Coverage Policy Manual
Policy #: 2016011
Category: Pharmacy
Initiated: April 2016
Last Review: September 2022
  PCSK9 INHIBITORS (e.g., Evolocumab) (e.g., Alirocumab)

Description:
The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are a novel class of medications to treat hypercholesterolemia. PCSK9 is a regulatory serine protease that increases circulating levels of low-density lipid cholesterol (LDL-C). PCSK9 binding leads to a degradation of LDL receptors and a corresponding inhibition of LDL-C breakdown.  By inhibiting the binding of PCSK9 to LDL receptors, the PCSK9 inhibitors have been shown in clinical trials to induce potent lowering of LDL-C.
 
In July 2015, the U.S. FDA approved alirocumab (e.g., Praluent) injection, the first PCSK9 inhibitor approved for the use in addition to diet, alone or in combination with other lipid lowering therapies, for the treatment of adult patients with heterozygous familial hypercholesterolemia (HeFH), or primary hyperlipidemia. Alirocumab (e.g., Praluent) is also approved to reduce the risk of myocardial infarction, stroke, and unstable angina requiring hospitalization in adult patients with clinical atherosclerotic cardiovasular disease..
 
In August 2015, the FDA approved a second PCSK9 inhibitor, evolocumab (e.g., Repatha™), as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (ASCVD), who require additional lowering of low-density lipoprotein cholesterol (LDL-C).
 
Evolocumab (e.g., Repatha™) is also indicated as an adjunct to diet and other LDL-lowering therapies (e.g. statins, ezetimibe, LDL apheresis) in patients with homozygous familial hypercholesterolemia (HoFH) who require additional lowering of LDL-C.   
 
In April 2021, the FDA approved alirocumab (e.g., Praluent) for adults with homozygous familial hypercholesterolemia.

Policy/
Coverage:
Subcutaneous PCSK9 Inhibitors are 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 have a PCSK9 Inhibitor as a formulary option. Covered product is dependent on member’s formulary.
 
Effective January 2022
 
I. REQUIRED DOCUMENTATION
The following information is necessary to initiate the prior authorization review:
For initial authorization:
 
        • Prior and current lipid-lowering treatments and response (e.g., medication, dose, and treatment duration, LDL-C reduction, reason for discontinuation)
        • Recent (e.g., within 120 days of the prior authorization request) cholesterol test
 
For continuation of treatment:
 
        • Pretreatment and current LDL-C levels, including percentage and absolute reductions in LDL-C
        • If triglycerides are >= 400, a direct LDL measurement is required.
 
II. CRITERIA FOR INITIAL APPROVAL
 
A. Clinical Atherosclerotic Cardiovascular Disease (ASCVD) (FDA, ACC/AHA)
Authorization for 12 months may be granted for members who meet ALL of the criteria listed below:
 
    1. Member is 18 years of age or older (FDA)
 
2. Member has a history of ASCVD or one of the following cardiovascular events: (FDA, AHA/ACC)
• Acute coronary syndrome
• Myocardial infarction
• Stable or unstable angina
• Coronary or other arterial revascularization procedure (e.g., PTCA, CABG)
• Stroke of presumed atherosclerotic origin
• Transient ischemic attack (TIA)
• Peripheral arterial disease of presumed atherosclerotic origin
• Finding from CT angiogram or catheterization consistent with ASCVD, AND
 
3. Member meets at least ONE of the following requirements (AHA/ACC):
a. Member has a current LDL-C level 70 after at least three months of an adherent treatment with a high-intensity statin (atorvastatin 40 mg or rosuvastatin 20 mg daily) plus ezetimibe 10 mg daily. OR
b. Member has a current LDL-C level 70 with contraindication*or failure of statin and is taking ezetimibe with or without other lipid lowering medications at maximally tolerated doses or at the maximum doses approved by the FDA. OR
c. Member has a current LDL-C level 70 on high intensity statin but has intolerance or failure of ezetimibe.
 
