Repatha (evolocumab) Policy Number: Last Review: 06/2018 Origination: 07/2015 Next Review: 06/2019

Transcription

1 Repatha (evolocumab) Policy Number: Last Review: 06/2018 Origination: 07/2015 Next Review: 06/2019 Policy Blue Cross and Blue Shield of Kansas City (Blue KC) will provide coverage for Repatha when it is determined to be medically necessary because the criteria listed below are met. When Policy Topic is covered Food and Drug Administration (FDA)-Approved Indications 1. Heterozygous Familial Hypercholesterolemia [HeFH] or Homozygous Familial Hypercholesteremia. * Approve Repatha for 12 months if the patient meets the following criteria (A, B, C, D and E): A) The patient is aged 18 years; AND B) The patient has an LDL-C level 160 mg/dl (after treatment with antihyperlipidemic agents but prior to PCSK9 inhibitor therapy such as Praluent or Repatha) [documentation required]; AND C) The patient meets one of the following criteria (i or ii): i. The patient has tried at least 2 statins with at least one being a high-intensity statin therapy (i.e., atorvastatin 40 mg daily; Crestor 20 mg daily [as a single-entity or as a combination product]) * AND Zetia (ezetimibe tablets) [as a single-entity or as a combination product] concomitantly for 8 continuous weeks [documentation required]; AND the LDL-C level remains 70 mg/dl [documentation required]; OR ii. The patient has been determined to be statin intolerant by meeting one of the following criteria (a or b): a) The patient experienced statin-related rhabdomyolysis (statin-induced muscle breakdown with signs and symptoms such as muscle pain, weakness, tenderness, acute renal failure and/or elevated creatine kinase [CK] levels [e.g., 10 times the upper limit of normal]) [documentation required]; OR b) The patient experienced skeletal-related muscle symptoms (e.g., myopathy [muscle weakness] or myalgia [muscle aches, soreness, stiffness, or tenderness]) and meets both of the following criteria [(1) and (2)]: (1) The skeletal-related muscle symptoms (e.g., myopathy or myalgia) occurred while receiving separate trials of both atorvastatin and Crestor (as single-entity or as combination products) [documentation required]; AND (2) When receiving separate trials of both atorvastatin and Crestor (as singleentity or as combination products) the skeletal-related muscle symptoms (e.g., myopathy, myalgia) resolved upon discontinuation of each respective statin therapy (atorvastatin and Crestor); AND D) Repatha is prescribed by, or in consultation with, a cardiologist; an endocrinologist; or a physician who focuses in the treatment of cardiovascular (CV) risk management and/or lipid disorders; AND E) If able to tolerate statins, the patient continues to receive the maximum tolerated dose of a statin while receiving Repatha therapy.

2 2. Hyperlipidemia in Patients with Clinical Atherosclerotic Cardiovascular Disease (ASCVD). * Approve Repatha for 12 months if the patient meets the following criteria (A, B, C, D and E): A) The patient is aged 18 years; AND B) The patient meets the following criteria (i and ii): i. The patient has an LDL-C level 70 mg/dl (after treatment with antihyperlipidemic agents but prior to PCSK9 inhibitor therapy such as Praluent or Repatha) [documentation required]; AND ii. The patient has had one of the following conditions or diagnoses (a, b, c, d, or e): a) The patient has had a previous myocardial infarction (MI) or has a history of an acute coronary syndrome (ACS); OR b) The patient has a diagnosis of angina (stable or unstable); OR c) The patient has a past history of stroke or transient ischemic attack (TIA); OR d) The patient has peripheral arterial disease (PAD); OR e) The patient has undergone a coronary or other arterial revascularization procedure in the past; AND C) The patient meets one of the following criteria (i or ii): i. The patient has tried at least 2 statins with at least one being a high-intensity statin therapy (i.e., atorvastatin 40 mg daily; Crestor 20 mg daily [as a single-entity or as a combination product]) * AND Zetia (ezetimibe tablets) [as a single-entity or as a combination product] concomitantly for 8 continuous weeks [documentation required]; AND the LDL-C level remains 70 mg/dl [documentation required]; OR ii. The patient has been determined to be statin intolerant by meeting one of the following criteria (a or b): a) The patient experienced statin-related rhabdomyolysis (statin-induced muscle breakdown with signs and symptoms such as muscle pain, weakness, tenderness, acute renal failure and/or elevated creatine kinase [CK] levels [e.g., 10 times the upper limit of normal]) [documentation required]; OR b) The patient experienced skeletal-related muscle symptoms (e.g., myopathy [muscle weakness] or myalgia [muscle aches, soreness, stiffness, or tenderness]) and meets both of the following criteria [(1) and (2)]: (1) The skeletal-related muscle symptoms (e.g., myopathy or myalgia) occurred while receiving separate trials of both atorvastatin and Crestor (as single-entity or as combination products) [documentation required]; AND (2) When receiving separate trials of both atorvastatin and Crestor (as singleentity or as combination products) the skeletal-related muscle symptoms (e.g., myopathy, myalgia) resolved upon discontinuation of each