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Inclisiran is a small interfering RNA (siRNA) that inhibits PCSK9 (proprotein convertase subtilisin kexin type 9) synthesis. Elevated levels of PCSK9 are associated with increased low-density lipoprotein (LDL) and poor cardiovascular outcomes. This drug is administered by subcutaneous injection by a health care provider.

The U.S. Food and Drug Administration (FDA) has approved inclisiran (Leqvio®) as an adjunct to diet and statin therapy for the treatment of adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH), to reduce low density lipoprotein cholesterol (LDL-C).

Familial hypercholesterolemia (FH) is a common genetic disease caused by mutation of one or more of the genes required for low-density lipoprotein cholesterol (LDL-C) catabolism. The clinical syndrome is characterized by extremely elevated levels of LDL-C and a likelihood of early onset atherosclerotic cardiovascular disease. Heterozygous FH indicates the presence of a single DNA alteration (mutation) that is inherited from one affected parent, whereas homozygous FH is caused by a variant from both affected parents.

Definitions:

Heterozygous familial hypercholesterolemia (HeFH) has been defined using several recognized diagnostic criteria schemes:

Broome Criteria 

Definite Familial Hypercholesterolemia:

• Adult total cholesterol (TC) > 290 mg/dL or LDL-C > 190 mg/dL; and
• One or more of the following:
  • Tendon xanthomas or tendon xanthomas in first or second degree relative; or
  • Genetic testing indicating LDL-receptor mutation, familial defective apo B-100, or PCSK9 mutation

Probable Familial Hypercholesterolemia:

• Adult total cholesterol (TC) > 290 mg/dL or LDL-C > 190 mg/dL; and
• One or more of the following:
  • Family history of early myocardial infarction defined as one of the following:
    • Age 60 years or younger in first-degree relative
    • Age 50 years or younger in second-degree relative
  • OR
  • Family history of total cholesterol (TC) defined as one of the following:
    • > 290 mg/dL in adult first- or second-degree relative
    • > 260 mg/dL in child, brother or sister aged younger than 16 years

Dutch Lipid Clinic Network Criteria

Assign the highest applicable score per group then add the points from each group to achieve the total score.

• Definitive FH diagnosis: greater than 8 points
• Probable FH diagnosis: 6 to 8 points
• Possible FH diagnosis:  3 to 5 points
• Unlikely FH diagnosis:   0 to 2 points

I.    Initial Review for Inclisiran (Leqvio®)

Inclisiran may be considered MEDICALLY NECESSARY AND APPROPRIATE when ALL of the following criteria are met:

• Age 18 years or older; AND
• Diagnosis of ONE of the following:
  • Heterozygous familial hypercholesterolemia (HeFH) as defined by ONE of the following:
    • Genetic confirmation of one mutant allele at the LDLR, APOB, or PCSK9 or LDLRAP1 gene; or 
    • Definite or probable familial hypercholesterolemia as defined by Broome or Dutch Lipid Clinic Network criteria;
  • OR
  • Primary hyperlipidemia (e.g., clinical atherosclerotic cardiovascular disease (ASCVD) or increased risk to ASCVD), including one or more of the following:
    • Acute coronary syndrome;
    • Coronary artery disease (CAD);
    • History of myocardial infarction (MI);
    • Stable or unstable angina;
    • Coronary or other arterial revascularization;
    • Stroke;
    • Transient ischemic attack (TIA);
    • Peripheral arterial disease (PAD);
• AND
• ONE of the following:
  • Currently receiving maximally tolerated high-intensity statin therapy (i.e., rosuvastatin greater than or equal to 20 mg daily, atorvastatin greater than or equal to 40 mg daily) for a minimum of 12 continuous weeks AND ONE of the following:
    • Not achieved a 50% reduction in LDL-C from baseline; or
    • In patients without ASCVD, LDL-C remains ≥ 100 mg/dL; or
    • If diagnosed with ASCVD, LDL-C remains ≥ 70 mg/dL; OR
  • Documented intolerance, FDA labeled contraindication, or hypersensitivity to ALL statins;
• AND
• In patients on statin therapy, ONE of the following:
  • Tried and had an inadequate response to ezetimibe; OR
  • Documented intolerance, FDA labeled contraindication, or hypersensitivity to ezetimibe;
• AND
• ONE of the following:
  • Tried and had an inadequate response to a PCSK9 inhibitor [evolocumab (Repatha®)]; OR 
  • Documented intolerance, FDA labeled contraindication, or hypersensitivity to ALL PCSK9 inhibitors;
• AND
• Not used in combination with another PCSK9 or ANGPTL3 inhibitor (e.g., alirocumab [Praluent®], evolocumab [Repatha®], evinacumab [Evkeeza™]); AND
• Prescribed by or in consultation with a specialist (e.g., cardiologist, endocrinologist); AND
• No FDA labeled contraindications to inclisiran (see table 1 below); AND
• Requested dose is within the FDA labeled dose for the labeled indication (see table 2 below); AND
• For commercial health plan members only, inclisiran is administered in accordance with site of service criteria (see policy XI-06); AND
• For commercial and Medicaid health plan members only, step therapy supplement criteria may apply for select conditions (see policy II-242: Step Therapy Supplement).

