Coverage Policy Manual - Arkansas Blue Cross and Blue Shield

Metreleptin (e.g., Myalept)

Description:

Metreleptin is a recombinant human leptin analog that binds to and activates the human leptin receptor (ObR), which belongs to the class I cytokine family of receptors that signals through the JAK/STAT transduction pathway. Activation of the leptin receptor by metreleptin mimics native leptin, which is responsible for signaling the CNS with the status of energy stores in the body.

Metreleptin (Myalept) was approved by the U.S. Food and Drug Administration (FDA) in February 2014 as an adjunct to diet as replacement therapy to treat the complications of leptin deficiency in those with congenital or acquired generalized lipodystrophy. The safety and effectiveness of metreleptin for the treatment of complications of partial lipodystrophy or liver disease (including nonalcoholic steatohepatitis) has not been established. Additionally, metreleptin is not indicated for use in those with HIV-related lipodystrophy or in those with metabolic disease without concurrent evidence of generalized lipodystrophy. The FDA has required a Risk Evaluation and Mitigation Strategy for metreleptin due to the potential for serious side effects, including anti-metreleptin antibodies with neutralizing activity and lymphoma.

Policy/
Coverage:

Metreleptin (e.g., Myalept) is not covered under the medical benefit. Please check the member’s pharmacy benefit for coverage. This policy applies to members whose plan utilizes AR BCBS pharmacy and has metreleptin as a formulary option. (Please see Coverage Policy 2020005, Self-Administered Medication)

Effective April 01, 2018, Prior Approval is required for metreleptin (e.g., Myalept)

Effective December 2023

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Initial authorization is for 6 months

The use of metreleptin meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when ALL the following conditions are met:

1. Individual has a confirmed diagnosis of either complete congenital generalized lipodystrophy [confirmed by genetic testing] or complete acquired lipodystrophy when used as an adjunct to diet as replacement therapy (FDA, Myalept, 2014); AND

2. Individual has documentation of leptin deficiency (FDA, Myalept, 2014); AND

3. Individual has at least one of the following metabolic abnormalities: diabetes mellitus with evidence of insulin resistance or hypertriglyceridemia (FDA,Myalept, 2014) uncontrolled (e.g., HgA1C > 7% and/or triglycerides > 200 mg on standard therapies [metformin, insulin, statins, etc.]; (Araujo-Vilar, 2019); AND

4. Participation in REMS program as required under FDA labeling (FDA, Myalept, 2014); AND

5. Will not be used for the following conditions:

a. Partial congenital lipodystrophy; OR

b. Treatment of liver disease, including nonalcoholic steatohepatitis (NASH); OR

c. HIV-related lipodystrophy; OR

d. Treatment of metabolic disease, without concurrent evidence of generalized lipodystrophy; OR

e. Treatment of obesity; OR

f. Dementia; AND

6. Must be dosed in accordance with FDA label.

Continuation of Metreleptin

Continuation of metreleptin injection meets the definition of medical necessity when ALL of the following criteria are satisfied:

1. Individual met initial criteria for metreleptin administration; AND

2. Individual is compliant with diet and other measures used as adjuncts to treatment; AND

3. Documented metabolic benefit from prior or current metreleptin treatment, defined as one or more of the following:

a. TG reduction greater than or equal to 30%; OR

b. Absolute reduction of HbA1c greater than or equal to 1%; OR

c. Decrease in insulin requirements greater than or equal to 40%; OR

d. Decrease in episodes of pancreatitis; OR

e. Improvement in steatohepatitis as evidenced by liver biopsy or normalized AST/ALT; AND

4. For any loss of efficacy during treatment or for any request to increase dosage (maximum dose of 10 mg per day), testing for neutralizing antibodies is required (FDA, Myalept, 2014).

Note: If neutralizing antibodies are present, treatment no longer is covered (see below).