respective statin therapy (atorvastatin and Crestor); AND D) Repatha is prescribed by, or in consultation with, a cardiologist; an endocrinologist; or a physician who focuses in the treatment of cardiovascular (CV) risk management and/or lipid disorders; AND E) If able to tolerate statins, the patient continues to receive the maximum tolerated dose of a statin while receiving Repatha therapy. * Note: The number of drug-drug interactions that are categorized as severe or as unmodifiable by using lower doses or alternating to another statins or medications to manage the condition are limited. Exceptions based on current use of these other medications are not intentionally provided for in this policy. Repatha is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with HeFH or clinical ASCVD who require additional lowering of LDL-C. The safety and effectiveness of Repatha have not been established in pediatric patients with primary hyperlipidemia or

3 HeFH. 1 In this criteria, ASCVD was defined according to that described in the 2013 ACC/AHA guidelines for the treatment of blood cholesterol. 7 Guidelines have recognized that patients with ASCVD have a very high risk of CV events. 7-8 Statins are well-established therapies and should be utilized first-line in all eligible patients with elevated LDL-C levels for patients without contraindications for use who are able to tolerate these agents. Data with statins, as well as Zetia added to a statin, have noted reductions in CV events. 11,18-21 At this time, CV outcomes data are not available with Repatha. Patients with ASCVD are recommended to utilize maximally tolerated high-intensity therapy (atorvastatin 40 mg daily; Crestor 20 mg daily) first-line, along with Zetia, prior to Repatha therapy. The recently published IMPROVE-IT trial with Zetia demonstrated a reduction in CV events when Zetia was added to statin therapy (simvastatin) compared with simvastatin monotherapy in patients who had been recently hospitalized for an ACS event. 11 As in the Repatha clinical trials and as recommended in the Repatha prescribing information, patients should continue to receive the maximally tolerated dose of statin to continue to receive the benefits established regarding CV event reduction. 1,3-6 Use of Repatha should be judicious and under the guidance of a specialist physician (cardiologist, endocrinologist, or a physician who focuses in the treatment of CV risk management and/or lipid disorders) to assure other lipid lowering therapies have been maximized and to promote safe use of Repatha. The criteria also recognize situations in which patients are unable to take statin therapy (i.e., muscle-related AEs) and that rechallenge with a different statin in such scenarios can lead to successful treatment with statin therapy However, rhabdomyolysis, albeit rare, is a serious event and patients should not be rechallenged with statin therapy. The criteria were developed based on nationally-recognized guidelines regarding lipid management, clinical data for Repatha and other antihyperlipidemic therapies (e.g., statins, Zetia) as well as the professional opinion of specialized physicians. When Policy Topic is not covered Conditions Not Recommended for Approval Repatha has not been shown to be effective, or there are limited or preliminary data or potential safety concerns that are not supportive of general approval for the following conditions. Rationale for noncoverage for these specific conditions is provided below. (Note: This is not an exhaustive list of Conditions Not Recommended for Approval.) 1. Concurrent use of Repatha with Praluent (alirocumab injection for SC use), Juxtapid (lomitapide capsules) or Kynamro (mipomersen injection). Praluent is another PCSK9 inhibitor and should not be used with Repatha. 2 Juxtapid and Kynamro are agents indicated as an adjunct to lipid-lowering medications and diet to modify lipid parameters (e.g., reduce LDL-C levels) in patients with HoFH The efficacy and safety of using Praluent, Juxtapid and Kynamro in combination with Repatha have not been established. 2. Coverage is not recommended for circumstances not listed in the Recommended Authorization Criteria. Criteria will be updated as new published data are available. Considerations Prior authorization is recommended for prescription benefit coverage of Repatha. Although Repatha lowers LDL-C and could possibly be used in a variety of patients with hyperlipidemia, the most benefit with Repatha is noted among patients in conditions for which it is indicated (adults with HeFH or ASCVD). The intent of this policy is to recommend coverage in such patients who are likely to benefit from Repatha if LDL-C remains elevated after trial of other proven therapies (i.e., high-dose statins, Zetia). Because of the specialized skills required for evaluation and monitoring of this new therapy, approval requires Repatha to be prescribed by or in consultation with a physician who specializes in the condition being treated. All approvals are provided for 12 months in duration. Documentation: For the Comprehensive Program, documentation will be required where noted in the criteria as [documentation required]. Documentation may include, but is not limited to, chart notes, prescription claims records, prescription receipts and/or laboratory data.

