Effective Date

Date of Origin 

03-01-2024            

03-01-2024

Resmetirom

Treatment of nonalcoholic steatohepatitis (NASH)

1

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

Nonalcoholic fatty liver disease (NAFLD) is the build up 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 prevalance 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 guideliens 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)

• Bariatric surgery should be considered as a therapeutic option in patients who meet criteria for metabolic weight loss surgery, as it effectively resolves NAFLD or NASH in the majority of patients without cirrhosis and reduces mortality from CVD and malignancy.(2) Persons undergoing bariatric surgery should be evaluated for the presence and severity of NASH, and a liver biopsy should be considered at the time of bariatric surgery. Liver biopsy should be recommended if presurgical stratification suggests indeterminate or high risk of liver fibrosis.(4) Bariatric surgery can induce sustained weight loss, improve diabetes, and reduce CVD and cancer risks, which are common comorbidities in NAFLD. Weight loss induced by bariatric surgery unquestionably improves steatosis, steatohepatitis, and, to a lesser extent, hepatic fibrosis and HCC.(2,4)
• Clinicians should use liver fibrosis prediction calculations to assess the risk of NAFLD with liver fibrosis. The preferred noninvasive initial test (NIT) is the fibrosis-4 index (FIB-4).

NITs derived from clinical variables can estimate of the presence of advanced fibrosis. Several have been developed (eg, 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, originally proposed to help assess hepatic fibrosis in patients with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfection, 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)

• In persons with T2D, clinicians should consider screening for clinically significant fibrosis (stages F2-F4) using the FIB-4, even if they have normal liver enzyme levels.
• In persons with T1D, clinicians may consider screening for NAFLD with clinically significant fibrosis (stages F2-F4) using the FIB-4, only if there are risk factors such as obesity, features of metabolic syndrome, elevated plasma aminotransferase levels (>30 U/L), or hepatic steatosis on imaging.

Those who may have a moderate or high risk of advanced disease based on FIB-4 should undergo secondary risk assessment. In the primary care setting, vibration-controlled transient elastography (VCTE) or ultrasound-based methods such as acoustic radio force impulse (as available) are favored over magnetic resonance elastography (MRE), as initial secondary assessments due to cost considerations. The Enhanced Liver Fibrosis (ELF) test is approved for prognostication when advanced fibrosis is suspected, although it can be ordered for secondary risk assessment, particularly because the availability of elastography may be limited in some settings. If secondary risk assessment is still consistent with an intermediate or high risk of fibrosis, patients should be referred to specialty care for further evaluation and potential intervention.(2) 

• Clinicians must manage persons with NAFLD for obesity, metabolic syndrome, prediabetes, diabetes mellitus, dyslipidemia, hypertension, and CVD based on the current standards of care.
• Clinicians should recommend lifestyle changes in persons with excess adiposity and NAFLD with a goal of at least 5%, preferably greater than 10% weight loss, as more weight loss is often associated with greater liver histologic and cardiometabolic benefit, depending on individualized risk assessments. Clinicians must recommend participation in a structured weight loss program, when possible, tailored to the individual’s lifestyle and personal preferences.
• Clinicians must recommend dietary modification in persons with NAFLD, including a reduction of macronutrient content to induce an energy deficit (with restriction of saturated fat, starch, and added sugar) and adoption of healthier eating patterns, such as the Mediterranean diet.
• In persons with NAFLD, clinicians must recommend physical activity that improves body composition and cardiometabolic health. Participation in a structured exercise program should be recommended, when possible, tailored to the individual’s lifestyle and personal preferences.
• Pioglitazone or GLP-1 RAs are recommended for persons with T2D and biopsy-proven NASH.
• Clinicians must consider treating diabetes with pioglitazone and/or GLP-1 RAs when there is an elevated probability of having NASH based on elevated plasma aminotransferase levels and noninvasive tests.
• To offer cardiometabolic benefit in persons with T2D and NAFLD, clinicians must consider treatment with GLP-1 RAs, pioglitazone, or SGLT2 inhibitors; however, there is no evidence of benefit for treatment of steatohepatitis with SGLT2 inhibitors.
• Due to the lack of evidence of efficacy, metformin, acarbose, dipeptidyl peptidase IV inhibitors, and insulin are not recommended for the treatment of steatohepatitis (no benefit on hepatocyte necrosis or inflammation) but may be continued as needed for the treatment of hyperglycemia in persons with T2D and NAFLD or NASH.
• Vitamin E can be considered for the treatment of NASH in persons without T2D, but there is not enough evidence at this time to recommend for persons with T2D or advanced fibrosis.

