic dysfunction-associated steatohepatitis (MASH, previously NASH), fibrosis, cirrhosis and MASH-related hepatocellular carcinoma (HCC). With MASH, fat buildup progresses to inflammation, then tissue damage and scarring (fibrosis). Metabolic dysfunction-associated steatohepatitis (MASH) is inflammation of the liver caused by excess fat cells in it (steatotic liver disease). MASH is characterized by histological features of hepatocellular ballooning and lobular inflammation. Chronic inflammation causes progressive liver damage. MASL refers to the presence of MASLD in the absence of steatohepatitis.(2,10,12)

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most common chronic liver disease, and its prevalence will likely continue to rise. Often, MASLD has no symptoms. When symptoms do occur, they may include fatigue, weakness, weight loss, loss of appetite, nausea, abdominal pain, spider-like blood vessels, yellowing of the skin and eyes (jaundice), itching, fluid buildup and swelling of the legs (edema) and abdomen (ascites), and mental confusion. MASLD is initially suspected if blood tests show high levels of liver enzymes with an absence of chronic alcohol intake. However, other liver diseases are first ruled out through additional tests (e.g., Wilson's disease, hepatitis).(2,3,4) 

The presence of MASLD is tightly linked to type 2 diabetes (T2D), obesity and other cardiometabolic risk factors. Studies suggest that one-third to two-thirds of people with type 2 diabetes have MASLD. Research suggests that MASLD is present in up to 75% of people who are overweight and in more than 90% of people who have severe obesity. MASLD is associated with an increased risk of cardiovascular events, chronic kidney disease, hepatic and extrahepatic malignancies, and liver-related outcomes, including liver failure and hepatocellular carcinoma (HCC).(2,10,12) 

The following are the adult cardiometabolic risk factors (at least 1 out of 5) in the definition of MASLD:(10,12)

• Weight (BMI or WC)
  • Overweight or Obesity Body mass index(BMI):  Greater than or equal to 25 kg/m^2 (greater than or equal to 23 kg/m^2 in people of Asian ethnicity) OR
  • Waist Circumference (WC): 94 cm (male), 80 cm (female) or ethnicity adjusted equivalent
• Prediabetes or type 2 diabetes:
  • Fasting serum glucose greater than or equal to 5.6 mmol/L (100mg/dL) OR
  • 2-hour post load glucose levels greater than or equal to 7.8 mmol/L (greater than or equal to 140 mg/dL) OR
  • HbA1c greater than or equal to 5.7% OR
  • Type 2 diabetes OR
  • Treatment for type 2 diabetes
• Plasma triglycerides:
  • Greater than or equal to 1.7 mmol/L (greater than or equal to 150 mg/dL) OR
  • Lipid-lowering treatment
• HDL cholesterol:
  • Less than or equal to 1.0 mmol/L (less than or equal to 39 mg/dL) in men and less than or equal to 1.3 mmol/L (less than or equal to 50 mg/dL) in women OR
  • Lipid-lowering treatment
• Blood pressure:
  • Greater than or equal to 130/85 mmHG OR
  • Specific antihypertensive drug treatment

The 2021 AACE and 2023 AASLD practice guidelines recommend the following:(2,4)

• Clinicians should consider persons with obesity and/or features of metabolic syndrome, those with prediabetes or type 2 diabetes (T2D), and those with hepatic steatosis on any imaging study and/or persistently elevated plasma aminotransferase levels (over 6 months) to be “high risk” and screen for NAFLD and advanced fibrosis. Metabolic syndrome is defined as any 3 of the following: obesity, high blood pressure, high blood triglycerides, low levels of HDL cholesterol and insulin resistance.

Initial evaluation in persons with suspected or incidental finding of hepatic steatosis on imaging should include investigations to exclude competing causes for hepatic steatosis and liver disease (e.g., hepatitis B and C serology, antimitochondrial antibodies, antinuclear antibodies, anti–smooth muscle antibodies, serum ferritin, alpha 1 antitrypsin, and evaluation for metabolic syndrome). It is important to note that normal values provided by most laboratories are higher than what should be considered normal in MASLD, in which a true normal alanine aminotransferase (ALT) ranges from 29 to 33 U/L in men and from 19 to 25 U/L in women.(2,4,5)

The American Gastroenterology Association guidelines recommend the following best practice advice in the diagnosis of MASH/MASLD:(7) 