 *Note: Contraindication, for the purpose of this guideline is defined as:
            • Anaphylactic reaction to 2 high intensity statins  
            • Statin intolerance due to myalgias after failure of two or more statins at varying intensities (e.g. Atorvastatin 40mg and Simvastatin 10mg) There should be documentation of efforts to overcome statin intolerance. Examples include alternate day statin or starting with a low dose or less potent statin and titrating the dose upward over time.   
            • Prior documentation of statin-associated rhabdomyolysis (CK level greater than 10,000 IU/L or elevation accompanied by significant increase in creatinine level)  
            • Prior documentation of statin-associated myositis (CK >3 times the upper limit of normal and either severe myalgia or weakness)  
 
B. Heterozygous Familial Hypercholesterolemia (FH) (FDA, AHA/ACC)
Authorization for 12 months may be granted for members who meet ALL of the criteria listed below:
    1. Member is 18 years of age or older. (FDA)
 
2. Member has a definite diagnosis of familial hypercholesterolemia as evidenced by meeting one of the following diagnostic criteria: (FDA)
a. Simon-Broome Diagnostic Criteria for definite FH
• Total cholesterol > 290 mg/dL or LDL-C > 190 mg/dL, plus tendon xanthomas in first- (parent, sibling or child) or second-degree relative (grandparent, uncle or aunt) ; OR
b. Dutch Lipid Clinic Network Criteria for definite FH
• Total score > 8 points.
 
3. Member meets at least ONE of the following requirements: (AHA/ACC)
a. With ASCVD: Criteria in Section A must be met.
b. Without ASCVD: Member has a current LDL-C level 100 after at least three months of an adherent treatment with a high-intensity statin (atorvastatin 40 mg or rosuvastatin 20 mg daily) plus ezetimibe 10 mg daily.
c. Member has a current LDL-C level 100 with contraindication* to statin and is taking ezetimibe with or without other lipid lowering medications at maximally tolerated doses or at the maximum doses approved by the FDA.
d. Member has a current LDL-C level 100 and contraindication* to both statin and ezetimibe.
 
*Note: Contraindication, for the purpose of this guideline is defined as:
        • Anaphylactic reaction  
        • Statin intolerance due to myalgias after failure of two or more statins at varying intensities (e.g. Atorvastatin 40mg and Simvastatin 10mg)  
        • Prior documentation of statin-associated rhabdomyolysis (CK level greater than 10,000 IU/L or elevation accompanied by significant increase in creatinine level)  
        • Prior documentation of statin-associated myositis (CK >3 times the upper limit of normal and either severe myalgia or weakness)  
 
C. Homozygous Familial Hypercholesterolemia (FDA)
Authorization for 12 months may be granted for members who meet ALL of the applicable criteria listed below:
1. Repatha for members 13 years of age or older OR Praluent for members 18 years of age or older (FDA)
 
2. Member has a diagnosis of homozygous FH confirmed by genetic analysis or clinical criteria as defined (FDA):
a. Genetic diagnosis
        • Mutations in both alleles at LDL receptor, ApoB, PCSK9 or LDL receptor adaptor protein gene locus
b. Clinical diagnosis
        • Untreated LDL-C > 500mg/dL OR unknown untreated LDL-C with treated LDL-C > 300mg/dL; PLUS  
        • One of the following:
          • Tendon or cutaneous xanthomas at age 10 or younger
          • Diagnosis of definite FH by either:
            • Simon-Broome Diagnostic Criteria- Total cholesterol > 290 mg/dL or LDL-C > 190 mg/dL, plus tendon xanthomas in first- (parent, sibling or child) or second-degree relative (grandparent, uncle or aunt); OR
            • Dutch Lipid Clinic Network Criteria- Total score > 8 points.
          • Evidence of FH in both parents with a history including any of the following:
            • Total cholesterol >310 mg/dL
            • Premature ASCVD (before 55 years in men and 60 years in women
            • Tendon xanthoma
            • Sudden premature cardiac death
 
3. For adolescents (between 13 and 18 years of age): Member meets at least ONE of the following requirements (De Ferranti, 2020):
a. Member has a current LDL-C level 135 mg/dL after at least three months of an adherent treatment with atorvastatin 20 mg or rosuvastatin 20 mg daily plus ezetimibe 10 mg daily.
b. Member has a current LDL-C level 135 mg/dL with contraindication* to statins and is taking ezetimibe with or without other lipid-lowering therapy.
c. Member has a current LDL-C level 135 mg/dL and contraindication* to both statin and ezetimibe and is receiving other lipid-lowering therapy.
d. Member has a current LDL-C level 135 mg/dL AND has received at least a three-month supply of Juxtapid or Kynamro through a prior authorization process for a pharmacy or medical benefit within the previous 120 days. And the member will not take evolocumab (Repatha) concurrently with lomitapide (Juxtapid) or mipomersen (Kynamro).
e. Member has been treated regularly with lipid apheresis for at least 3months within the previous 120 days.
 
