Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors (PG068) Form

This can lead to an aortic aneurysm, where a section of the aorta becomes overly large and may rupture, a life-threatening event.

Ezetimibe

is a cholesterol-lowering medication that works by blocking the absorption of dietary cholesterol in the small intestine, which in turn decreases total and LDL cholesterol levels in the bloodstream.

Heterozygous Familial Hypercholesterolemia (HeFH)

is a genetic disorder, inherited from one parent, that results in high levels of LDL cholesterol, often leading to premature atherosclerotic cardiovascular disease.

Homozygous Familial Hypercholesterolemia (HoFH)

is a more severe form of familial hypercholesterolemia, inherited from both parents, that leads to extremely high LDL cholesterol levels. This can cause serious cardiovascular complications at a young age.

Low-Density Lipoprotein Cholesterol (LDL-C)

is often referred to as "bad" cholesterol, LDL-C transports cholesterol to the cells throughout the body. High levels of LDL-C can lead to a buildup of cholesterol in arteries, contributing to atherosclerosis.

Proprotein Convertase Subtilisin Kexin 9 (PCSK9)

is a protein that regulates the number of LDL receptors on the surface of cells. Inhibitors of PCSK9 increase the number of LDL receptors available to clear LDL cholesterol from the bloodstream.

Ribonucleic Acid (RNA)

is a single-stranded molecule involved in protein synthesis, gene regulation, and as the genetic material of some viruses. RNA plays a significant role in transmitting genetic information and cellular functioning.

Small Interfering RNA (siRNA)

is a type of RNA molecule that interferes with the expression of specific genes with complementary nucleotide sequences by degrading mRNA after transcription, preventing translation into protein. Inclisiran (Leqvio) uses siRNA technology to inhibit the production of PCSK9 protein, leading to lower LDL cholesterol levels.

Statins

refers to the class of medications, including drugs like atorvastatin and lovastatin, that lower cholesterol levels by inhibiting an enzyme (HMG-CoA reductase) involved in cholesterol synthesis in the liver.

Xanthoma

is a skin condition characterized by the deposition of fat beneath the skin's surface, leading to the formation of yellowish growths or bumps. Xanthomas are often indicative of underlying lipid disorders, including high cholesterol or triglyceride levels.

Clinical Indications

The Plan considers Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors medically necessary when ALL the following are met:

1. The member meets ALL the criteria relevant to the product and indications listed below; AND
2. Chart documentation and supporting lab work are submitted to validate the applicable criteria; AND
3. The requested product will be prescribed within the manufacturer’s published dosing guidelines or falls within dosing guidelines found in a compendia of current literature.

Medical Necessity Criteria for Initial Authorization

Praluent (alirocumab)

The Plan considers Praluent (alirocumab) medically necessary when ALL the following criteria are met for the applicable indication listed below:

Treatment of established atherosclerotic cardiovascular disease (ASCVD)

1. The member has clinical documentation showing a history of established ASCVD; AND
2. The member meets ONE of the following:
   • Current LDL-C level ≥ 70 mg/dL after a minimum three-month trial with at least TWO high-intensity statins (totaling 6 months) used in combination with ezetimibe; or
   • Current LDL-C level ≥ 70 mg/dL and the member has a documented contraindication or intolerance to statins.

Treatment of primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH)

1. The member has had an LDL-C level ≥ 190 mg/dL before any lipid-lowering therapies; AND
2. The member meets ONE of the following:
   • Current LDL-C level ≥ 100 mg/dL after a minimum three-month trial with at least TWO high-intensity statins (totaling 6 months) used in combination with ezetimibe; or

• Current LDL-C level ">= 100 mg/dL and the member has a documented contraindication or intolerance to statins.

Treatment of homozygous familial hypercholesterolemia (HoFH)

1. The member has a diagnosis of HoFH confirmed by ONE of the following:
   • Genetic testing demonstrating a mutation at the LDL receptor, ApoB, PCSK9, or ARH adaptor protein gene; or
   • Untreated LDL-C higher than 500mg/dL or treated LDL-C >=300 mg/dL and ONE of the following:
     1. Presence of cutaneous or tendinous xanthoma before the age of 10 years; or
     2. Elevated LDL-C levels consistent with heterozygous familial hypercholesterolemia in both parents;
2. The member has experienced an LDL-C level ">= 190 mg/dL before any lipid-lowering therapies;
3. The member meets ONE of the following:
   • Current LDL-C level ">= 100 mg/dL after a minimum three-month trial with at least TWO high-intensity statins (totaling 6 months) used in combination with ezetimibe; or
   • Current LDL-C level ">= 100 mg/dL and the member has a documented contraindication or intolerance to statins

If the above prior authorization criteria are met, Praluent (alirocumab) will be approved for 6 months.

