Description
Inclisiran (Leqvio^®) is a double-stranded small interfering ribonucleic acid (siRNA), conjugated on the sense strand with triantennary N-Acetylgalactosamine (GalNAc) to facilitate uptake by hepatocytes. In hepatocytes, inclisiran utilizes the RNA interference mechanism and directs catalytic breakdown of mRNA for PCSK9. This increases LDL-C receptor recycling and expression on the hepatocyte cell surface, which increases LDL-C uptake and lowers LDL-C levels in the circulation.

Coverage is subject to benefit plan.

Background
Leqvio is a small interfering RNA (siRNA) directed to proprotein convertase subtilisin kexin type 9 (PCSK9) mRNA indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who require additional lowering of LDL-C (low density lipoprotein cholesterol). In hepatocytes, Leqvio utilizes the RNA interference mechanism and directs catalytic breakdown of mRNA for PCSK9. This increases LDL-C receptor recycling and expression on the hepatocyte cell surface, which increases LDL-C uptake and lowers LDL-C levels in the circulation. Leqvio’s dosage is 284 mg administered as a subcutaneous injection initially, again at 3 months, and then every 6 months. Leqvio should be administered by a healthcare professional.

It should be noted that the effects of Leqvioon cardiovascular morbidity and mortality have not been determined. Leqvio and the PCSK9 inhibitors have not been studied head to head, but have similar LDL-C reductions. Currently, the PCSK9 inhibitors offer an equally efficacious and more cost-effective option for the lowering of cholesterol in patients with HeFH or atherosclerotic cardiovascular disease.

Hypercholesterolemia/Treatment Guidelines
Approximately 30% of the United States population has elevated LDL-C (low density lipoprotein cholesterol). There is also a subset of hypercholesterolemia, known as familial hypercholesterolemia, which can affect nearly 1 in 300 individuals. Familial hypercholesterolemia can further be broken down into homozygous and heterozygous forms o f familial hypercholesterolemia. The homozygous form is by far the rarest with an estimated incidence of 1 in 1,000,000 individuals. The gold standard for the treatment of elevated LDL-C levels is a statin given along with ezetimibe (Zetia) to provide the greatest amount of LDL-C lowering. Statin products also have proven cardiovascular outcomes. Genetic testing is available to determine whether or not an individual has familial hypercholesterolemia, however clinical signs/symptoms are often a more practic al method of diagnosing this condition. Clinical studies have used the WHO/Dutch Lipid Clinic Network Familial Hypercholesterolemia diagnostic criteria to determine if an individual had familial hypercholesterolemia. A score of > 8 is representative of “definite” familial hypercholesterolemia. The criteria are located in the following chart:

WHO (World Health Organization)/Dutch Lipid Clinic Network Familial Hypercholesterolemia Criteria

Premature = < 55 years in men; < 60 years in women

The 95th percentile in the “WHO/Dutch Lipid Clinic Network Familial Hypercholesterolemia 
Criteria” chart refers to the following LDL cholesterol values:

The above chart comes from Lipid Research Clinic Data 1983. Available at: http://www.ncbi.nlm.nih.gov/books/NBK351/table/A968/?report=objectonly

The following link for the ATP III- A distribution of LDL Cholesterol in the US Adult Population also provides percentile values. It is located at: http://circ.ahajournals.org/content/106/25/3237/T2.expansion.html.    

The American College of Cardiology (ACC)/American Heart Association (AHA) treatment guidelines no longer set treatment goals for hyperlipidemia. The guidelines instead emphasize the appropriate intensity of statin therapy to reduce cardiovascular risk in patients who will benefit. These guidelines also emphasize the benefits of LDL-C reduction. The National Lipid Association does set LDL-C treatment goal levels for patients at various risk stratifications. Those with clinical atherosclerotic cardiovascular disease would fall into the “very high risk” category an d would therefore be treated to an LDL-C of less than 70 mg/dL. Patients with familial hypercholesterolemia could fall into either the “very high risk” or “high risk” categories, based on their patient characteristics and would therefore have a treatment goal of less than 70 mg/dL or 100 mg/dL (respectively). Risk stratification (per the National Lipid Association) is as follows:

Risk Classifications:
Very High Risk:

1. ASCVD (atherosclerotic cardiovascular disease)#; OR
2. Diabetes Mellitus with ≥ 2 other Major ASCVD risk factors^ OR diabetes mellitus with end organ damage [e.g., increased albumin/creatinine ratio ( ≥ 30mg/g), chronic kidney disease, or retinopathy]

High Risk:

1. ≥ 3 major ASCVD risk factors^; OR
2. Diabetes Mellitus with 0 – 1 other Major ASCVD risk factors^; OR
3. Chronic kidney disease (GFR ≤ 44 mL/min); OR
4. LDL-C ≥ 190 mg/dL (untreated); OR
5. Quantitative risk score reaching the high risk threshold (one of the following)
   1. ≥ 10% using Adult Treatment Panel III Framingham risk score for hard coronary heart disease (CHD, MI, or CHD death); OR
   2. ≥ 15% using the 2013 Pooled Cohort Equations for hard ASCVD (MI, stroke, or death from CHD or stroke); OR
   3. ≥ 45% using the Framingham long-term CVD (MI, CHD death or stroke) risk calculator

^#ASCVD (includes one of more of the following):

1. Myocardial infarction or other acute coronary syndrome
2. Coronary or other revascularization procedure
3. Transient ischemic attack
4. Ischemic stroke
5. Atherosclerotic peripheral arterial disease (ABI of < 0.90)
6. Other documented atherosclerotic diseases such as
   1. Coronary atherosclerosis 
   2. Renal atherosclerosis 
   3. Aortic aneurysm secondary to atherosclerosis 
   4. Carotid plaque ( ≥ 50% stenosis)

^ASCVD Risk factors:

1. Age
   1. Male ≥ 45 years
   2. Female ≥ 55 years
2. Family history of early CHD (MI, death, or coronary revascularization procedure)
   1. < 55 years of age in a male first degree relative or 
   2. < 65 years of age in a female first degree relative 
3. Current cigarette smoking
4. High blood pressure ( ≥ 140/ ≥ 90 mm Hg) or on a blood pressure medication)
5. Low HDL-C
   1. Male < 40 mg/dL 
   2. Female < 50 mg/dL

Treatment Goals:

Primary Hypercholesterolemia/Atherosclerotic Cardiovascular Disease 
These products do not have any cardiovascular outcomes data to date.

Statin Intolerance 
Statins have been associated with muscle-related adverse effects such as myalgia (e.g., muscle aches, soreness, stiffness, or tenderness), myopathy (muscle weakness), and/or myositis (muscle inflammation). Although the incidence is variable, muscle adverse effects are reported in around 5% of patients receiving statins, but may be due to other causes (e.g., excessive exercise, other medical conditions [hypothyroidism], non-statin medications). It is advisable to assess for drug interactions as well as to check vitamin D levels and thyroid function status. Rhabdomyolysis, which is uncommon with statin therapy, is a severe muscle-related adverse effect that results in muscle breakdown associated with muscle-related symptoms (e.g., muscle pain, weakness, tenderness) along with acute renal failure and elevated creatine kinase [CK] levels (myonecrosis). In patients with statin-related muscle adverse events, symptoms may not re-occur if the patient switches to a different statin therapy. Pravastatin and fluvastatin appear to have much less intrinsic muscle toxicity than other statins and could be considered for those who had statin related intolerable muscle symptoms.

In 2014, the NLA Statin Intolerance Panel published an update. It was stated that most statin intolerance is due to myalgia. The strongest evidence at present for statin intolerance in a population is that myalgia appears but then remits with withdrawal but reoccurs with re -challenge. The incidence of statin intolerance is widely variable. The Panel states that statins are among the safest medications available. The Panel does advise that due to statin benefits, it is safe to recommend a patient continue statin therapy even when some degree of statin intolerance is present, if the patient can reasonably tolerate the statin. A pivotal trial with Praluent called ODYSSEY ALTERNATIVE defined statin intolerance as the inability to take at least two different statins due to muscle -related adverse effects, of which one statin was administered at the lowest approved starting dose. Data also suggest that many patients who are re-challenged with statin therapy after an adverse event may be able to tolerate statin therapy long-term. Of note, in the ODYSSEY ALTERNATIVE trial with Praluent, 69.8% of patients who were considered statin intolerant were treated with atorvastatin 20 mg daily and completed the double-blind 24-week portion of the trial. This suggests that re-challenge with a statin in those purported to be statin intolerant is reasonable and may lead to successful use of a statin therapy.