5. Continued authorization is for 6 months with submission of evidence meeting criteria as described above.

Dosing and Administration

Dosing per FDA Guidelines

Baseline weight less than or equal to 40 kg (males and females:

Starting Daily Dose = 0.06 mg/kg (0.012 mL/kg)
Dose Adjustments = 0.02 mg/kg (0.004 mL/kg)
Maximum Daily Dose= 0.13 mg/kg (0.026 mL/kg)

Baseline weight for males greater than 40 kg

Starting Daily Dose = 2.5 mg (0.5 mL)
Dose Adjustments = 1.25 mg (0.25 mL) to 2.5 mg (0.5 mL)
Maximum Daily Dose = 10 mg (2mL)

Baseline weight for females greater than 40 kg

Starting Daily Dose = 5 mg (1 mL)
Dose Adjustments = 1.25 mg (0.25 mL) to 2.5 mg (0.5mL)
Maximum Daily Dose = 10 mg (2mL)

Metreleptin is supplied as a sterile, white, solid, lyophilized cake of 11.3 mg metreleptin per vial to deliver 5 mg per mL when reconstituted in 2.2 mL of BWFI or WFI.

Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

The use of metreleptin, for any indication or circumstance not described above, does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For members with contracts without primary coverage criteria, the use of metreleptin, for any indication or circumstance not described above, is considered investigational.

Investigational services are specific contract exclusions in most member benefit certificates of coverage.

The use of metreleptin when neutralizing antibodies are present does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness and is not covered.

For members with contracts without primary coverage criteria, the use of metreleptin when neutralizing antibodies are present is considered not medically necessary. Services that are not medically necessary are specific contract exclusions in most member benefit certificates of coverage.

Effective October 2021 to November 2023

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Initial authorization is for 6 months

The use of metreleptin meets primary coverage criteria that there be scientific evidence of effectiveness when ALL the following conditions are met:

1. Individual has a confirmed diagnosis of either complete congenital generalized lipodystrophy [confirmed by genetic testing] or complete acquired lipodystrophy when used as an adjunct to diet as replacement therapy (FDA, Myalept, 2014); AND

2. Individual has documentation of leptin deficiency (FDA, Myalept, 2014); AND

3. Individual has at least one of the following metabolic abnormalities: diabetes mellitus with evidence of insulin resistance or hypertriglyceridemia (FDA,Myalept, 2014) uncontrolled (e.g., HgA1C > 7% and/or triglycerides > 200 mg on standard therapies [metformin, insulin, statins, etc.]; (Araujo-Vilar, 2019); AND

4. Participation in REMS program as required under FDA labeling (FDA, Myalept, 2014); AND

5. Must be dosed in accordance with FDA label.

Continuation of Metreleptin

Continuation of metreleptin injection meets the definition of medical necessity when ALL of the following criteria are satisfied:

1. Individual met initial criteria for metreleptin administration; AND

2. Individual is compliant with diet and other measures used as adjuncts to treatment; AND

3. Documented metabolic benefit from prior or current metreleptin treatment, defined as one or more of the following:

a. TG reduction greater than or equal to 30%; OR

b. Absolute reduction of HbA1c greater than or equal to 1%; OR

c. Decrease in insulin requirements greater than or equal to 40%; OR

d. Decrease in episodes of pancreatitis; OR

e. Improvement in steatohepatitis as evidenced by liver biopsy or normalized AST/ALT; AND

4. For any loss of efficacy during treatment or for any request to increase dosage (maximum dose of 10 mg per day), testing for neutralizing antibodies is required (FDA, Myalept, 2014).

Note: If neutralizing antibodies are present, treatment no longer is covered (see below).

5. Continued authorization is for 6 months with submission of evidence meeting criteria as described above.

Dosing and Administration

Dosing per FDA Guidelines

Baseline weight less than or equal to 40 kg (males and females:

Starting Daily Dose = 0.06 mg/kg (0.012 mL/kg)
Dose Adjustments = 0.02 mg/kg (0.004 mL/kg)
Maximum Daily Dose= 0.13 mg/kg (0.026 mL/kg)

Baseline weight for males greater than 40 kg

Starting Daily Dose = 2.5 mg (0.5 mL)
Dose Adjustments = 1.25 mg (0.25 mL) to 2.5 mg (0.5 mL)
Maximum Daily Dose = 10 mg (2mL)

Baseline weight for females greater than 40 kg

Starting Daily Dose = 5 mg (1 mL)
Dose Adjustments = 1.25 mg (0.25 mL) to 2.5 mg (0.5mL)
Maximum Daily Dose = 10 mg (2mL)

Metreleptin is supplied as a sterile, white, solid, lyophilized cake of 11.3 mg metreleptin per vial to deliver 5 mg per mL when reconstituted in 2.2 mL of BWFI or WFI.

Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

The use of metreleptin for any condition or circumstance including but not limited to the following list does not meet primary coverage criteria that there be scientific evidence of effectiveness and is not covered:

Partial congenital lipodystrophy
Treatment of liver disease, including nonalcoholic steatohepatitis (NASH)
HIV-related lipodystrophy
Treatment of metabolic disease, without concurrent evidence of generalized lipodystrophy
Treatment of obesity
Dementia

For members with contracts without primary coverage criteria, the use of metreleptin for any condition or any circumstance including but not limited to the following list is considered investigational:

Partial congenital lipodystrophy
Treatment of liver disease, including nonalcoholic steatohepatitis (NASH)
HIV-related lipodystrophy
Treatment of metabolic disease, without concurrent evidence of generalized lipodystrophy
Treatment of generalized obesity
Dementia

Investigational services are specific contract exclusions in most member benefit certificates of coverage.

For members with contracts without primary coverage criteria, the use of metreleptin when neutralizing antibodies are present is considered not medically necessary. Services that are not medically necessary are specific contract exclusions in most member benefit certificates of coverage.

Effective Prior to October 2021

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

The use of metreleptin meets primary coverage criteria that there be scientific evidence of effectiveness when ALL of the following conditions are met:

1. Member has a confirmed diagnosis of either complete congenital generalized lipodystrophy or complete acquired lipodystrophy when used as an adjunct to diet as replacement therapy; AND

2. Member has documentation of leptin deficiency: <4.0 ng/mL in males, <7.0 ng/mL in females*; AND

3. Member has at least one of the following metabolic abnormalities: type 2 diabetes mellitus resistant to insulin therapy, insulin resistance (fasting insulin level ≥30 µIU/mL), or hypertriglyceridemia (fasting triglyceride levels >200 mg/dL); AND

4. Participation in REMS program as required under FDA labeling; AND

5. Initial authorization is for 6 months.

Continuation of metreleptin injection meets the definition of medical necessity when ALL the following criteria are satisfied:

1. Member met initial criteria for metreleptin administration; AND

2. Member is compliant with diet and other measures used as adjuncts to treatment; AND

3. Documented metabolic benefit from prior or current metreleptin treatment, defined as one or more of the following:

TG reduction greater than or equal to 30% OR
Absolute reduction of HbA1c greater than or equal to 1% OR
Decrease in insulin requirements greater than or equal to 40% OR
Decrease in episodes of pancreatitis OR
Improvement in steatohepatitis as evidenced by liver biopsy or normalized AST/ALT; AND

4. For any loss of efficacy during treatment or for any request to increase dosage (maximum dose of 10 mg per day), testing for neutralizing antibodies is required.

Note: If neutralizing antibodies are present, treatment no longer is covered (see below).

5. Continued authorization is for 6 months with submission of evidence meeting criteria as described above.

*As defined by the levels less than the 7th percentile of normal values reported by the 3rd National Health and Nutrition Examination survey. In the study leading to FDA approval, the median fasting leptin concentration at baseline was 0.7 ng/mL in males (range: 0.3 -3.3 ng/mL) and 1.0 ng/mL in females (range: 0.3 -3.3 ng/mL); in the Brown et al The Journal of Clinical Endocrinology & Metabolism, Volume 102, Issue 5, 1 May 2017, NIH study, the median fasting leptin was 1.1 ng/ml (range 0.4 to 3.1 ng/ml).

Dosing Guidelines:

1. Baseline weight less than or equal to 40 kg (males and females:

Starting Daily Dose = 0.06 mg/kg (0.012 mL/kg)
Dose Adjustments = 0.02 mg/kg (0.004 mL/kg)
Maximum Daily Dose= 0.13 mg/kg (0.026 mL/kg)

2. Baseline weight for males greater than 40 kg

Starting Daily Dose = 2.5 mg (0.5 mL)
Dose Adjustments = 1.25 mg (0.25 mL) to 2.5 mg (0.5 mL)
Maximum Daily Dose = 10 mg (2mL)