Repatha (evolocumab)

The Plan considers Repatha (evolocumab) medically necessary when ALL the following criteria are met for the applicable indication listed below:

Treatment of clinical atherosclerotic cardiovascular disease (ASCVD)

1. The member has clinical documentation showing a history of established ASCVD; AND
2. The member meets ONE of the following:
   • Current LDL-C level ">= 70 mg/dL after a minimum three-month trial with at least TWO high-intensity statins (totaling 6 months) used in combination with ezetimibe; or
   • Current LDL-C level ">= 70 mg/dL and the member has a documented contraindication or intolerance to statins;
3. The member has a documented trial and failure, intolerance to, or contraindication from trying Praluent (alirocumab).

Treatment of primary hyperlipidemia including heterozygous familial hypercholesterolemia (HeFH)

1. The member is 10 years of age or older; AND
2. The member has had an LDL-C level ">= 190 mg/dL before any lipid-lowering therapies; AND
3. The member meets ONE of the following:
   • Current LDL-C level ">= 100 mg/dL after a minimum three-month trial with at least TWO high-intensity statins (totaling 6 months) used in combination with ezetimibe; or
   • Current LDL-C level ">= 100 mg/dL and the member has a documented contraindication or intolerance to statins;
4. The member has a documented trial and failure, intolerance to, or contraindication to trying Praluent (alirocumab).

Treatment of homozygous familial hypercholesterolemia (HoFH)

1. The member is 10 years of age or older; AND
2. The member has a diagnosis of HoFH confirmed by ONE of the following:
   • Genetic testing demonstrating a mutation at the LDL receptor, ApoB, PCSK9, or ARH adaptor protein gene; or
   • Untreated LDL-C higher than 500mg/dL or treated LDL-C >=300 mg/dL and ONE of the following:
     1. Presence of cutaneous or tendinous xanthoma before the age of 10 years; or
     2. Elevated LDL-C levels consistent with heterozygous familial hypercholesterolemia in both parents;
3. The member has experienced an LDL-C level ">= 190 mg/dL before any lipid-lowering therapies; AND
4. The member meets ONE of the following:
   • Current LDL-C level ">= 100 mg/dL after a minimum three-month trial with at least TWO high-intensity statins (totaling 6 months) used in combination with ezetimibe; or
   • Current LDL-C level ">= 100 mg/dL and the member has a documented contraindication or intolerance to statins;

The member has a documented trial and failure, intolerance to, or contraindication to trying Praluent (alirocumab).

If the above prior authorization criteria are met, Repatha (evolocumab) will be approved for 6 months.

Leqvio (inclisiran)

The Plan considers Leqvio (inclisiran) medically necessary when ALL the following criteria are met for the applicable indication listed below:

For the treatment of clinical atherosclerotic cardiovascular disease (ASCVD)

1. The member has clinical documentation showing a history of established ASCVD; AND
2. The member meets ONE of the following:
   • Current LDL-C level ≥ 70 mg/dL after a minimum three-month trial with at least TWO high-intensity statins (totaling 6 months) used in combination with ezetimibe; or
   • Current LDL-C level ≥ 70 mg/dL and the member has a documented contraindication or intolerance to statins;
3. The member has a documented trial and failure, intolerance to, or contraindication from trying Praluent (alirocumab).

For the treatment of heterozygous familial hypercholesterolemia (HeFH)

1. The member has experienced LDL-C level ≥ 190 mg/dL prior to any lipid-lowering therapies; AND
2. The member meets ONE of the following:
   • Current LDL-C level ≥ 100 mg/dL after a minimum three-month trial with at least TWO high-intensity statins (totaling 6 months) used in combination with ezetimibe; or
   • Current LDL-C level ≥ 100 mg/dL and the member has a documented contraindication or intolerance to statins;
3. The member has a documented trial and failure, intolerance to, or contraindication to trying Praluent (alirocumab).

If the above prior authorization criteria are met, Leqvio (inclisiran) will be approved for 6 months.

Medical Necessity Criteria for Reauthorization

Reauthorization of 12 months will be granted if the member has chart documentation demonstrating a clinical improvement in symptoms since starting the requested medication and ONE of the following criteria is met:

1. The member has shown a reduction in LDL-C since starting the requested medication; OR
2. The member has reached the LDL-C goal and has maintained LDL-C levels

Experimental or Investigational / Not Medically Necessary

PCSK9 Inhibitors for any other indication is considered not medically necessary by the Plan, as it is deemed to be experimental, investigational, or unproven.

Appendix

The treatment of dyslipidemia involves multiple considerations, as recommended by several prominent professional organizations, including the American College of Cardiology, the American Heart Association, and the American Association of Clinical Endocrinology.