Regulatory Status
Leqvio is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who require additional lowering of LDL-C (low density lipoprotein cholesterol).

Policy
Legvio Criteria
Initial criteria

1. Member has one of the following diagnoses (a or b):
   1. Atherosclerotic cardiovascular disease (ASCVD) as evidenced by a history of any one of the following conditions:
      1. Acute coronary syndromes
      2. Coronary or other arterial revascularization
      3. Myocardial infarction
      4. Peripheral arterial disease presumed to be of atherosclerotic origin
      5. Stable or unstable angina
      6. Stroke or transient ischemic attack (TIA); OR
   2. Heterozygous Familial Hypercholesterolemia (HeFH) and member meets both of the following (I and II) and
      1. One of the following:
         1. Family history of myocardial infarction in first-degree relative less than 60 years of age
         2. Family history of myocardial infarction in second-degree relative less than 50 years of age
         3. Family history of LDL-C greater than 190 mg/dL in first- or second-degree relative
         4. Family history of familial hypercholesterolemia in first- or second-degree relative
         5. Family history of tendinous xanthomata and/or arcus cornealis in first- or second-degree relative
      2. One of the following:
   3. 1. 1. 1. Functional mutation in the LDL receptor, ApoB, or PCSK9 gene
            2. Tendinous xanthomata
            3. Arcus cornealis before age 45, And
2. Untreated/pre-treatment LDL-cholesterol (LDL-C) greater than 190 mg/dL, AND
3. Medication will not be used in combination with PCSK9 inhibitor therapy, AND
4. One of the following:
   1. Member has been receiving at least 12 consecutive weeks of high-intensity statin therapy [i.e., atorvastatin 40 – 80 mg, rosuvastatin 20 – 40 mg] and will continue to receive a high-intensity statin at maximally tolerated dose, or
   2. Both of the following:
      1. Member is unable to tolerate high-intensity statin as evidenced by one of the following intolerable and persistent (i.e., more than 2 weeks) symptoms:
      2. Myalgia (muscle symptoms without CK elevations)
      3. Myositis (muscle symptoms with CK elevations less than 10 times upper limit of normal [ULN]), and
   3. One of the following:
      1. Member has been receiving at least 12 consecutive weeks of moderate-intensity statin therapy [i.e., atorvastatin 10 – 20 mg, rosuvastatin 5 – 10 mg, simvastatin 20 – 40 mg, pravastatin 40 – 80 mg, lovastatin 40 mg, Lescol XL (fluvastatin XL) 80 mg, fluvastatin 40 mg twice daily, or Livalo (pitavastatin) 2 – 4 mg] and will continue to receive a moderate-intensity statin at maximally tolerated dose, or
      2. Member has been receiving at least 12 consecutive weeks of low-intensity statin therapy [i.e., simvastatin 10 mg, pravastatin 10 – 20 mg, lovastatin 20 mg, fluvastatin 20 – 40 mg, Livalo (pitavastatin) 1 mg] and will continue to receive a low-intensity statin at maximally tolerated dose, or
      3. Member is unable to tolerate low- or moderate-, and high-intensity statins as evidenced by one of the following intolerable and persistent (i.e., more than 2 weeks) symptoms for low- or moderate-, and high-intensity statins:
         1. Myalgia (muscle symptoms without CK elevations)
         2. Myositis (muscle symptoms with CK elevations less than 10 times ULN), or
      4. Member has a contraindication to all statins, or
      5. Member has experienced rhabdomyolysis or muscle symptoms with statin treatment with CK elevations greater than 10 times ULN, AND
5. Member meets one of the following:
   1. Member has been receiving at least 12 consecutive weeks of ezetimibe (Zetia) therapy as adjunct to maximally tolerated statin therapy, or
   2. Member has a history of contraindication or intolerance to ezetimibe.
6. Member is unable is unable to maintain adherence to proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor therapy, AND
7. Member’s medical record documents one of the following LDL-C values while on maximally tolerated lipid lowering therapy within the last 4 months:
   1. LDL-C greater than or equal to 70 mg/dL for diagnosis of ASCVD
   2. LDL-C greater than or equal to 100 mg/dL for diagnosis of HeFH, or
8. Prescribed by or in consultation with one of the following:
   1. Cardiologist
   2. Endocrinologist
   3. Lipid specialist