• A Fibrosis 4 Index score <1.3 is associated with strong negative predictive value for advanced hepatic fibrosis and may be useful for exclusion of advanced hepatic fibrosis in patients with NAFLD/MASLD.
• A combination of 2 or more NITs combining serum biomarkers and/or imaging-based biomarkers is preferred for staging and risk stratification of patients with NAFLD/MASLD whose Fibrosis 4 Index score is >1.3.
• Use of NITs in accordance with manufacturer’s specifications (e.g., not in patients with ascites or pacemakers) can minimize risk of discordant results and adverse events.
• NITs should be interpreted with context and consideration of pertinent clinical data (e.g., physical examination, biochemical, radiographic, and endoscopic) to optimize positive predictive value in the identification of patients with advanced fibrosis.
• Liver biopsy should be considered for patients with NIT results that are indeterminate or discordant; conflict with other clinical, laboratory, or radiologic findings; or when alternative etiologies for liver disease are suspected.
• Serial longitudinal monitoring using NITs for assessment of disease progression or regression may inform clinical management (i.e., response to lifestyle modification or therapeutic intervention).
• Patients with MASLD and NITs results suggestive of advanced fibrosis (F3) or cirrhosis (F4) should be considered for surveillance of liver complications (e.g., hepatocellular carcinoma screening and variceal screening per Baveno criteria). Patients with MASLD and NITs suggestive of advanced hepatic fibrosis (F3) or (F4), should be monitored with serial liver stiffness measurement; vibration controlled transient elastography; or magnetic resonance elastography, given its correlation with clinically significant portal hypertension and clinical decompensation.

NITs (non-invasive tests) derived from clinical variables can estimate of the presence of advanced fibrosis. Several have been developed (e.g., FIB-4, NAFLD/MASLD Fibrosis Score, AST Platelet Ratio Index); however, FIB-4 is the most validated. FIB-4 is calculated using a simple algorithm based upon age, ALT, AST, and platelet count and outperforms other calculations in its ability to identify patients with a low probability of advanced fibrosis. The FIB-4 index can be calculated from age and three parameters obtained in routine laboratory assessments: alanine aminotransferase (ALT), aspartate aminotransferase (AST), and platelet count. A change in FIB-4 status category from low risk (<1.3) to intermediate risk (1.3–2.67) to high risk (>2.67) may be used to assess clinical progression. Although FIB-4 is statistically inferior to other serum-based fibrosis markers such as the Enhanced Liver Fibrosis (ELF) panel, FIBROSpect II, and imaging-based elastography methods to detect advanced fibrosis, FIB-4 is still recommended as a first-line assessment for general practitioners and endocrinologists based on its simplicity and minimal added cost.(2,6,7)

Those who may have a moderate or high risk of advanced disease based on FIB-4 should undergo secondary risk assessment. Vibration-controlled transient elastography (VCTE) (e.g., FibroScan) is the most commonly used method to assess liver stiffness and can be used to exclude significant hepatic fibrosis. Magnetic resonance elastography (MRE) is more sensitive than VCTE in the detection of fibrosis stage greater than 2 and is considered to be the most accurate noninvasive imaging-based biomarker of fibrosis in NAFLD/MASLD. Although MRE is not a first-line approach to risk stratification in a patient with NAFLD/MASLD, it can be an important tool if clinical uncertainty exists, if there is a need for concomitant cross-sectional imaging, or when other elastography techniques are unavailable. Among patients with cirrhosis, a baseline liver stiffness measure (LSM) by MRE predicts future risk of incident hepatic decompensation and death. An LSM by MRE greater than or equal to kPa is suggestive of cirrhosis. Controlled Attenuation Parameter (CAP) as a point-of-care technique may also be used to identify steatosis. A liver biopsy is the optimal approach to confirm the diagnosis and stage of the severity of liver fibrosis. However, it is recognized that this may not be feasible or acceptable to several individuals.(2,4,7)