4. For adults (age 18 and older): Member meets at least ONE of the following requirements (AHA/ACC 2018):
a. With ASCVD- Must meet requirements in Section A.
b. Without ASCVD: Member has a current LDL-C level 100 mg/dL after at least three months of an adherent treatment with atorvastatin 40 mg or rosuvastatin 40 mg daily plus ezetimibe 10 mg daily.
c. Member has a current LDL-C level 100 mg/dL with contraindication* to statins and is taking ezetimibe with or without other lipid-lowering therapy.
d. Member has a current LDL-C level 100 mg/dL and contraindication* to both statin and ezetimibe and is receiving other lipid-lowering therapy.
e. Member has a current LDL-C level 100 mg/dL (or 70 mg/dL with ASCVD) AND has received at least a three-month supply of Juxtapid or Kynamro through a prior authorization process for a pharmacy or medical benefit within the previous 120 days. And the member will not take evolocumab (Repatha) concurrently with lomitapide (Juxtapid) or mipomersen (Kynamro).
f. Member has been treated regularly with lipid apheresis for at least 3months within the previous 120 days.
 
*Note: Contraindication, for the purpose of this guideline is defined as:
        • Anaphylactic reaction  
        • Statin intolerance due to myalgias after failure of two or more statins at varying intensities (e.g. Atorvastatin 40mg and Simvastatin 10mg)  
        • Prior documentation of statin-associated rhabdomyolysis (CK level greater than 10,000 IU/L or elevation accompanied by significant increase in creatinine level)  
        • Prior documentation of statin-associated myositis (CK >3 times the upper limit of normal and either severe myalgia or weakness)  
 
III.CRITERIA FOR CONTINUATION OF THERAPY
A. ASCVD
1. Authorization of 12 months may be granted for members who have received at least a three-month supply of the requested medication through prior authorization process for a pharmacy or medical benefit and achieved
a. LDL-C reduction 35% OR
b. Reduction below the LDL-C of 100 mg/dL
 
B. Heterozygous FH
1. Authorization of 12 months may be granted for members without ASCVD who have received at least a three-month supply of the requested medication through prior authorization process for a pharmacy or medical benefit and achieve or maintain a LDL-C reduction, as defined below;
a. LDL-C reduction 35% OR
b. Reduction below the LDL-C of 100 mg/dL
 
C. Homozygous FH
1. Authorization of 12 Authorization of 12 months may be granted for members < 18 years of age who have received at least a three-month supply of the requested medication through prior authorization process for a pharmacy or medical benefit and achieve or maintain a LDL-C reduction, as defined below:
a. LDL-C reduction 20% OR
b. Reduction below the LDL-C level of 135 mg/dL
2. Authorization of 12 months may be granted for members 18 years of age who have received at least a three-month supply of the requested medication through prior authorization process for a pharmacy or medical benefit and achieve or maintain a LDL-C reduction, as defined below:
a. LDL-C reduction 20% OR
b. Reduction below the LDL-C of 100 mg/dL with or without ASCVD
 
IV. DOSAGE AND ADMINISTRATION
In accordance with FDA labeling
 
Effective April 2021 - January 2022
 
I. REQUIRED DOCUMENTATION
The following information is necessary to initiate the prior authorization review:
For initial authorization:
    • Prior and current lipid-lowering treatments and response (e.g., medication, dose, and treatment duration, LDL-C reduction, reason for discontinuation)
    • Recent (e.g., within 120 days of the prior authorization request) cholesterol test
For continuation of treatment:
    • Pretreatment and current LDL-C levels, including percentage and absolute reductions in LDL-C
    • If triglycerides are >= 400, a direct LDL measurement is required.
 
