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Resmetirom Prior Authorization with Quantity Limit Program Summary
Policy Number: PH-1215
This program applies to Blue Partner, Commercial, GenPlus, NetResults A series, SourceRx and Health Insurance Marketplace formularies.
POLICY REVIEW CYCLE
Effective Date |
Date of Origin |
10-01-2024 |
03-01-2024 |
FDA LABELED INDICATIONS AND DOSAGE
Agent(s) |
FDA Indication(s) |
Notes |
Ref# |
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 |
See package insert for FDA prescribing information: https://dailymed.nlm.nih.gov/dailymed/index.cfm
CLINICAL RATIONALE
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)
NASH is more likely to occur in adults who:(3)
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)
The diagnosis of NAFLD is based on the following:(2)
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 (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) |
REFERENCES
Number |
Reference |
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. |
POLICY AGENT SUMMARY PRIOR AUTHORIZATION
Target Brand Agent(s) |
Target Generic Agent(s) |
Strength |
Targeted MSC |
Available MSC |
Final Age Limit |
Preferred Status |
|
||||||
Rezdiffra |
resmetirom |
100 MG ; 60 MG ; 80 MG |
M ; N ; O ; Y |
N |
|
|
POLICY AGENT SUMMARY QUANTITY LIMIT
Target Brand Agent Name(s) |
Target Generic Agent Name(s) |
Strength |
QL Amount |
Dose Form |
Day Supply |
Duration |
Addtl QL Info |
Allowed Exceptions |
Targeted NDCs When Exclusions Exist |
|
|||||||||
Rezdiffra |
resmetirom |
60 MG |
30 |
Tablets |
30 |
DAYS |
|
|
|
Rezdiffra |
resmetirom |
80 MG |
30 |
Tablets |
30 |
DAYS |
|
|
|
Rezdiffra |
resmetirom |
100 MG |
30 |
Tablets |
30 |
DAYS |
|
|
|
CLIENT SUMMARY – PRIOR AUTHORIZATION
Target Brand Agent Name(s) |
Target Generic Agent Name(s) |
Strength |
Client Formulary |
Rezdiffra |
resmetirom |
100 MG ; 60 MG ; 80 MG |
Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx |
CLIENT SUMMARY – QUANTITY LIMITS
Target Brand Agent Name(s) |
Target Generic Agent Name(s) |
Strength |
Client Formulary |
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 |
PRIOR AUTHORIZATION CLINICAL CRITERIA FOR APPROVAL
Module |
Clinical Criteria for Approval |
|
Initial Evaluation Target Agent(s) will be approved when ALL the following are met:
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:
Length of Approval: 12 months NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria. |
QUANTITY LIMIT CLINICAL CRITERIA FOR APPROVAL
Module |
Clinical Criteria for Approval |
|
Quantity limit for the Target Agent(s) will be approved when ONE of the following is met:
Length of Approval: up to 12 months |
This pharmacy policy is not an authorization, certification, explanation of benefits or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All pharmacy policies are based on (i) information in FDA approved package inserts (and black box warning, alerts, or other information disseminated by the FDA as applicable); (ii) research of current medical and pharmacy literature; and/or (iii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.
The purpose of Blue Cross and Blue Shield of Alabama’s pharmacy policies are to provide a guide to coverage. Pharmacy policies are not intended to dictate to physicians how to practice medicine. Physicians should exercise their medical judgment in providing the care they feel is most appropriate for their patients.
Neither this policy, nor the successful adjudication of a pharmacy claim, is guarantee of payment.
Commercial _ PS _ Resmetirom__PAQL _ProgSum_ 10-01-2024