Incorporating pharmacological treatment with agents known to reverse NASH/MASH is crucial to more effectively prevent progression to cirrhosis. Treatment guidelines for individuals with type 2 diabetes (T2D) and NASH/MASH focus on managing hyperglycemia and/or obesity alongside NASH/MASH, particularly if clinically significant fibrosis (stage F2 or higher) is present, to avert the development of cirrhosis. Some medications that are effective for treating T2D and NASH/MASH, such as pioglitazone and GLP-1 receptor agonists (RAs), also contribute to reducing cardiovascular disease (CVD), which is the leading cause of death in this group. Two antidiabetic drugs, pioglitazone and GLP-1 RAs, have shown safety and effectiveness in reversing NASH/MASH in individuals with obesity, prediabetes, or T2D, though they are not yet FDA approved for this purpose. While weight loss can reverse NASH/MASH, typically in relation to the extent of weight loss, the ability to halt fibrosis progression is less consistent and can vary significantly among individuals.(2,4)

The 2024 European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD) and European Association for the Study of Obesity (EASO) guidelines suggest in adults with MASLD, lifestyle modification which includes weight loss, dietary changes, physical exercise and discouraging alcohol consumption. In addition, they recommend optimal management of comorbidities, including use of incretin-based therapies (e.g., semaglutide, tirzepatide) for T2D or obesity, if indicated. Bariatric surgery is also an option in individuals with MASLD and obesity. If locally approved and dependent on the label, adults with non-cirrhotic MASH and significant liver fibrosis (stage greater than or equal to 2) should be considered for a MASH-targeted treatment with resmetirom, which demonstrated histological effectiveness on steatohepatitis and fibrosis with an acceptable safety and tolerability profile. No MASH-targeted pharmacotherapy can currently be recommended for the cirrhotic stage. Management of MASH-related cirrhosis includes adaptations of metabolic drugs, nutritional counselling, surveillance for portal hypertension and HCC, as well as liver transplantation in decompensated cirrhosis.(10)

While an initial study with liraglutide indicated a histological benefit in MASH, drugs that are being developed for MASH now include semaglutide, and dual GLP1-GIP (e.g., tirzepatide), dual GLP1-glucagon (e.g., cotadutide, survodutide, efinopegdutide) or triple GLP1-GIP-glucagon (e.g., retatrutide) agonists. The largest available trial on semaglutide in MASH (vs. placebo over an 18-month treatment period) demonstrated resolution of steatohepatitis but no fibrosis improvement. A large registrational, phase III study with semaglutide is ongoing. Tirzepatide (GLP1/GIP RA) has been shown to significantly reduce both liver and visceral fat in those with T2D, in association with major weight loss (comparable to bariatric surgery), and promising results on steatohepatitis resolution from a phase II study in MASH have been communicated.(10)

Efficacy

Resmetirom is a once daily, oral, thyroid hormone receptor (THR)-beta selective agonist designed to target key underlying causes of NASH in the liver. Hypothyroidism is associated with NAFLD/NASH; specifically, intrahepatic hypothyroidism drives lipotoxicty in preclinical models. Agonists of thyroid hormone receptor (THR)-beta, which is primarily found in the liver, can promote lipophagy, mitochondrial biogenesis and mitophagy, stimulating increased hepatic fatty acid β-oxidation, and thereby decreasing the burden of lipotoxic lipids, while promoting low-density lipoprotein (LDL) uptake and favorable effects on lipid profiles.(8)

The efficacy of Rezdiffra was evaluated based on an efficacy analysis at Month 12 in Trial 1 (NCT03900429), a 54-month, randomized, double-blind, placebo-controlled trial. Enrolled patients had metabolic risk factors and a baseline or recent liver biopsy showing NASH with fibrosis stage 2 or 3 and a NAFLD Activity Score (NAS) of at least 4. Efficacy determination was based on the effect of Rezdiffra on resolution of steatohepatitis without worsening of fibrosis and one stage improvement in fibrosis without worsening of steatohepatitis, on post-baseline liver biopsies collected at 12 months. The month 12 analysis included 888 F2 and F3 (at eligibility) patients randomized 1:1:1 to receive placebo (n = 294), Rezdiffra 80 mg once daily (n = 298), or Rezdiffra 100 mg once daily (n = 296), in addition to lifestyle counseling on nutrition and exercise. Patients were on stable doses of medications for diabetes, dyslipidemia, and hypertension.(1) 

Demographic and baseline characteristics were balanced between treatment and placebo groups. Overall, the median age of patients at baseline was 58 (51 to 65) years, 56% were female, 21% were Hispanic, 89% were White, 3% were Asian, and 2% were Black or African American. Median body mass index (BMI) was 35 (31 to 40) kg/m2 and median body weight was 99 (85 to 114) kg.(1)