II.   Renewal Review for Inclisiran (Leqvio®)

Inclisiran may be considered MEDICALLY NECESSARY AND APPROPRIATE when ALL of the following criteria are met:

• Previously approved for inclisiran through the initial review process; AND
• Continued positive clinical response to inclisiran (e.g., 30% decrease in LDL-C from baseline at 6 months); AND
• Currently receiving treatment with maximally tolerated high-intensity statin therapy (e.g., rosuvastatin, atorvastatin) or documented intolerance, FDA labeled contraindication, or hypersensitivity to ALL statins; AND
• Not used in combination with another PCSK9 or ANGPTL3 inhibitor (e.g., alirocumab [Praluent®], evolocumab [Repatha®], evinacumab [Evkeeza™]); AND
• Prescribed by or in consultation with a specialist (e.g., cardiologist, endocrinologist); AND
• No FDA labeled contraindications to inclisiran (see table 1 below); AND
• Requested dose is within the FDA labeled dose for the labeled indication (see table 2 below): AND
• For commercial health plan members only, inclisiran is administered in accordance with site of service criteria (see policy XI-06).

III.  Experimental / Investigative Uses

All other uses of inclisiran are considered EXPERIMENTAL/INVESTIGATIVE due to the lack of clinical evidence demonstrating an impact on improved health outcomes.

Table 1.  FDA Labeled Contraindications

Table 2. Dosing

NOTE:  See documentation submission requirements below if the requested dose is outside of the dosing criteria provided in this table.

Documentation Submission:

Documentation supporting the medical necessity criteria described in the policy must be included in the prior authorization. In addition, the following documentation must also be submitted:

Initial Review 

1. Clinical notes describing the diagnosis and associated symptoms.
2. Genetic testing and laboratory documentation as required in the policy criteria.
3. Clinical notes describing current and past medications for the diagnosis, including response to the medications.
4. The dose being requested. If the requested dose is outside of the dosing criteria provided in the table above, a clear explanation for medical necessity of the requested dose MUST be submitted, including prior dosing (strength and frequency) associated with inadequate response.
5. For commercial and Medicaid health plan members only, when step therapy requirements apply for the requested indication, documentation for one or more of the step therapy supplement criteria MUST be provided (see policy II-242).
6. For commercial health plan members only, the site of service for inclisiran administration is specified, including CMS place of service code (see policy XI-06). If inclisiran is administered in a hospital outpatient facility, a clear explanation for the medical necessity of the site of service MUST be submitted, including documentation for one or more of the site of service criteria provided in policy XI-06.

Renewal Review

1. Documentation of prior approval for inclisiran through the initial review process.
2. Laboratory documentation as required in the policy criteria.
3. Documentation, since most recent approval, supporting continued positive clinical response (e.g., percentage decreased LDL since began treatment with inclisiran).
4. The dose being requested.  If the requested dose is outside of the dosing criteria provided in the table above, a clear explanation for medical necessity of the requested dose MUST be submitted, including prior dosing (strength and frequency) associated with inadequate response.
5. For commercial health plan members only, the site of service for inclisiran administration is specified, including CMS place of service code (see policy XI-06). If inclisiran is administered in a hospital outpatient facility, a clear explanation for the medical necessity of the site of service MUST be submitted, including documentation for one or more of the site of service criteria provided in policy XI-06.