4 Description of Procedure or Service Repatha, a proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor antibody, is indicated as an adjunct to diet and 1) maximally tolerated statin therapy for 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) and 2) other low-density lipoprotein [LDL]-lowering therapies (e.g., statins, Zetia [ezetimibe tablets], LDL apheresis) in patients with homozygous familial hypercholesterolemia (HoFH) who require additional lowering of LDL-C. 1 The effect Repatha on cardiovascular (CV) morbidity and mortality has not been determined. Repatha is administered by subcutaneous (SC) injection. The recommended dose in patients with HeFH or patients with primary hyperlipidemia with established clinical ASCVD is either 140 mg SC once every 2 weeks (Q2W) or 420 mg SC once monthly (QM). For patients with HoFH, the recommended dose is 420 mg SC QM. In patients with HoFH, assess LDL-C levels 4 to 8 weeks after Repatha initiation since response to therapy depends on the degree of LDL-receptor function. For patients receiving the 420 mg dose, administer three Repatha SC injections consecutively within 30 minutes. Administration sites include the abdomen, thigh or upper arm. Common adverse events (AEs) with Repatha include nasopharyngitis, upper respiratory tract infection, influenza, back pain, and injection-site reactions. The safety and effectiveness of Repatha have not been established in pediatric patients with primary hyperlipidemia or HeFH. The safety and effectiveness of Repatha have not been established in pediatric patients with HoFH aged < 13 years. Data from a 12-week placebo-controlled trial involving patients with HoFH included 10 adolescent children who were aged 13 to 17 years; seven adolescent patients received Repatha. The effect of Repatha on LDL-C was similar to that observed in adult patients with HoFH. Fourteen adolescent patients with HoFH received Repatha in an open-label setting for a median exposure of 9 months with similar results compared with adult patients with HoFH. 1 Praluent (alirocumab injection for SC use) is another PCSK9 inhibitor antibody indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with HeFH or clinical ASCVD, who require additional lowering of LDL-C. 2. Rationale Clinical Data The efficacy of Repatha was assessed in several studies. 1 LAPLACE-2 (LDL-C Assessment with PCSK9 Monoclonal Antibody Inhibition Combined with Statin Therapy) 1,3 was a multicenter, doubleblind, randomized controlled trial that involved patients who were initially assigned to an open-label specific statin regimen for a 4-week lipid stabilization period followed by randomization to Repatha 140 mg SC Q2W, Repatha 420 mg SC QM, or placebo for 12 weeks. The trial included 296 patients with clinical ASCVD who received Repatha or placebo as add-on therapy to daily doses of atorvastatin 80 mg, Crestor (rosuvastatin tablets) 40 mg, or simvastatin 40 mg. Following 4 weeks of statin therapy, the mean baseline LDL-C was 108 mg/dl. Among patients with clinical ASCVD who were on maximum doses of statin therapy, the difference between Repatha and placebo in the mean percent change in LDL-C from baseline to Week 12 was -71% (P < ) and -63% (P < ) for Repatha 140 mg SC Q2W and Repatha 420 mg SC QM, respectively. 1,3 DESCARTES (Durable Effect of PCSK9 Antibody Compared with Placebo Study) 1,4 was a multicenter, double-blind, randomized, placebocontrolled, 52-week trial that included 139 patients with ASCVD who received protocol-determined background lipid-lowering therapy of atorvastatin 80 mg once daily (QD) with or without Zetia 10 mg QD. Following stabilization on background therapy, patients were randomized to receive placebo or Repatha 420 mg SC QM. After stabilization on background statin therapy, the mean baseline LDL-C was 105 mg/dl. In patients with ASCVD on maximum-dose atorvastatin therapy, with or without Zetia, the difference between Repatha 420 mg SC QM and placebo in the mean percent change in LDL-C from baseline to Week 52 was -54%. 1,4 RUTHERFORD-2 (Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder) 1,5 was a multicenter, double-blind, randomized, placebo-controlled 12-week trial involving 329 patients with HeFH who were receiving statins, with or without other lipid lowering therapies. Patients were randomized to receive Repatha 140 mg SC Q2W, Repatha 420 mg SC QM or placebo. HeFH was diagnosed by Simon Broome