The rationale for pharmacologic treatment of NASH in persons with T2D (in addition to lifestyle changes) is based on the following aspects:(2)

• NASH has reached epidemic proportions with clinically significant fibrosis (stage greater than or equal to F2) being present in approximately 12% to 21% of individuals in T2D;
• NASH with clinically significant fibrosis is associated with an increased risk of mortality from liver-related complications;
• Early diagnosis and treatment offer a window of opportunity to prevent disease progression;
• Type 2 diabetes (T2D) appears to accelerate progression to cirrhosis in NASH, making a dual intervention versus diabetes and NASH more cost-effective;
• 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
• 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.

Taken together, it follows that adding pharmacologic therapy with agents proven to reverse NASH is warranted to prevent progression to cirrhosis more effectively. At present, there are no FDA-approved drugs for the treatment of NASH. Therefore, 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.(2,4)

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. 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.(2,4)

• Statins are safe and recommended for CVD risk reduction in patients with NAFLD across the disease spectrum, including compensated cirrhosis.
• Limited data exist on the safety and efficacy of statins in patients with decompensated cirrhosis, although statin use with careful monitoring could be considered in patients with high CVD risk.
• Hypertriglyceridemia can be managed through lifestyle changes and supplementation with omega-3 fatty acids, icosapent ethyl, or fibrates.

Management of dyslipidemia in NAFLD should include the use of moderate-intensity to high-intensity statins as first-line therapy based on lipid risk levels and atherosclerotic CVD risk scores. Combination therapies of statins with other hypolipemic agents, such as ezetimibe, PCSK-9 inhibitors, inclisiran, bempedoic acid, fibrates, omega 3 fatty acids, or icosapent ethyl, should be considered when monotherapy with a statin does not achieve therapeutic goals. Statins are safe in patients with NAFLD across the disease spectrum, including advanced liver disease, and lead to a demonstrable reduction in cardiovascular morbidity and mortality. However, in clinical practice, they are often underused despite extensive data demonstrating safety, even among patients with cirrhosis. Statins are also considered safe in the context of compensated cirrhosis. Although statins have been safely used in patients with decompensated cirrhosis, the risk of statin-induced adverse events might be higher in this population, and thus more caution is warranted. In patients with decompensated cirrhosis and high CVD risk undergoing evaluation for liver transplantation, statin use can be considered with careful monitoring.(2)

• Although standard ultrasound can detect hepatic steatosis, it is not recommended as a tool to identify hepatic steatosis due to low sensitivity across the NAFLD spectrum.
• Controlled Attenuation Parameter (CAP) as a point-of-care technique may be used to identify steatosis. MRI-PDFF (MRI–proton density fat fraction) can additionally quantify steatosis.
• If FIB-4 is  greater than or equal to 1.3, VCTE, MRE, or ELF may be used to exclude advanced fibrosis.

