Effective Date

Date of Origin 

10-01-2024            

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

Nonalcoholic fatty liver disease (NAFLD) and Nonalcoholic steatohepatitis (NASH)    

Nonalcoholic fatty liver disease (NAFLD) is the accumulation of extra fat in liver cells that is not caused by alcohol. It is normal for the liver to contain some fat. However, if more than 5% - 10% percent of the liver’s weight is fat, then it is called "fatty liver" or steatosis. The more severe form of NAFLD is called nonalcoholic steatohepatitis (NASH). Nonalcoholic steatohepatitis (NASH), more likely to progress to advanced stages of fibrosis, is characterized by the presence of active hepatocyte injury (ballooning) and inflammation in addition to steatosis. The progression of NASH with fibrosis can lead to cirrhosis, liver cancer, liver failure, and increased cardiovascular risk.(2,3,4)

About 100 million individuals in the United States are estimated to have nonalcoholic fatty liver (NAFL) with it being the most common form of liver disease in children, more than doubling in prevalence over the past 20 years. Of those with NAFLD, about 20 percent have NASH (5% of adults in the U.S.). NASH has rapidly emerged as a leading cause of liver transplantation in the United States. NAFLD is the most common cause of chronic liver disease in children in the United States. Researchers estimate that close to 10 percent of U.S. children ages 2 to 19 years old (about six million children) have NAFLD. It’s become more common in children in recent decades, in part due to the growing epidemic of childhood obesity. The majority of children with NAFLD have simple fatty liver typically don’t develop liver complications. However, compared with adults who develop NAFLD, children with NAFLD are more likely to have NASH and related complications or liver disease as adults.(2,3)

The exact cause of nonalcoholic fatty liver disease is unknown. Patients are at higher risk to develop NAFLD or NASH if they have the following:(3)

• Overweight or are obese
• Type 2 diabetes or pre-diabetes
• Elevated triglycerides, LDL or low HDL
• Hypertension

NASH is more likely to occur in adults who:(3)

• Are older (although also diagnosed in children)
• Have type 2 diabetes
• Are Hispanic or Asian
• Have high blood pressure
• Are post-menopausal women
• Are obese with body fat concentrated around the waist
• Have obstructive sleep apnea

Nonalcoholic fatty liver disease often has no symptoms. When symptoms 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 build up and swelling of the legs (edema) and abdomen (ascites), and mental confusion. Nonalcoholic fatty liver disease is initially suspected if blood tests show high levels of liver enzymes. However, other liver diseases are first ruled out through additional tests (e.g., Wilson's disease).(2)

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.

The diagnosis of NAFLD is based on the following:(2)

• Presence of hepatic steatosis
• Lack of significant alcohol consumption (defined as ongoing or recent alcohol consumption of >21 standard drinks [1 drink = 14 g of pure alcohol]/week for men and >14 standard drinks/week for women)
• Exclusion of other liver diseases (e.g., Wilson's disease, hepatitis). 

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 NAFLD, 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 NASH/NAFLD:(7) 

• NITs can be used for risk stratification in the diagnostic evaluation of patients with NAFLD.
• 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.
• 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 whose Fibrosis 4 Index score is >1.3.
• Use of NITs in accordance with manufacturer’s specifications (eg, 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 (eg, 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 (ie, response to lifestyle modification or therapeutic intervention).
• Patients with NAFLD and NITs results suggestive of advanced fibrosis (F3) or cirrhosis (F4) should be considered for surveillance of liver complications (eg, hepatocellular carcinoma screening and variceal screening per Baveno criteria). Patients with NAFLD 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 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. Serum AST levels are often used clinically to identify patients with liver disease but can be normal in patients with diabetes, NASH, and advanced hepatic fibrosis. Of note, although AST levels are neither sensitive nor specific for the identification of NAFLD/NASH with advanced fibrosis, intermittently (i.e., fluctuating above and below normal thresholds) or chronically (greater than or equal to 6 to 12 months) elevated ALT or AST above a threshold of 30 U/L may suggest the presence of chronic liver injury. These thresholds are below the upper reference range values provided by most clinical laboratories, which is likely related to the lack of exclusion of patients with risks for NAFLD from reference populations.(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. Although MRE is not a first-line approach to risk stratification in a patient with NAFLD, 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.(2,4,7)

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. Therefore, in high-risk populations (i.e., those with obesity and T2D), pharmacologic therapy to treat obesity or diabetes may also be considered in the presence of elevated plasma aminotransferase levels and/or FIB-4 scores of >1.3 and confirmatory imaging (i.e., VCTE and MRE) or proprietary fibrosis biomarkers, such as the ELF test when suggestive of clinically significant liver fibrosis, if imaging not available.(2,4,7)

Adding pharmacologic therapy with agents proven to reverse NASH is warranted to prevent progression to cirrhosis more effectively. Treatment recommendations for persons with T2D and NASH are centered on the dual purpose of treating hyperglycemia and/or obesity and NASH, especially if clinically significant fibrosis (stage, greater than or equal to F2) is present, to prevent development of cirrhosis. Some medications effective to treat T2D and NASH (pioglitazone and GLP-1 RAs) also reduce cardiovascular disease (CVD), the leading cause of death in this population. Two antidiabetic agents have proven to be safe and effective, but not FDA approved, to reverse NASH in persons with obesity, prediabetes, or T2D: pioglitazone and GLP-1 RA. While weight loss alone may reverse NASH, usually in proportion to the magnitude of weight loss, halting fibrosis progression is less predictable and highly variable among individuals.(2,4)

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

Institute for Clinical and Economic Review. Resmetirom and Obeticholic Acid for Non-Alcoholic Steatohepatitis (NASH), May 2023, icer.org/wp-content/uploads/2022/10/NASH-Final-Report_For-Publication_053023.pdf.

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.

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

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

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) with moderate to advanced liver fibrosis (medical records required) AND ALL of the following: 
   1. The patient has stage F2 or F3 fibrosis AND
   2. ONE of the following:
      1. The patient is less than or equal to 65 years of age and has a FIB-4 score greater than 1.3 OR
      2. The patient is greater than 65 years of age and has a FIB-4 score greater than 2.0 AND
   3. The patient has ONE of the following:
      1. A liver biopsy within the past 2 years OR
      2. At least TWO of the following: 
         1. Vibration-controlled transient elastography (VCTE, e.g., Fibroscan) score greater than 8.1
         2. Enhanced liver fibrosis (ELF) score greater than 7.7
         3. Magnetic resonance elastography (MRE) score greater than 2.6 AND
2. 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
3. The patient is being monitored and/or treated for any comorbid conditions (e.g., cardiovascular disease, diabetes, dyslipidemia, hypertension) AND
4. BOTH of the following:
   1. The patient is currently on a weight loss regimen of a low-calorie diet, increased physical activity, and behavioral modifications AND
   2. The patient will continue the weight loss regimen in combination with the requested agent AND
5. 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
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.

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. BOTH of the following:
   1. The patient is currently on a weight loss regimen of a low-calorie diet, increased physical activity, and behavioral modifications AND
   2. The patient will continue the weight loss regimen in combination with the requested agent AND
3. The patient has had clinical benefit with the requested agent AND
4. 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
5. 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