5 criteria. The average LDL-C at baseline was 156 mg/dl, and 76% of patients were receiving highintensity statin therapy. In total, 38% of patients had clinical ASCVD. In these patients receiving statins, with or without other lipid lowering therapies, the differences between Repatha and placebo in the mean percent change in LDL-C from baseline to Week 12 was -61% and -60% for the Repatha 140 mg SC Q2W (P < ) and Repatha 420 mg SC QM doses (P < ), respectively. 1,5 TESLA Part B (Trial Evaluating PCSK9 Antibody in Subjects with LDL-Receptor Abnormalities Part B) 1,6 was a multicenter, double-blind, randomized, placebo-controlled, 12-week trial involving 49 patients with HoFH who were not receiving LDL apheresis. In this study, 33 patients received Repatha 420 mg SC QM and 16 patients received placebo as an adjunct to other lipid-lowering therapies (e.g., statins, Zetia). The mean age at baseline was 31 years and the trial included 10 adolescents (aged 13 to 17 years). The mean LDL-C at baseline was 349 mg/dl with all patients receiving statins (atorvastatin or Crestor); 92% of patients were on Zetia. The diagnosis of HoFH was made by genetic confirmation or a clinical diagnosis based on a history of an untreated LDL-C > 500 mg/dl, together with either xanthoma prior to age 10 years or evidence of HeFH in both parents. In these patients with HoFH, the difference between Repatha and placebo in the mean percent change in LDL-C from baseline to Week 12 was -31% (P < ). Of note, patients known to have two LDL-receptor negative alleles (little or no residual function) did not respond to Repatha. Guidelines Repatha has not yet been addressed in clinical guidelines. Many guidelines are available regarding the treatment of patients with dyslipidemia. Two nationally recognized organizations (the American College of Cardiology [ACC]/American Heart Association [AHA] and the National Lipid Association [NLA]) have guidelines regarding the management of patients with elevated cholesterol and related conditions which are detailed below. ACC/AHA Treatment of Blood Cholesterol to Reduce Atherosclerotic CV Risk in Adults In 2013, the ACC/AHA published guidelines on the treatment of blood cholesterol to reduce atherosclerotic CV risk in adults. 7 The guidelines state that many randomized controlled trials have demonstrated a consistent reduction in ASCVD events with use of statins in both primary and secondary prevention among populations most likely to benefit. The ACC/AHA guidelines identify four major groups who should be treated with an appropriate statin-intensive therapy. These groups include: 1) patients with clinical ASCVD, which includes patients with a past acute coronary syndrome (ACS), or history of a myocardial infarction (MI), stable or unstable angina, coronary or other arterial revascularization, stroke, transient ischemic attack (TIA), or peripheral arterial disease (PAD) presumed to be atherosclerotic origin; 2) patients with primary elevations of LDL-C 190 mg/dl; 3) patients 40 to 75 years of age with diabetes and an LDL-C between 70 and 189 mg/dl (without ASCVD); and 4) patients without clinical ASCVD or diabetes with an LDL-C between 70 and 189 mg/dl, and have an estimated 10-year ASCVD risk 7.5%. The ACC/AHA guidelines emphasize the appropriate intensity of statin therapy to reduce CV risk in patients who will benefit. 