Auth duration: 6 months

Reauthorization criteria

1. Documentation that member is responsive to therapy as demonstrated by LDL-C reduction from baseline while on therapy, AND
2. Medication will not be used in combination with PCSK9 inhibitor therapy, AND
3. Prescribed by or in consultation with one of the following:
   1. Cardiologist
   2. Endocrinologist
   3. Lipid specialist, AND
4. Member meets one of the following:
   1. Member continues to receive other lipid-lowering therapy (e.g., statins, ezetimibe) at the maximally tolerated dose, or
   2. Member has a documented inability to take other lipid-lowering therapy (e.g., statins, ezetimibe)

Auth duration: 12 months

Rationale
This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. Food and Drug Administration approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines. 

The efficacy of Leqvio was investigated in three randomized, double-blind, placebo-controlled trials that enrolled 3,457 adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (ASCVD), who were taking maximally tolerated statin therapy and who required additional LDL-C (low density lipoprotein cholesterol) lowering. Demographics and baseline disease characteristics were balanced between the treatment arms in all trials.

LDL-C Reduction in Patients With ASCVD 
Study 1 (ORION-10) was a multicenter, double-blind, randomized, placebo-controlled 18-month trial in which 1,561 patients with ASCVD were randomized 1:1 to receive subcutaneous injections of either Leqvio 284 mg (n = 781) or placebo (n = 780) on Day 1, Day 90, Day 270, and at Day 450. Patients were taking a maximally tolerated dose of statin with or without other lipid modifying therapy, and required additional LDL-C reduction. Patients were stratified by current use of statins or other lipid-modifying therapies. Patients taking PCSK9 inhibitors were excluded from the trial. The mean baseline LDL-C was 105 mg/dL. At the time of randomization, 89% of patients were receiving statin therapy and 69% were receiving high-intensity statin therapy. The primary efficacy outcome measure in Study 1 was the percent change from baseline to Day 510 in LDL-C. The difference between the Leqvio and placebo groups in mean percentage change in LDL-C from baseline to Day 510 was -52% (95% CI: -56%, -49%; p < 0.0001). 

Study 2 (ORION-11) was a multicenter, double-blind, randomized, placebo-controlled 18-month trial in which 1,414 adults with ASCVD were randomized 1:1 to receive subcutaneous injections of either Leqvio 284 mg (n = 712) or placebo (n = 702) on Day 1, Day 90, Day 270, and Day 450. Patients were taking a maximally tolerated dose of statin with or without other lipid modifying therapy, and required additional LDL-C reduction. Patients were stratified by country and by current use of statins or other lipid-modifying therapies. Patients taking PCSK9 inhibitors were excluded from the trial. The mean baseline LDL-C was 101 mg/dL. At the time of randomization, 96% of 
patients were receiving statin therapy and 80% were receiving high-intensity statin therapy. The primary efficacy outcome measure in Study 2 was the percent change from baseline to Day 510 in LDL-C. The difference between the Leqvio and placebo groups in mean percentage change in LDL-C from baseline to Day 510 was -51% (95% CI: -54%, -47%; p < 0.0001). 