II. CRITERIA FOR INITIAL APPROVAL
A. Clinical Atherosclerotic Cardiovascular Disease (ASCVD)
Authorization for 12 months may be granted for members who meet ALL of the criteria listed below:
1. Member is 18 years of age or older
2. Member has a history of ASCVD or one of the following cardiovascular events:
• Acute coronary syndrome
• Myocardial infarction
• Stable or unstable angina
• Coronary or other arterial revascularization procedure (e.g., PTCA, CABG)
• Stroke of presumed atherosclerotic origin
• Transient ischemic attack (TIA)
• Peripheral arterial disease of presumed atherosclerotic origin
• Finding from CT angiogram or catheterization consistent with ASCVD,  AND
 
3. Member meets at least ONE of the following requirements:
a. Member has a current LDL-C level 70 after at least three months of an adherent treatment with a high-intensity statin (atorvastatin 40 mg or rosuvastatin 20 mg daily) plus ezetimibe 10 mg daily. OR
b. Member has a current LDL-C level 70 with contraindication*or failure of statin and is taking ezetimibe with or without other lipid lowering medications at maximally tolerated doses or at the maximum doses approved by the FDA. OR
c. Member has a current LDL-C level 70 on high intensity statin but has intolerance or failure of ezetimibe. AND
4. Member’s current triglyceride is less than 400 mg/dl.
 
 *Note: Contraindication, for the purpose of this guideline is defined as:
            • Anaphylactic reaction  to 2 high intensity statins
            • Statin intolerance due to myalgias after failure of two or more statins at varying intensities (e.g. Atorvastatin 40mg and Simvastatin 10mg) There should be documentation of efforts to overcome statin intolerance. Examples include alternate day statin or starting with a low dose or less potent statin and titrating the dose upward over time.  
            • Prior documentation of statin-associated rhabdomyolysis (CK level greater than 10,000 IU/L or elevation accompanied by significant increase in creatinine level)  
            • Prior documentation of statin-associated myositis (CK >3 times the upper limit of normal and either severe myalgia or weakness)  
 
 
B. Heterozygous Familial Hypercholesterolemia (FH)
Authorization for 12 months may be granted for members who meet ALL of the criteria listed below:
1. Member is 18 years of age or older.
2. Member has a definite diagnosis of familial hypercholesterolemia as evidenced by meeting one of the following diagnostic criteria:
a. Simon-Broome Diagnostic Criteria for definite FH
• Total cholesterol > 290 mg/dL or LDL-C > 190 mg/dL, plus tendon xanthomas in first- (parent, sibling or child) or second-degree relative (grandparent, uncle or aunt) ; OR
b. Dutch Lipid Clinic Network Criteria for definite FH
• Total score > 8 points.
3. Member meets at least ONE of the following requirements:
a. With ASCVD: Criteria in Section A must be met.
b. Without ASCVD: Member has a current LDL-C level 100 after at least three months of an adherent treatment with a high-intensity statin (atorvastatin 40 mg or rosuvastatin 20 mg daily) plus ezetimibe 10 mg daily.
c. Member has a current LDL-C level 100 with contraindication* to statin and is taking ezetimibe with or without other lipid lowering medications at maximally tolerated doses or at the maximum doses approved by the FDA.
d. Member has a current LDL-C level 100 and contraindication* to both statin and ezetimibe.
 
*Note: Contraindication, for the purpose of this guideline is defined as:
            • Anaphylactic reaction
            • Statin intolerance due to myalgias after failure of two or more statins at varying intensities (e.g. Atorvastatin 40mg and Simvastatin 10mg)
            • Prior documentation of statin-associated rhabdomyolysis (CK level greater than 10,000 IU/L or elevation accompanied by significant increase in creatinine level)  
            • Prior documentation of statin-associated myositis (CK >3 times the upper limit of normal and either severe myalgia or weakness)  
4. Member’s current triglyceride is less than 400 mg/dL.
 