7 No statin is preferred, but instead, statins with related doses are categorized as high-intensity (lowers LDL-C by approximately 50%), moderate-intensity (lowers LDL-C by approximately 30% to < 50%), and low-intensity (lowers LDL-C by < 30%). Only atorvastatin and Crestor are categorized as high-intensity statin therapy, which is recommended for many patient populations at high CV risk. Table 1 categorizes the different statin regimens as high-, moderate-, and low-intensity. Refer to the guideline for the most appropriate intensity for the individual patient. These guidelines do not focus on LDL-C goals but emphasize the benefits of LDL-C reduction. Evidence from randomized controlled trials demonstrates that ASCVD events are reduced when patients use the maximum tolerated statin intensity in the groups in which benefits have been demonstrated. Table 1. High-, Moderate-, and Low-Intensity Statin Therapy. 7* High-Intensity Statin Therapy Moderate-Intensity Statin Low-Intensity Statin Therapy Therapy Daily dose lowers LDL-C on Daily dose lowers LDL-C on Daily dose lowers LDL-C on

6 average by approximately average by approximately average by < 30%. 50%. 30% to < 50%. Atorvastatin (40 mg ) to 80 mg Crestor 20 mg (40 mg) Atorvastatin 10 mg (20 mg) Crestor (5 mg) 10 mg Simvastatin 20 mg to 40 mg Pravastatin 40 mg (80 mg) Lovastatin 40 mg Lescol XL 80 mg Fluvastatin 40 mg BID Livalo 2 mg to 4 mg Simvastatin 10 mg Pravastatin 10 mg to 20 mg Lovastatin 20 mg Fluvastatin 20 mg to 40 mg Livalo 1 mg * Individual responses to statin therapy varied in the randomized controlled trials and should be expected to vary in clinical practice. There might be a biologic basis for a less-than-average response; Specific statins and doses are bolded that were evaluated in randomized controlled trials in which a major reduction in cardiovascular events was demonstrated. Statins and doses that are approved by the Food and Drug Administration but were not tested in randomized controlled trials are in italics; LDL- C Low-density lipoprotein cholesterol; Evidence from one randomized controlled trial only and down titration is recommended if the patient is unable to tolerate atorvastatin 80 mg; Although simvastatin 80 mg was assessed in randomized controlled trials, initiation of simvastatin 80 mg or titration to 80 mg is not recommended by the Food and Drug Administration due to the increased risk of myopathy, including rhabdomyolysis; BID Twice daily. NLA Management of Dyslipidemia In 2014, the NLA published recommendations for patient-centered management of dyslipidemia. 8-9 The guidelines recommend treatment goals. Regarding LDL-C, patients at low, moderate, or high risk are recommended to obtain an LDL-C level < 100 mg/dl. Patients at very high risk are recommended to achieve an LDL-C level < 70 mg/dl. Patients with ASCVD are included among the patients defined as being very high risk. Patients at high risk include those with an LDL-C 190 mg/dl, which suggests that patients may have a form of familial hypercholesterolemia (FH). Unless contraindicated, first-line drug therapy for the treatment of disorders involving dyslipidemia includes a moderate- or high-intensity statin. High-intensity statin therapy includes atorvastatin (40 to 80 mg QD) or Crestor (20 to 40 mg QD), which leads to an LDL-C reduction of 50%. The guidelines also note that one risk indicator also includes patients with an LDL-C 160 mg/dl. NLA Familial Hypercholesterolemia (FH) In 2011, the NLA published guidelines for the screening, diagnosis, and management of pediatric and adult patients with FH. 10 FH encompass a group of genetic defects that cause severe elevations in LDL-C levels, as well as other lipid parameters. HeFH occurs in approximately 1 in 300 to 500 patients and is present in childhood. Total cholesterol (total-c) levels in HeFH range from 350 to 550 mg/dl. HoFH is rare and occurs in 1 out of 1,000,000 individuals and total-c level range from 650 to 1,000 mg/dl. Both conditions can lead to premature ASCVD. Aggressive lipid-lowering therapy is recommended to achieve LDL-C reductions of at least 50%. Both children and adults with LDL-C levels 190 mg/dl following lifestyle modifications will require medication therapy. Statins are the initial treatment for all adults with FH. High or moderate intensity statins are recommended; low potency statins are generally inadequate for patients with FH due to the markedly elevated LDL-C levels. Higher risk patients may require intensification of drug therapy to achieve the more aggressive treatment