Once the presence of NAFLD is established, fibrosis risk stratification is essential. The first test recommended is the FIB-4, which often allows separation of those at low risk versus those at high risk of liver fibrosis. However, a significant proportion of persons will fall in a “gray zone” of indeterminate risk that requires additional testing to decide referral to the liver specialist. The second test recommended is LSM or, if unavailable, an ELF blood test. This should determine the risk in most individuals. Persons with a low risk of cirrhosis should be managed in primary care and/or endocrinology clinics, while those with an indeterminate to high risk of liver fibrosis merit referral to the liver specialist and a multidisciplinary approach to management.(2,4)

MRI–proton density fat fraction (PDFF) is an accurate, reproducible, and precise MRI-based biomarker for liver fat quantification that is routinely used in clinical research. Its role in clinical practice is evolving, although it is being increasingly used in tertiary care centers. Although MRI-PDFF is superior to CAP in the diagnosis as well as the quantification of liver fat, this advantage is tempered by cost, patient acceptance, and the disadvantage of not being a point-of-care technique.(2,4)

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. The range of LSM values that correlate with the stage of fibrosis is technique-dependent. An LSM by MRE greater than or equal to kPa is suggestive of cirrhosis. Liver stiffness assessed by MRE may also be useful to assess the risk of decompensation.(2,4)

Histological evaluation of NAFLD should provide three basic pieces of information: diagnosis, grading of necroinflammatory activity, and staging of fibrosis severity. Within the spectrum of NAFLD there are several distinct patterns: the common zone 3 injury pattern of adult steatohepatitis, the zone 1 steatosis-fibrosis pattern observed most often in young children, and steatosis with or without mild inflammation that does not meet criteria for steatohepatitis. Reporting of severity includes description of the pattern and degree of steatosis, inflammation, ballooning changes, and fibrosis. Although fibrosis stage is the best predictor of long-term outcome in multivariable analyses, ballooning injury and portal inflammation are short-term predictors of fibrosis progression or regression and are commonly combined as measures of disease grade. Composite histological scores such as the NAFLD activity score (NAS) and the steatosis, activity, fibrosis score combine histological features and are used in clinical studies to offer a structured overall assessment of severity. Liver biopsy, the "gold standard", remains the best method for providing information on the architectural distortion and the complex anatomic interrelationships of cellular injury, inflammation, and fibrosis.(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 favourable effects on lipid profiles.(9) Four Phase 3 clinical trials to evaluate the safety and efficacy of resmetirom for the treatment of NASH are at various stages, two are included below: MAESTRO-NASH, MAESTRO-NAFLD-1, MAESTRO-NAFLD-OLE, and MAESTRO-NASH-OUTCOMES.(8)

The key trial is MAESTRO-NASH, a large phase 3 trial with 966 patients randomized to receive once-daily resmetirom 80 mg, resmetirom 100 mg, or placebo. Adult patients were enrolled if they had biopsy-proven NASH based on a recent liver biopsy with fibrosis stages 1 to 3 and a NAFLD Activity Score (NAS) of ≥ 4, with a score of at least 1 in each component, and had ≥ 8% liver fat on magnetic resonance imagingproton density fat fraction (MRI-PDFF). Patients were also eligible if they had suspected or confirmed diagnosis of NASH with metabolic risk factors, AST ≥ 20 U/L, and liver fibrosis defined using either biochemical test (PRO-C3 >14 ng/mL or ELF ≥9) or Fibroscan (≥8.5 kPa and controlled attenuation parameter ≥280 dB.m-1) or historical liver biopsy.(10)

The co-primary outcomes were ≥ 1 point improvement in fibrosis stage with no worsening of NAS and NASH resolution with ≥ 2 point reduction in NAS without worsening of fibrosis. The mean age for all participants was 57 years and 89% were White with a mean BMI of 36 kg/m2  and 21% were hispanic. Comorbidities including type 2 diabetes (67%), hypertension (78%), and dyslipidemia (71%) were common among the MAESTRO-NASH trial participants.4 Approximately 95% of the MAESTRO-NASH trial participants had F2-F3 fibrosis stages, 33% F2 and 62% F3; the remaining 5% had stage F1B. Other than the phase 2 trial and open label extension phase including a significant proportion of NASH participants with F1 stage, baseline characteristics were similar in all resmetirom trials included in this review.(10)