C. Homozygous Familial Hypercholesterolemia
Authorization for 12 months may be granted for members who meet ALL of the applicable criteria listed below:
1. Member is 13 years of age or older.
2. Member has a diagnosis of homozygous FH confirmed by genetic analysis or clinical criteria as defined:
a. Genetic diagnosis
            • Mutations in both alleles at LDL receptor, ApoB, PCSK9 or LDL receptor adaptor protein gene locus
b. Clinical diagnosis
            • Untreated LDL-C > 500mg/dL OR unknown untreated LDL-C with treated LDL-C > 300mg/dL; PLUS  
            • One of the following:
o Tendon or cutaneous xanthomas at age 10 or younger
o Diagnosis of definite FH by either:
§ Simon-Broome Diagnostic Criteria- Total cholesterol > 290 mg/dL or LDL-C > 190 mg/dL, plus tendon xanthomas in first- (parent, sibling or child) or second-degree relative (grandparent, uncle or aunt); OR
§ Dutch Lipid Clinic Network Criteria- Total score > 8 points.
o Evidence of FH in both parents with a history including any of the following:
§ Total cholesterol >310 mg/dL
§ Premature ASCVD (before 55 years in men and 60 years in women
§ Tendon xanthoma
§ Sudden premature cardiac death
3. For adolescents (between 13 and 18 years of age): Member meets at least ONE of the following requirements.
a. Member has a current LDL-C level 135 mg/dL after at least three months of an adherent treatment with atorvastatin 20 mg or rosuvastatin 20 mg daily plus ezetimibe 10 mg daily.
b. Member has a current LDL-C level 135 mg/dL with contraindication* to statins and is taking ezetimibe with or without other lipid-lowering therapy.
c. Member has a current LDL-C level 135 mg/dL and contraindication* to both statin and ezetimibe and is receiving other lipid-lowering therapy.
d. Member has a current LDL-C level 135 mg/dL AND has received at least a three-month supply of Juxtapid or Kynamro through a prior authorization process for a pharmacy or medical benefit within the previous 120 days. And the member will not take evolocumab (Repatha) concurrently with lomitapide (Juxtapid) or mipomersen (Kynamro).
e. Member has been treated regularly with lipid apheresis for at least 3months within the previous 120 days.
4. For adults (age 18 and older): Member meets at least ONE of the following requirements:
a. With ASCVD- Must meet requirements in Section A.
b. Without ASCVD: Member has a current LDL-C level 100 mg/dL after at least three months of an adherent treatment with atorvastatin 40 mg or rosuvastatin 40 mg daily plus ezetimibe 10 mg daily.
c. Member has a current LDL-C level 100 mg/dL with contraindication* to statins and is taking ezetimibe with or without other lipid-lowering therapy.
d. Member has a current LDL-C level 100 mg/dL and contraindication* to both statin and ezetimibe and is receiving other lipid-lowering therapy.
e. Member has a current LDL-C level 100 mg/dL (or 70 mg/dL with ASCVD) AND has received at least a three-month supply of Juxtapid or Kynamro through a prior authorization process for a pharmacy or medical benefit within the previous 120 days. And the member will not take evolocumab (Repatha) concurrently with lomitapide (Juxtapid) or mipomersen (Kynamro).
f. Member has been treated regularly with lipid apheresis for at least 3months within the previous 120 days.
 
*Note: Contraindication, for the purpose of this guideline is defined as:
            • Anaphylactic reaction
            • Statin intolerance due to myalgias after failure of two or more statins at varying intensities (e.g. Atorvastatin 40mg and Simvastatin 10mg)
            • Prior documentation of statin-associated rhabdomyolysis (CK level greater than 10,000 IU/L or elevation accompanied by significant increase in creatinine level)  
            • Prior documentation of statin-associated myositis (CK >3 times the upper limit of normal and either severe myalgia or weakness)  
5. Member’s current triglyceride level is less than 400 mg/dL.
 
III.CRITERIA FOR CONTINUATION OF THERAPY
A. ASCVD
1. Authorization of 12 months may be granted for members who have received at least a three-month supply of the requested medication through prior authorization process for a pharmacy or medical benefit and achieved
a. LDL-C reduction 35% OR
b. Reduction below the LDL-C of 100 mg/dL
B. Heterozygous FH
1. Authorization of 12 months may be granted for members without ASCVD who have received at least a three-month supply of the requested medication through prior authorization process for a pharmacy or medical benefit and achieve or maintain a LDL-C reduction, as defined below;
a. LDL-C reduction 35% OR
b. Reduction below the LDL-C of 100 mg/dL
C. Homozygous FH
1. Authorization of 12 Authorization of 12 months may be granted for members < 18 years of age who have received at least a three-month supply of the requested medication through prior authorization process for a pharmacy or medical benefit and achieve or maintain a LDL-C reduction, as defined below:
a. LDL-C reduction 20% OR
b. Reduction below the LDL-C level of 135 mg/dL
2. Authorization of 12 months may be granted for members 18 years of age who have received at least a three-month supply of the requested medication through prior authorization process for a pharmacy or medical benefit and achieve or maintain a LDL-C reduction, as defined below:
a. LDL-C reduction 20% OR
b. Reduction below the LDL-C of 100 mg/dL with or without ASCVD
 
IV. DOSAGE AND ADMINISTRATION
In accordance with FDA labeling.
 
Effective April 13, 2016 to April 2021
 
The use of evolocumab and alirocumab is not covered under the medical benefit.  
 