goals. Intensification of medication therapy should be considered if LDL-C remains 160 mg/dl or if an initial 50% reduction in LDL-C is not achieved. Other lipid modifying therapies used for FH include Zetia, bile acid sequestrants, or niacin. Although statins, with or without other lipid modifying therapies are effective in many patients, some individuals will require LDL apheresis, especially those with HoFH. Other Lipid Modifying Therapies The ACC/AHA guidelines note that there is substantially less evidence for non-statin medications in reducing ASCVD risk. 7 However, the guidelines became available prior to publication of the IMPROVE-

7 IT trial (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) with Zetia. 11 The trial involved patients (n = 18,144) who had been hospitalized for an ACS within the last 10 days; the mean LDL-C at baseline was 93.8 mg/dl. Patients receiving standard therapy for the treatment of ACS were also randomized in a double-blind manner to receive Zetia 10 mg QD plus simvastatin 40 mg QD or simvastatin 40 mg QD. The median follow-up was 6 years. The median time-weighted average LDL-C level during the trial was 53.7 mg/dl in the Zetia plus simvastatin 40 mg group compared with 69.5 mg/dl in the simvastatin 40 mg monotherapy group (P < 0.001). The Kaplan-Meier event rate for the primary endpoint at 7 years (composite of CV death, nonfatal MI, unstable angina requiring rehospitalization, coronary revascularization [ 30 days after randomization] or nonfatal stroke) was 32.7% with Zetia plus simvastatin 40 mg QD vs. 34.7% with simvastatin 40 mg QD (P = 0.016). 11 Of note, adding Zetia to statins leads to additional decreases of LDL-C by up to -25% The NLA guidelines for the management of dyslipidemia recommend therapy with a statin plus additional agents for those who have not achieved treatment goals for atherogenic cholesterol levels, especially for patients at very high or high risk. 8-9 Statin-Associated Adverse Events Statins have been associated with muscle-related AEs such as myalgia (e.g., muscle aches, soreness, stiffness, or tenderness), myopathy (muscle weakness), and/or myositis (muscle inflammation). 14 Although the incidence is variable, muscle AEs 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). Rhabdomyolysis, which is uncommon with statin therapy, is a severe musclerelated AE that results in muscle breakdown and may or may not be associated with muscle-related symptoms (e.g., muscle pain, weakness, tenderness) along with acute renal failure and/or elevated creatine kinase [CK] levels. In patients with statin-related muscle AEs, symptoms may not re-occur if the patient switches to a different statin therapy. In 2014 the NLA Statin Intolerance Panel published an update. 15 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 re-occurs with rechallenge. 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. 15 Data also suggest that many patients who are rechallenged with statin therapy after an AE may be able to tolerate statin therapy long-term References 1. Repatha injection for subcutaneous use [prescribing information]. Thousand Oaks, CA: Amgen; August Praluent injection for subcutaneous use [prescribing information]. Bridgewater, NJ and Tarrytown, NY: sanofi-aventis and Regeneron Pharmaceuticals; July Robinson JG, Nedergaard BS, Rogers WJ, et al, for the LAPLACE-2 Investigators. Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia. The LAPLACE-2 randomized clinical trial. JAMA. 2014;311(18): [Supplemental Appendix]. 4. Blom DJ, Hala T, Bolognese M, et al, for the DESCARTES Investigators. A 52-week placebocontrolled trial of evolocumab in hyperlipidemia. N Engl J Med. 2014;370: [Supplemental Appendix]. 5. Raal FJ, Stein EA, Dufour R, et al, for the RUTHERFORD-2 Investigators. PCSK9 inhibition with evolocumab (AMG145) in heterozygous familial hypercholesterolemia (RUTHERFORD-2): a randomized, double-blind, placebo-controlled trial. Lancet. 2015;385: [Supplemental Appendix]. 6. Raal FJ, Honarpour N, Blom DJ, et al, for the TESLA Investigators. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolemia (TESLA Part B): a randomized, doubleblind, placebo-controlled trial. Lancet. 2015;385:

8 7. Stone NJ, Robinson J, Lichtenstein AH, et al 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 Accessed on July 23, Jacobson TA, Ito MK, Maki KC, et al. National Lipid Association recommendations for patientcentered management of dyslipidemia: Part 1-executive summary. J Clin Lipidol. 2014;8: Available at: Accessed on July 23, Jacobson TA, Ito MK, Maki KC, et al. National Lipid Association recommendations for patientcentered management of dyslipidemia: Part 1-full report. J Clin Lipidol. 2015;9: Goldberg AC, Hopkins PN, Toth PP, et al. Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients. J Clin Lipidol. 2011;5:S1-S Cannon CP, Blazing MA, Giugliano RP, et al, for the IMPROVE-IT investigators. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372(25): Zetia tablets [prescribing information]. Whitehouse Station, NJ: Merck; August Morrone D, Weintraub WS, both PP, et al. Lipid-altering efficacy of ezetimibe plus statin and statin monotherapy and identification of factors associated with treatment response: a pooled analysis of over 21,000 subjects from 27 clinical trials. Atherosclerosis. 2012;223(2): 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-S Guyton JR, Bays HE, Grundy SM, Jacobson TA. An assessment by the Statin Intolerance Panel: 2014 update. J Clin Lipidol. 2014;8:S72-S Zhang H, Plutzky J, Skentzos S, et al. Discontinuation of statins in routine care settings. Ann Intern Med. 2013;158(7): 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): Cholesterol Treatment Trialists (CTT) Collaborators. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet. 2012;380: Taylor F, Huffman MD, Macedo AF, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev Jan 31;1:CD Cholesterol Treatment Trialists (CCT) Collaborators, Kearney PM, Blackwell L, Collins R, et al. Efficacy of cholesterol lowering therapy in 18,686 people with diabetes in 14 randomized trials: a meta-analysis. Lancet. 2008;371(9607) Baigent C, Keech A, Kearney PM, et al, for the Cholesterol Treatment Trialists (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomized trials of statins. Lancet. 2005;366(9493): Cuchel M, Bruckert E, Ginsberg HN, et al, for the European Atherosclerosis Society Consensus Panel on Familial Hypercholesterolemia. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholestolaemia of the European Atherosclerosis Society. Eur Heart J. 2014;35: Zocor tablets [prescribing information]. Whitehouse Station, NJ: Merck; March Lipitor tablets [prescribing information]. New York, NY: Pfizer; March Crestor tablets [prescribing information]. Wilmington, DE: AstraZeneca; June Vytorin tablets [prescribing information]. Whitehouse Station, NJ: Merck; March Liptruzet tablets [prescribing information]. Whitehouse Station, NJ: Merck; May Kynamro solution for subcutaneous injection [prescribing information]. Cambridge, MA: Genzyme; March Juxtapid capsules [prescribing information]. Cambridge, MA: Aegerion Pharmaceuticals; April 2015.

9 Billing Coding/Physician Documentation Information Repatha is a pharmacy benefit Additional Policy Key Words ; Praluent Policy Implementation/Update Information 07/2015 New policy titled Repatha (evolocumab) 07/2016 Annual review-removed draft status and finalized Repatha policy-no changes to policy statement 07/2017 Annual review-no changes to policy statement 06/2018 Annual review-no changes to policy statement State and Federal mandates and health plan contract language, including specific provisions/exclusions, take precedence over Medical Policy and must be considered first in determining eligibility for coverage. The medical policies contained herein are for informational purposes. The medical policies do not constitute medical advice or medical care. Treating health care providers are independent contractors and are neither employees nor agents Blue KC and are solely responsible for diagnosis, treatment and medical advice. No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic, photocopying, or otherwise, without permission from Blue KC.