3. Baseline weight for females greater than 40 kg

Starting Daily Dose = 5 mg (1 mL)
Dose Adjustments = 1.25 mg (0.25 mL) to 2.5 mg (0.5mL)
Maximum Daily Dose = 10 mg (2mL)

Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Partial congenital lipodystrophy
Treatment of liver disease, including nonalcoholic steatohepatitis (NASH)
HIV-related lipodystrophy
Treatment of metabolic disease, without concurrent evidence of generalized lipodystrophy
Treatment of generalized obesity
Dementia

Partial congenital lipodystrophy
Treatment of liver disease, including nonalcoholic steatohepatitis (NASH)
HIV-related lipodystrophy
Treatment of metabolic disease, without concurrent evidence of generalized lipodystrophy
Treatment of generalized obesity
Dementia

Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Rationale:

Lipodystrophy is a group of clinically heterogeneous metabolic disorders that are either acquired or inherited and result in loss of adipose tissue. This leads to disruption of various metabolic pathways. The disease is classified primarily based on 2 factors: whether it is genetic or acquired and whether fat loss is generalized or partial.

The major classifications:

Congenital generalized lipodystrophy (CGL), also known as Berardinelli–Seip syndrome
Familial partial lipodystrophy (FPL)
Acquired generalized lipodystrophy (AGL)
Acquired partial lipodystrophy (APL), also known as Barraquer–Simons syndrome

Many genetic mutations have been identified in congenital and familial lipodystrophies, such as AGPAT2, seipin,LMNA, PPARγ, ZMPSTE24, and LMNB2. These mutations can follow autosomal recessive (AGPAT2, seipin) or autosomal dominant (LMNA) inheritance patterns. Acquired lipodystrophies can be autoimmune-associated. Patients with CGL, AGL, and APL often present with metabolic abnormalities during childhood or adolescence.

Adipose tissue is an endocrinologically active tissue as it secretes multiple hormones (leptin and adiponectin) and cytokines. Leptin is a key regulator in energy homeostasis as well as fat and glucose metabolism. The relative leptin deficiency that occurs as a result of loss of adipose tissue has been implicated as a key pathogenic mechanism underlying lipodystrophy. Lipodystrophy is associated with deposition of fat in ectopic locations (e.g., liver and muscle) and metabolic abnormalities (eg, insulin resistance, hypertriglyceridemia, and diabetes).

Common clinical complications and manifestations of lipodystrophy include:

Insulin-resistant diabetes mellitus and resulting complications
Severe hypertriglyceridemia, which may lead to acute pancreatitis
Hepatic steatosis or steatohepatitis which may progress to cirrhosis
Proteinuric nephropathies, which may lead to renal failure
Severe cardiovascular complications, such as premature atherosclerotic disease and hypertrophic cardiomyopathy
Reproductive and hormonal abnormalities in women
Increased appetite leading to hyperphagia.