The use of PCSK9 Inhibitors is addressed under the pharmacy benefit.  
 

Rationale:
Evolocumab (e.g., Repatha)
Koren and colleagues (2014) reported on the results of the MENDEL-2, a randomized controlled, phase III monotherapy trial to compare biweekly and monthly evolocumab with placebo and oral ezetimibe in those with hypercholesterolemia. The trial included 614 participants with LDL-C levels • 100 and < 190 mg/dl and a 10-year Framingham coronary heart disease risk score of • 10%.
 
Participants were randomized to receive evolocumab (n=306), ezetimibe (n=154) or placebo (n=155). At 12 weeks, LDL-C levels had decreased from baseline by an average of 57.0% (95% CI, -59.5%
to -54.6%) with biweekly evolocumab versus 0.1% (95% CI, -3.2% to 3.4%) with placebo and 17.8% (95% CI, -21.0% to -14.5%) with ezetimibe (p<0.001). All individuals in the evolocumab group realized a reduction in baseline LDL-C levels as compared to approximately 92% of the ezetimibe group. Treatment-emergent adverse event rates were comparable between all groups, 44% for eaach group. These adverse events lead to study treatment discontinuation in 7 (2.3%) in the evolocumab group, 5 (3.2%) of the ezetimibe group and 6 (3.9%) of the placebo group.
 
The randomized controlled, double-blinded GAUSS-2 trial of 307 participants reported by Stroes and colleagues (2014) assessed the effectiveness and safety of evolocumab against ezetimibe in individuals with hypercholesterolemia intolerant to at least two statins. Participants were randomized to receive evolocumab plus placebo (n=205) or ezetimibe plus placebo (n=102) either biweekly or monthly. Mean percent reductions from baseline at a 10-12 week mean were 56.1% (95% CI, 59.7% to 52.5%) biweekly and 55.3% (95% CI, 58.3% to 52.3%) monthly as compared to ezetimibe at 36.9% (95% CI, 42.3% to 31.6%) and 38.7% (95% CI, 43.1% to 34.3%), respectively (p<0.001). After 12 weeks, LDL-C levels in the evolocumab group were reduced by 53%-56% compared to a 37%-39% reduction in the ezetimibe group (p<0.001). Treatment adverse events leading to study discontinuation was reported in 6 of the evolocumab group and 14 of the ezetimibe group.
 
In a trial assessing the effect of evolocumab on cardiovascular events, 4465 participants of earlier phase II or III trials were recruited into two open-label, randomized trials (OSLER-1 and OSLER-2). Eligible individuals included those who had elevated LDL-C levels without history of lipid therapy, those on statin therapy with or without ezetimibe with incomplete response, statin tolerant individuals or those with HeFH with continued LDL-C elevation despite statin therapy. Participants were randomized to receive evolocumab with standard therapy (n=2976) or standard therapy (n=1489) over a 1 year period. Data from both trials were combined. At 12 weeks, the LDL-C level was significantly lower in the evolocumab group versus standard therapy with the LDL-C reduced by 61% (95% CI, 59 to 63; p<0.001). Serious adverse event occurrences were 7.5% in each group. The authors noted that the evolocumab group reported more neurocognitive adverse events; however, the rate of these events were low (<1%). Researchers used the Kaplan–Meier method to estimate the rate of cardiovascular events at 1 year: 0.95% in the evolocumab group verses 2.18% the standard therapy group (Hazard ratio, [HR] 0.47; 95% CI, 0.28- 0.78; p=0.003). The authors note that while it is plausible to suggest PCSK9 inhibitors will affect cardiovascular outcomes similar to statins as they have the same mechanism of action, currently, there is no data to support this (Sabatine, 2015).
 
Several ongoing trials are underway to evaluate the long-term efficacy and tolerability of evolocumab. These studies include the EBBINGHAUS (Evaluating PCSK9 Binding anti-Body Influence oN coGnitive HeAlth in High cardiovascUlar Risk Subjects) study which will assess neurocognitive changes in evolocumab therapy and is estimated to be completed in 2017. The FOURIER study will address whether the additional evolocumab–related decrease in LDL-C levels will result in a decrease in cardiovascular events in individuals with CVD.
 