The exclusion criteria are as follows:(11)

• History of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to Screening.
• Regular use of drugs historically associated with NAFLD,
• Thyroid diseases, active hyperthyroidism, untreated clinical hypothyroidism defined by thyroid stimulating hormone (TSH) >7 IU/L with symptoms of hypothyroidism or >10 IU/L without symptoms.
• Patients who have had a thyroidectomy and are on replacement thyroxine doses >75 µg per day are allowed.
• History of bariatric surgery or intestinal bypass surgery within the 5 years prior to randomization or planned during the conduct of the study.
• Recent significant weight gain or loss.
• HbA1c greater than or equal to 9.0%.
• Glucagon-like peptide 1(GLP-1) agonist, high dose Vitamin E (> 400 IU/day), or pioglitazone therapy unless stable dose for 24 weeks prior to biopsy.
• Presence of cirrhosis on liver biopsy defined as stage 4 fibrosis.
• Diagnosis of hepatocellular carcinoma (HCC).
• MELD score ≥12, as determined at Screening, unless due to therapeutic anti coagulation.
• Hepatic decompensation.
• Chronic liver diseases other than NASH.
• Active autoimmune disease.
• Serum ALT > 250 U/L.
• Active, serious medical disease with a likely life expectancy < 2 years.

Both doses of resmetirom, 80 mg and 100 mg, met the primary endpoints of NASH resolution and no worsening of fibrosis on liver biopsy. NASH resolution was achieved in 26% (P < .0001) in the 80 mg resmetirom group, 30% (P < .0001) in the 100 mg group, and 10% in those taking placebo. And greater than or equal to 1-stage improvement in fibrosis with no worsening of the NAFLD activity score (NAS) was achieved by 24% (P < .0002), 26% (P < .0001), and 14% in these groups respectively. The key secondary endpoint of LDL cholesterol lowering was also achieved with statistical significance. Likewise, improvement was seen in liver enzymes, and liver and spleen volumes. Patients enrolled in MAESTRO-NASH (approximately 1,750 total enrollment) continued on therapy after the initial 52-week treatment period for up to 54 months to accrue and measure hepatic clinical outcome events including progression to cirrhosis on biopsy (52 weeks and 54 months) and hepatic decompensation events, as well as all-cause mortality. This portion of the study is designed to generate confirmatory data that, if positive, will help verify resmetirom’s clinical benefit and support full approval.(10)

MAESTRO-NAFLD-1 (NCT04197479) was a 52-week randomized, double-blind, placebo-controlled phase 3 trial evaluating the safety of resmetirom in adults with nonalcoholic fatty liver disease and presumed NASH. MAESTRO-NAFLD-1 might be considered a “real-world” NASH study in that diagnosis was based on noninvasive measures rather than liver biopsy. The primary endpoint was to evaluate the safety and tolerability of resmetirom. The primary endpoint was to evaluate the safety and tolerability of resmetirom. Patients were randomized to three double-blind arms (100 mg resmetirom (n = 325), 80 mg resmetirom (n = 327) or placebo (n = 320)) or open-label 100 mg resmetirom (n = 171). The primary end point was incidence of treatment-emergent adverse events (TEAEs) over 52 weeks and key secondary end points were LDL-C, apoB, triglycerides, hepatic fat, and liver stiffness. Resmetirom was safe and well tolerated. TEAEs occurred in 86.5% (open-label 100 mg resmetirom), 86.1% (100 mg resmetirom), 88.4% (80 mg resmetirom) and 81.8% (placebo) of patients. TEAEs in excess of placebo included diarrhea and nausea at the initiation of treatment. Key secondary end points included least square means difference from placebo at 80 mg, 100 mg resmetirom: LDL-C (−11.1%, −12.6%), apoB (−15.6%, −18.0%), triglycerides (−15.4%, −20.4%), 16-week hepatic fat (−34.9%, −38.6%), (P < 0.0001) and liver stiffness (−1.02, −1.70) and 52-week hepatic fat (−28.8, −33.9). These findings demonstrate resmetirom was safe and well tolerated in adults with presumed NASH.(7,8)

Safety

Resmetirom does not have any contraindications.(TBD)

1

Remisetirom prescribing information. Madrigal Pharmaceuticals, Inc. TBD. 