Overall, 966 patients formed the primary analysis population (322 in the 80-mg resmetirom group, 323 in the 100-mg resmetirom group, and 321 in the placebo group). NASH resolution with no worsening of fibrosis was achieved in 25.9% of the patients in the 80-mg resmetirom group and 29.9% of those in the 100-mg resmetirom group, as compared with 9.7% of those in the placebo group. Fibrosis improvement by at least one stage with no worsening of the NAFLD activity score was achieved in 24.2% of the patients in the 80-mg resmetirom group and 25.9% of those in the 100-mg resmetirom group, as compared with 14.2% of those in the placebo group. The change in low-density lipoprotein cholesterol levels from baseline to week 24 was -13.6% in the 80-mg resmetirom group and -16.3% in the 100-mg resmetirom group, as compared with 0.1% in the placebo group. Both the 80-mg dose and the 100-mg dose of resmetirom were superior to placebo with respect to NASH resolution and improvement in liver fibrosis by at least one stage.(1,9)

Safety

Resmetirom does not have any contraindications.(1)

1

Rezdiffra prescribing information. Madrigal Pharmaceuticals, Inc. March 2024.

2

Rinella, Mary E, Neuschwander-Tetri, Brent A, et al. AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology 77(5):p 1797-1835, May 2023. DOI: 10.1097/HEP.0000000000000323.

3

Nash causes & risk factors. American Liver Foundation. (2023, November 1). https://liverfoundation.org/liver-diseases/fatty-liver-disease/nonalcoholic-steatohepatitis-nash/nash-causes-risk-factors/.

4

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 May;28(5):528-562. doi: 10.1016/j.eprac.2022.03.010.

5

U.S. Department of Health and Human Services. (2023). Drinking levels defined. National Institute on Alcohol Abuse and Alcoholism. https://www.niaaa.nih.gov/alcohol-health/overview-alcohol-consumption/moderate-binge-drinking.

6

Blanco-Grau A, et al., Assessing Liver Fibrosis Using the FIB4 Index in the Community Setting. Diagnostics (Basel). 2021 Nov 29;11(12):2236. doi: 10.3390/diagnostics11122236.

7

Wattacheril J, Abdelmalek MF, Lim JK, Sanyal AJ. AGA Clinical Practice Update on the Role of noninvasive biomarkers in the evaluation and management of nonalcoholic fatty liver Disease: Expert review. Gastroenterology. 2023;165(4):1080-1088. doi:10.1053/j.gastro.2023.06.013.

8

Karim G, Bansal MB. Resmetirom: An Orally Administered, Small Molecule, Liver-directed, β-selective THR Agonist for the Treatment of Non-alcoholic Fatty Liver Disease and Non-alcoholic Steatohepatitis. touchREV Endocrinol. 2023 May;19(1):60-70. doi: 10.17925/EE.2023.19.1.60.

9

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/NEJMoa2309000.

10

Tacke F, Horn P, Wong VWS, et al. EASL–EASD–EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). Journal of Hepatology. Published online June 1, 2024. doi:10.1016/j.jhep.2024.04.031.

11

Clinicaltrials.gov. A Phase 3 Study to Evaluate the Efficacy and Safety of MGL-3196 (Resmetirom) in Patients With NASH and Fibrosis (MAESTRO-NASH). Published 2019. https://clinicaltrials.gov/study/NCT03900429.

12

Kanwal F, Neuschwander-Tetri BA, Loomba R, Rinella ME. 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. 2023;79(5):1212-1219. doi:10.1097/hep.0000000000000670.

Rezdiffra

resmetirom

100 MG ; 60 MG ; 80 MG

M ; N ; O ; Y

N

Rezdiffra

resmetirom

60 MG

30

Tablets

30

DAYS

Rezdiffra

resmetirom

80 MG

30

Tablets

30

DAYS

Rezdiffra

resmetirom

100 MG

30

Tablets

30

DAYS

Rezdiffra

resmetirom

100 MG ; 60 MG ; 80 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Rezdiffra

resmetirom

60 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Rezdiffra

resmetirom

100 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Rezdiffra

resmetirom

80 MG

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PA

Initial Evaluation

Target Agent(s) will be approved when ALL the following are met:

1. The patient has a diagnosis of noncirrhotic nonalcoholic steatohepatitis (NASH) or metabolic dysfunction associated steatohepatitis (MASH) (medical records required) AND 
2. The patient has stage F2 or F3 fibrosis as confirmed by BOTH of the following (prior to therapy with the requested agent):
   1. A FIB-4 score consistent with stage F2 or F3 fibrosis adjusted for age AND
   2. The patient has ONE of the following:
      1. A liver biopsy within the past 2 years OR
      2. Vibration-controlled transient elastography (VCTE, e.g., Fibroscan) OR
      3. Enhanced liver fibrosis (ELF) score OR
      4. Magnetic resonance elastography (MRE) AND
3. If the patient has an FDA labeled indication, then ONE of the following: 
   1. The patient’s age is within FDA labeling for the requested indication for the requested agent OR
   2. There is support for using the requested agent for the patient’s age for the requested indication AND
4. ONE of the following:
   1. If the patient's sex is female then the patient's alcohol consumption is less than 20 grams/day (Note: one standard alcoholic drink contains roughly 14 grams of pure alcohol, which is found in 12 ounces of regular beer, 5 ounces of wine, or 1.5 ounces of distilled spirits) OR
   2. If the patient's sex is male then the patient's alcohol consumption is less than 30 grams/day (Note: one standard alcoholic drink contains roughly 14 grams of pure alcohol, which is found in 12 ounces of regular beer, 5 ounces of wine, or 1.5 ounces of distilled spirits) AND
5. The patient is being monitored and/or treated for any comorbid conditions (e.g., cardiovascular disease, diabetes, dyslipidemia, hypertension) AND
6. BOTH of the following:
   1. The patient is currently on a weight management regimen of a low-calorie diet, increased physical activity, and behavioral modifications AND
   2. The patient will continue the weight management regimen in combination with the requested agent AND
7. The patient does NOT have ANY of the following:
   1. Decompensated cirrhosis AND
   2. Moderate to severe hepatic impairment (Child-Pugh Class B or C) AND
   3. Any other liver disease (e.g., Wilson's disease, hepatocellular carcinoma, hepatitis) AND
8. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., hepatologist, gastroenterologist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
9. The patient does NOT have any FDA labeled contraindications to the requested agent

Length of Approval:  12 months

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.

Renewal Evaluation

Target Agent(s) will be approved when ALL of the following are met:

1. The patient has been previously approved for the requested agent through the plan’s Prior Authorization process [Note: patients not previously approved for the requested agent will require initial evaluation review] AND
2. ONE of the following:
   1. If the patient's sex is female then the patient's alcohol consumption is less than 20 grams/day (Note: one standard alcoholic drink contains roughly 14 grams of pure alcohol, which is found in 12 ounces of regular beer, 5 ounces of wine, or 1.5 ounces of distilled spirits) OR
   2. If the patient's sex is male then the patient's alcohol consumption is less than 30 grams/day (Note: one standard alcoholic drink contains roughly 14 grams of pure alcohol, which is found in 12 ounces of regular beer, 5 ounces of wine, or 1.5 ounces of distilled spirits) AND
3. BOTH of the following:
   1. The patient is currently on a weight management regimen of a low-calorie diet, increased physical activity, and behavioral modifications AND
   2. The patient will continue the weight management regimen in combination with the requested agent AND
4. The patient does NOT have ANY of the following:
   1. Decompensated cirrhosis AND
   2. Moderate to severe hepatic impairment (Child-Pugh Class B or C) AND
   3. Any other liver disease (e.g., Wilson's disease, hepatocellular carcinoma, hepatitis) AND
5. The patient has had clinical benefit with the requested agent AND
6. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., hepatologist, gastroenterologist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
7. The patient does NOT have any FDA labeled contraindications to the requested agent

Length of Approval:  12 months

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.

Quantity limit for the Target Agent(s) will be approved when ONE of the following is met:

1. The requested quantity (dose) does NOT exceed the program quantity limit OR
2. The requested quantity (dose) exceeds the program quantity limit AND ONE of the following:
   1. BOTH of the following:
      1. The requested agent does NOT have a maximum FDA labeled dose for the requested indication AND
      2. There is support for therapy with a higher dose for the requested indication OR
   2. BOTH of the following:
      1. The requested quantity (dose) does NOT exceed the maximum FDA labeled dose for the requested indication AND
      2. There is support for why the requested quantity (dose) cannot be achieved with a lower quantity of a higher strength that does NOT exceed the program quantity limit

Length of Approval:  up to 12 months