Published clinical trials indicate PCSK9 inhibitors reduce LDL-C by 48% to 66% in individuals at high- risk for CV events (HeFH or non-HeFH) treated with maximum tolerated doses of a statin, with or without other lipid lowering agents; such as ezetimibe (Kereiakes, 2015; Koren, 2015; McKinney, 2012; Raal, 2015; Robinson, 2015; Sabatine, 2015). PSCK9 inhibitors reduced LDL-C by approximately 30% more than adding ezetimibe to statins (Cannon, 2015; Roth, 2014). However, data has not been published to demonstrate that use of PSCK9 inhibitors result in greater reduction in CV events compared to statins alone or in combination with other lipid lowering agents. Trials investigating CV outcomes are ongoing with anticipated completion in 2017 and 2018.
 
There is no consensus on an optimal LDL-C target treatment level. The authors of the ACC/AHA 2013 Guidelines on the Treatment of Blood Cholesterol removed specific LDL-C treatment target goals from their recommendations for either primary or secondary prevention of ASCVD. The authors noted that while there is RCT evidence to support that the use of maximally tolerated statin intensity therapy reduced ASCVD events, there were no studies which have assessed specific LDL-C goals against improved ASCVD outcomes. In addition, the authors noted, "As of yet, there are no data to show that adding a non-statin drug(s) to high-intensity statin therapy will provide incremental ASCVD risk reduction benefit with an acceptable margin of safety."
 
Alirocumab (Praluent)
The ODYSSEY program is a series of phase III trials designed to evaluate the safety and efficacy of alirocumab in multiple clinical populations. This program includes 14 multinational trials and more than 23,500 participants (Kastelein, 2014). The ODYSSEY Outcomes trial, with approximately 18,000 individuals with a recent history of acute myocardial infarction or unstable angina, aims to evaluate the effect of alirocumab in combination with intensive statin therapy, on future cardiovascular events. The expected completion of ODYSSEY Outcomes trial is 2016 (Schwartz, 2014). The primary outcome of interest will be the efficacy of alirocumab to reduce the rate cardiovascular events.
 
In the ODYSSEY MONO trial, the first ODYSSEY study to report results, Roth and colleagues (2014) compared alirocumab to ezetimibe as a monotherapy in individuals with hypercholesterolemia at moderate cardiovascular risk. Eligible individuals included those with a 1% to 5% - 10 year risk of fatal CD events based on the European Systematic Coronary Risk Estimation. Participants were randomized to receive alirocumab plus ezetimibe placebo (n=52) or alirocumab placebo plus ezetimibe (n=51). At week 12, the estimated proportions of those with • 50% LDL-C reduction was 58% in alirocumab arm versus 3% in the ezetimibe arm. At week 24, least squares mean standard error (SE) LDL-C reductions from baseline were 47% (3) alirocumab versus 16% (3) ezetimibe; with a statistically significant LS mean SE difference between groups of -32% (4) (p<0.0001). The initial dose of alirocumab was 75 mg every 2 weeks. Per protocol, if the LDL-C level was • 100 mg/dl at week 12, individuals would be up-titrated to 150 mg. However, due to administrative error, the up- titration was performed on those with LDL-C level • 70 mg/dl, a total of 13 additional individuals. An additional analysis was performed excluding those individuals. Results were similar to initial overall analysis. Rates of participants with at least one treatment-emergent adverse event (TEAE) were comparable between the two groups with 69% in the alirocumab group and 78% in the ezetimibe group. A total of 5 (10%) individuals experiencing TEAEs in the alirocumab group and 4 (8%) individuals in the ezetimibe group discontinued study treatment.
 
Robinson and colleagues (2015) assessed 2341 high-risk cardiovascular participants receiving maximal statin therapy with or without other lipid lowering drugs in the ODYSSEY LONG TERM trial. Eligible individuals included those with HeFH (established by genotyping or clinical criteria), those with a diagnosis of coronary heart disease (CHD) or those CHD risk equivalent individuals with an LDL-C level • 70 mg per deciliter. Participants were randomized to receive alirocumab or placebo in addition to high-dose or maximally tolerated statin therapy. The study reported a significant reduction in LDL- C levels from baseline (-61.0% alirocumab versus 0.8% placebo; difference -61.9%; p<0.001). Rates remained constant over the 78 week study period. In a post hoc analysis, the alirocumab group rate of major adverse cardiovascular events was lower than the placebo group (1.7% versus 3.3% respectively; p=0.02). However, the number of cardiovascular events was relatively small and confidence in the robustness of this data is limited.
 