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

Harrison, S.A., Taub, R., Neff, G.W. et al. Resmetirom for nonalcoholic fatty liver disease: a randomized, double-blind, placebo-controlled phase 3 trial. Nat Med 29, 2919–2928 (2023). https://doi.org/10.1038/s41591-023-02603-1.

8

Madrigal Pharmaceuticals Announces NDA Acceptance and Priority Review of the New Drug Application for Resmetirom for the Treatment of NASH with Liver Fibrosis. September 2023. https://ir.madrigalpharma.com/news-releases/news-release-details/madrigal-pharmaceuticals-announces-nda-acceptance-and-priority.

9

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 May;19(1):60-70. doi: 10.17925/EE.2023.19.1.60.

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.

Resmetirom

M ; N ; O ; Y

Y

Resmetirom

30

Capsules

30

DAYS

Resmetirom

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

Resmetirom

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 nonalcoholic steatohepatitis (NASH) as confirmed by ONE of the following: (medical records required)
   1. Liver biopsy within the past 2 years confirming steatosis AND ALL of the following:
      1. NAFLD Activity Score (NAS) greater than or equal to 4 AND
      2. A score of at least 1 in each NAS component [i.e., steatosis (scored 0 to 3), ballooning degeneration (scored 0 to 2), lobular inflammation (scored 0 to 3)] AND
      3. Fibrosis stage 1, 2, or 3 OR
   2. Vibration-controlled transient elastography (e.g., Fibroscan) with kPa greater than or equal to 8.5 AND CAP greater than or equal to 280 dB.m-1 OR
   3. Magnetic resonance elastography (MRE) greater than or equal to 2 and less than 4.0 OR
   4. ONE of the following historical biochemical tests for fibrosis:
      1. PRO-C3 >14 ng/mL OR
      2. ELF greater than or equal to 9 AND
2. The patient has an MRI-PDFF greater than or equal to 8% liver fat 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. The prescriber has provided information in support of using the requested agent for the patient’s age for the requested indication AND
4. The patient has an A1C < 9% AND
5. The patient does NOT have ANY of the following:
   1. History of significant alcohol consumption for a period of more than 3 consecutive months within the previous 12 months OR
   2. Hepatocellular carcinoma (HCC) OR
   3. Uncontrolled hypertension OR
   4. Any other liver disease (e.g., Wilson's disease, hepatitis) OR
   5. MELD score greater than or equal to 12 unless due to therapeutic anticoagulation OR
   6. History of bariatric surgery (within the past 5 years) AND
6. ONE of the following:
   1. BOTH of the following:
      1. The patient is currently treated with a statin agent (e.g., simvastatin, atorvastatin, rosuvastatin) AND
      2. The patient will continue a statin agent in combination with the requested agent OR
   2. The patient has an intolerance, hypersensitivity, or FDA labeled contraindication to ALL statin agents AND
7. The patient has implemented lifestyle modifications (e.g., diet, exercise)
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 AND
2. The patient has had clinical benefit with the requested agent AND
3. ONE of the following:
   1. BOTH of the following:
      1. The patient is currently treated with a statin agent (e.g., simvastatin, atorvastatin, rosuvastatin) AND
      2. The patient will continue a statin agent in combination with the requested agent OR
   2. The patient has an intolerance, hypersensitivity, or FDA labeled contraindication to ALL statin agents 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. ALL of the following:
   1. The requested quantity (dose) exceeds the program quantity limit AND
   2. The requested quantity (dose) does NOT exceed the maximum FDA labeled dose for the requested indication AND
   3. 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