1. Treatment Goals

Reduction of elevated atherogenic cholesterol to prevent cardiovascular events

• Reduction of elevated triglyceride levels to prevent acute pancreatitis
• Administration of statin therapy to patients with known cardiovascular disease regardless of baseline LDL-C levels
• Risk assessment for primary prevention of cardiovascular disease in high-risk patients

2. Treatment Targets

• The intensity of statin therapy for desired reduction of LDL-C levels is set by the American College of Cardiology/American Heart Association guidelines.
• LDL-C and non-HDL-C levels are set by the American Association of Clinical Endocrinology guideline and National Lipid Association guideline.

3. Treatment Options

• Lifestyle changes
• Pharmacologic therapy based on LDL-C levels and risk assessment

4. Recommendations for Specialist Referral

Patients with suspected primary or familial forms of dyslipidemia

• Pregnant patients¹
• Patients with diagnosed homozygous or severe heterozygous familial hypercholesterolemia
• Patients with severe hypertriglyceridemia

These guidelines provide a framework for the management of dyslipidemia, with the ultimate goal of reducing the risk of atherosclerotic cardiovascular disease and associated events.

The following tables summarize key recommendations from these diverse guidelines, highlighting the importance of individualized patient care based on specific clinical conditions, tolerability, and potential drug-drug interactions. Regular follow-ups are essential to ensure adherence to therapy and to assess response and side effects.

Recommendations

Treatment Goals

• Reduce atherogenic cholesterol: Use high-intensity statin therapy to reduce LDL-C levels by 50% or more
• Reduce triglyceride levels: Depending on severity, recommend lifestyle changes, fibrates, omega-3 fatty acids, or nicotinic acid
• Secondary prevention in patients with known CVD: Use high-intensity or maximally tolerated statin therapy
• Primary prevention: Statin therapy for patients aged 40-75 years with ≥7.5% 10-year ASCVD risk; lifestyle modifications for all adults

Treatment Intensity

• High Intensity: Reduce LDL-C by 50% or more
• Moderate Intensity: Reduce LDL-C by 30%-49%
• Low Intensity: Reduce LDL-C by less than 30%

AACE Risk Category

• Extreme Risk
• Very High Risk
• High Risk
• Moderate Risk
• Low Risk

Treatment Options

• Lifestyle Changes: Attain and maintain a healthy BMI, healthy diet, physical exercise, cessation of tobacco and alcohol use
• Pharmacologic Therapy: Based on LDL-C levels and risk assessment, consider statins, PCSK9 inhibitors, ezetimibe, and monoclonal antibodies

Recommendation for Specialist Referral

• Primary or familial forms of dyslipidemia: LDL-C level ≥190 mg/dL
• Diagnosed familial hypercholesterolemia: Treatment intensification as needed
• Severe hypertriglyceridemia: Specialist treatment as needed

References

1. Bajaj A, Cuchel M. Advancements in the treatment of homozygous familial hypercholesterolemia. J Atheroscler Thromb. 2022;29(8):1125-1135.
2. Blom DJ, Harada-Shiba M, Rubba P, et al. Efficacy and safety of alirocumab in adults with homozygous familial hypercholesterolemia: The ODYSSEY HoFH Trial. J Am Coll Cardiol.2020;76(2):131-142.
3. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. Circulation. 2019;139(25):e1082-e1143. doi:10.1161/CIR.0000000000000625
4. Koren MJ, et al. Long-Term Efficacy and Safety of Evolocumab in Patients With Hypercholesterolemia. Journal of the American College of Cardiology; Volume 74, Issue 17, October 2019. 2132-46. doi: 10.1016/j.jacc.2019.08.1024
5. Leqvio (inclisiran) [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; December 2021.
6. Leucker TM, et al. Effect of Evolocumab on Atherogenic Lipoproteins During the Peri- and Early Postinfarction Period. Circulation. 2020;142:419–421. doi:10.1161/CirculationAHA.120.046320.3
7. Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. 2017 Focused Update of the 2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways.

1. Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. 2022 ACC expert consensus decision pathway on the role of nonstatin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2022;80(14):1366-1418. doi:10.1016/j.jacc.2022.07.006
2. National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults: Adult Treatment Panel III Report. From AHA web site.
3. Praluent [package insert]. Tarrytown, NY: Regeneron Pharmaceuticals, Inc. April 2021.
4. Repatha [package insert]. Thousand Oaks, CA: Amgen Inc. September 2021.
5. Rosenson RS, Durrington P. Familial hypercholesterolemia in adults: Treatment. UpToDate.com. Available at: https://www.uptodate.com/contents/familial-hypercholesterolemia-in-adults-treatment. Updated July 07, 2020. Accessed August 22, 2020.
6. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713-22. doi:10.1056/NEJMoa1615664
7. Stone NJ, Robinson JG, 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:S1-S45.

Clinical Guideline Revision / History Information

• Original Date: 11/05/2020
• Reviewed/Revised: 10/14/2021, 12/01/2021, 05/22/2022 , 6/29/2023