In the 2015 ODYSSEY COMBO II trial, Cannon and colleagues compared the safety and efficacy of alirocumab to ezetimibe as add-on therapy to maximally tolerated statin therapy in high-risk cardiovascular individuals with inadequately controlled hypercholesterolemia. Eligible individuals included those with documented cardiovascular disease (CVD) and LDL-C • 70 mg/dL or no documented history of CVD but who were at high cardiovascular risk and had LDL-C • 100 mg/dL. Participants were randomized to receive subcutaneous (SQ) alirocumab plus oral placebo (n=479) or SQ placebo plus oral ezetimibe (n=241). At week 24, the differences were significant. The mean ± standard error (SE) reductions in LDL-C from baseline were -50.6 ± 1.4% in the alirocumab arm and -20.7 ± 1.9% in the ezetimibe arm with a mean SE difference of -29.8 (95% Confidence Interval (CI), -34.4 to -25.3; p<0.0001). Mean LDL-C concentrations dropped rapidly in both groups in the first 4 weeks, the alirocumab arm to a greater extent, and remained constant through week 52.
 
Overall, 71.2% of the alirocumab arm and 67.2% of the ezetimibe arm reported treatment-emergent adverse events (TEAEs) over a mean of 58 ± 19 weeks. These TEAEs resulted treatment discontinuation in 7.5% of the alirocumab group and 5.4% of the ezetimibe group. Result will continue to be reported through 104 weeks. The study did report slightly higher cardiovascular events in the alirocumab group (4.8%) vs. ezetimibe group (3.7%).
 
In the ODYSSEY COMBO I study, Kereiakes and colleagues (2015) evaluated the efficacy and safety of alirocumab as an add-on therapy in high-risk individuals with inadequately controlled hypercholesterolemia despite maximally tolerated daily statin, with or without other lipid-lowering therapy. The trial included 316 individuals randomized to receive either alirocumab or a matching placebo in addition to their current therapy. At week 24, the intention to treat (ITT) analysis results showed an LDL change in the alirocumab group of -48.2% (-52.0% to -44.4%) compared to -2.3% (-7.6% to 3.1%) for the placebo group (p<0.0001). These results were sustained throughout the 52 week study period. Reported treatment adverse event rates were similar across both groups. A total of 6.6% (13/197) of the alirocumab group developed anti-alirocumab antibodies, the presence of these antibodies was transient in 7 of the individuals despite continued treatment. The presence of these antibodies were not associated with any specific clinical events.
 
October 2021 Update
A literature search was conducted through October 2021. The following is a summary of the key literature to date.
 
The SAMSON (Self-Assessment Method for Statin Side-Effects Or Nocebo) trial evaluated 60 patients with a history of statin intolerance. 49 participants completed the trial (Toth, 2021; Howard, 2021). The participants rated their symptoms daily on a scale of 1-100 via phone app. They were given 12 1-month medication bottles: 4 with atorvastatin 20 mg, 4 placebo, and 4 empty bottles. The mean symptom score was 8 when taking no tablets. There was little difference between the symptom scores when taking atorvastatin (16.3) or placebo (15.4). Therapy was discontinued at the same frequency for the statin and placebo groups, and symptom relief was very similar between the 2 groups. It was determined that most of the symptoms were caused by nocebo (ratio of symptoms induced by taking statin was also induced by taking placebo). It could not be determined that statins caused symptom intensity or contributed to timing of symptoms since the placebo group had almost identical results.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through September 2022. No new literature was identified that would prompt a change in the coverage statement.

CPT/HCPCS:
J3490Unclassified drugs
J3590Unclassified biologics

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PRALUENT® (alirocumab)(2021) [package insert]. Tarrytown, NY, Regeneron Pharmaceuticals, Inc.; 2021

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REPATHA (evolocumab)(2021) [package insert]. Thousand Oaks, CA, Amgen, Inc.; 2021

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