Efficacy of metreleptin consists entirely of small observational studies. The largest was an NIDDK sponsored open-label single-arm study of patients with generalized lipodystrophy (non-HIV-related) and diabetes, insulin resistance, or hypertriglyceridemia. There is some question about the size of the study, since the original publication reported 55 subjects (Chan, 2011), but a more recent abstract lists 64 and the prescribing information states 48. It is not clear why some patients were excluded from the FDA-approved label. Treatment with metreleptin reduced mean HbA1c from baseline at 4 months -1.2% (95% CI, -1.6 to -0.8) (n=40) and at 3 years -2.1% (95% CI, -3.2 to -1.1) (n=18). Among all patients, the change in triglycerides from baseline to 4 months was -44.4 mg/dL (95% CI, -58.8 to -29.9) (n=40) and at 3 years it was -35.4 mg/dL (95% CI, -64.1 to -6.7) (n=19). These subjects were a heterogeneous group with varying type and level of metabolic abnormalities at baseline. In subgroups of patients whose HbA1c and triglyceride levels were elevated at baseline, the HbA1c reduction at 4 months and 3 years were -1.4 (95% CI, -1.8 to -0.9) and -2.6 (95% CI, -3.8 to -1.3) (n=14). The mean reduction in triglycerides among patients with elevated levels at baseline at 4 months and 3 years were 44.4 mg/dL (95% CI, -58.8 to -29.9) (n=30) and -51.2 mg/dL (95% CI, -87.5 to -14.8) (n=13), respectively. There was greater response in patients with elevated HbA1c and triglycerides at baseline. These results were consistent with those from smaller studies. Due to the subjects’ heterogeneity and the absence of a control group, it is difficult to quantify the true treatment effect of metreleptin. Changes in concomitant medications, diet or exercise may have confounded the results. Eighty four percent of patients displayed immunogenicity and expressed anti-metreleptin antibodies. Antimetreleptin antibodies with neutralizing activity are associated with loss of endogenous leptin activity as well as loss of metreleptin efficacy, as occurred in 6% of study patients. Most common adverse reactions in clinical trials were headache (13%), hypoglycemia (13%), decreased weight (13%) and abdominal pain (10%). T-cell lymphoma has been reported in 2 patients (4%). Both patients had immunodeficiency and severely abnormal bone marrow biopsy specimens at baseline. However, there was one case of anaplastic large cell lymphoma in a patient receiving metreleptin who did not have hematological abnormalities before treatment. Eighty four percent of patients displayed immunogenicity and expressed antimetreleptin antibodies. Anti-metreleptin antibodies with neutralizing activity associated with adverse events consistent with loss of endogenous leptin activity and/or loss of metreleptin efficacy. Severe infection and/or worsening metabolic control have been reported as a result of anti-metreleptin antibodies (increases in HbA1c and/or triglycerides) and observed in 6% of patients. For these two specific reasons metreleptin is only available through the MYALEPT REMS program. There were cases of acute pancreatitis in 5 patients (9%). All of these patients had a history of pancreatitis and severe hypertriglyceridemia. Chronic renal adverse events reported in 5 patients (9%), all of whom had a history of renal disease at baseline. Elevated LFT or events of liver disease are reported in 4 patients (7%). Given the small number of patient exposures, it is difficult to assess the probability of other less common but serious adverse events occurring.

2018 Update

A literature search conducted through December 2018 did not reveal any new information that would prompt a change in the coverage statement.

2019 Update

Annual policy review completed with a literature search using the MEDLINE database through December 2019. No new literature was identified that would prompt a change in the coverage statement.

December 2020 Update

Annual policy review completed with a literature search using the MEDLINE database through December 2020. No new literature was identified that would prompt a change in the coverage statement.

2021 Update

Annual policy review completed with a literature search using the MEDLINE database through December 2021. No new literature was identified that would prompt a change in the coverage statement.

2022 Update

Annual policy review completed with a literature search using the MEDLINE database through December 2022. No new literature was identified that would prompt a change in the coverage statement.

2023 Update

Annual policy review completed with a literature search using the MEDLINE database through December 2023. No new literature was identified that would prompt a change in the coverage statement.

CPT/HCPCS:

References:

Araújo-Vilar D, Santini F.(2018) Diagnosis and treatment of lipodystrophy: a step-by-step approach. J Endocrinol Invest. 2019 Jan;42(1):61-73. doi: 10.1007/s40618-018-0887-z. Epub 2018 Apr 27. PMID: 29704234; PMCID: PMC6304182.

Bristol-Myers Squibb.(2014) Myalept (metreleptin for injection) for subcutaneous use. Prescribing Information. 1334229. Princeton, NJ: Bristol-Myers Squibb; revised February 2014.

Chan J.L., Lutz K., Cochran E., et al.(2011) Clinical effects of long-term metreleptin treatment in patients with lipodystrophy. Endocr Pract. 2011 Nov-Dec;17(6):922-32. doi: 10.4158/EP11229.

Gupta N, Asi N, Farah W, et al.(2017) Clinical Features and Management of Non-HIV-Related Lipodystrophy in Children: A Systematic Review. J Clin Endocrinol Metab. 2017 Feb 1;102(2):363-374. doi: 10.1210/jc.2016-2271.

Quinn K, Chauhan S, Purcell SM.(2021) Lipodystrophies. 2021 Jul 18. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan–. PMID: 29083781

U.S. Food and Drug Administration (FDA). FDA(2014) FDA approves Myalept to treat rare metabolic disease. FDA News Release. Silver Spring, MD: FDA; February 25, 2014.

Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
CPT Codes Copyright © 2024 American Medical Association.