LDL-C Reduction in Patients With HeFH
Study 3 (ORION-9) was a multicenter, double-blind, randomized, placebo-controlled 18-month trial in which 482 patients with HeFH were randomized 1:1 to receive subcutaneous injections of either Leqvio 284 mg (n = 242) or placebo (n = 240) on Day 1, Day 90, Day 270, and at Day 450. Patients with HeFH were taking a maximally tolerated dose of statin with or without other lipid modifying therapy, and required additional LDL-C reduction. The diagnosis of HeFH was made either by genotyping or clinical criteria using either the Simon Broome or WHO/Dutch Lipid Network criteria. Patients were stratified by country and by current use of statins or other lipid-modifying therapies. Patients taking PCSK9 inhibitors were excluded from the trial. The mean baseline LDL-C was 153 mg/dL. At the time of randomization, 90% of patients were receiving statin therapy and 74% were receiving high-intensity statin therapy. Fifty-two percent (52%) of patients were treated with ezetimibe. The most commonly administered statins were atorvastatin and rosuvastatin. The primary efficacy outcome measure in Study 3 was the percent change from baseline to Day 510 in LDL-C. The difference between the Leqvio and placebo groups in mean percentage change in LDL-C from baseline to Day 510 was -48% (95% CI: -54%, -42%; p < 0.0001).

References

1. Leqvio (package insert). Novartis Pharmaceuticals Corporation. Easy Hanover, New Jersey. Updated December 2021. 
2. Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice guidelines. Circulation. 2014;129(25 Suppl 2):S1-S45. Available at http://circ.ahajournals.org/content/early/2013/11/11/01.cir.0000437738.63853.7a. 
3. Jacobson TA, Ito MK, Maki KC, et al. National Lipid Association recommendations for patient-centered management of dyslipidemia: Part 1-executive summary. J Clin Lipidol. 2014;8:473-488. Available at: http://www.lipidjournal.com/article/S1933-2874(14)00274-8/pdf.
4. Jacobson TA, Ito MK, Maki KC, et al. National Lipid Association recommendations for patient-centered management of dyslipidemia: Part 1-full report. J Clin Lipidol. 2015;9:129-169.
5. Rosenson RS, Baker SK, Jacobson TA, et al. An assessment by the statin muscle safety task force: 2014 update. J Clin Lipidol. 2014;8:S58-S71.
6. Guyton JR, Bays HE, Grundy SM, Jacobson TA. An assessment by the Statin Intolerance Panel: 2014 update. J Clin Lipidol. 2014;8:S72-S81. 
7. Moriarty PM, Jacobson TA, Bruckert E, et al. Efficacy and safety of alirocumab, a monoclonal antibody to PCSK9, in statin-intolerant patients: design and rationale of ODYSSEY ALTERNATIVE, a randomized phase 3 trial. J Clin Lipidol. 2014;8:554-561.
8. Zhang H, Plutzky J, Skentzos S, et al. Discontinuation of statins in routine care settings. Ann Intern Med. 2013;158(7):526-534.
9. Mampuya WM, Frid D, Rocco M, et al. Treatment strategies in patients with statin intolerance: the Cleveland Clinic Experience. Am Heart J. 2013;166(3):597-603.
10. 95th Percentile Chart: Chapter 31: Cholesterol, Triglycerides, and Associated Lipoproteins; In Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition. Walker HK, Hall WD, Hurst JW, et al. Available at: http://www.ncbi.nlm.nih.gov/books/NBK351/table/A968/?report=objectonly. 
11. Alternative percentile link: ATP III Final Report Appendix III-A Distributions of Total Cholesterol, LDL Cholesterol, HDL Cholesterol, and Triglycerides in the U.S. Adult Population, NHANES III Data (1988-1994. Available at: http://circ.ahajournals.org/content/106/25/3237/T2.expansion.html. 
12. Steg G, Schwartz GG, Szarek M, et al, on behalf of the ODYSSEY Outcomes Investigators and Committees. The ODYSSEY Outcomes trial: topline results. Alirocumab in patients after acute coronary syndrome. Presented at: the American College of Cardiology 67th Scientific Sessions; Orlando, FL; March 10-12, 2018. Presented March 10, 2018. Available at: http://www.acc.org/educationand-meetings/image-and-slide-gallery/media-detail?id=90e30055844c402ba16d54fb05e45136

Coding Sections

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each Policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

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