Kynamro Mipomersen MCP156

Subject: Kynamro (mipomersen) Original Effective Date: 10/30/2013

Policy Number: MCP-156 Revision Date(s):

Review Date(s): 12/16/15; 6/15/2016; 3/21/2017

DISCLAIMER This Medical Policy is intended to facilitate the Utilization Management process. It expresses Molina's determination as to whether certain services or supplies are medically necessary, experimental, investigational, or cosmetic for purposes of determining appropriateness of payment. The conclusion that a particular service or supply is medically necessary does not constitute a representation or warranty that this service or supply is covered (i.e., will be paid for by Molina) for a particular member. The member's benefit plan determines coverage. Each benefit plan defines which services are covered, which are excluded, and which are subject to dollar caps or other limits. Members and their providers will need to consult the member's benefit plan to determine if there are any exclusion(s) or other benefit limitations applicable to this service or supply. If there is a discrepancy between this policy and a member's plan of benefits, the benefits plan will govern. In addition, coverage may be mandated by applicable legal requirements of a State, the Federal government or CMS for Medicare and Medicaid members. CMS's Coverage Database can be found on the CMS website. The coverage directive(s) and criteria from an existing National Coverage Determination (NCD) or Local Coverage Determination (LCD) will supersede the contents of this Molina medical coverage Policy (MCP) document and provide the directive for all Medicare members.

SUMMARY OF EVIDENCE/POSITION

This policy addresses the use of Kynamro (mipomersen) for the treatment of homozygous familial hypercholesterolemia (HoFH).

∑ The covered FDA-approved indications are conditions that are considered medically necessary; however it is not inclusive of all conditions which may be approved by the Medical Reviewer. At the discretion of the Medical Director and on a case-by-case basis, Molina Healthcare may consider authorization of the biologic therapies addressed in this Policy for members with exceptional circumstances and for members with severe disease who may fall outside of the defined criteria.

∑ Molina Healthcare reserves the right to update this Policy and revise coverage criteria to include or omit any off-label condition(s) as necessary based on medical literature and clinical studies that may become available.

∑ The intent of this Policy is to ensure the safe, clinically appropriate and cost-effective use of Kynamro (mipomersen) while maintaining optimal therapeutic outcomes.

∑ The safety and effectiveness of Kynamro have not been established in patients with hypercholesterolemia who do not have HoFH.

∑ The effects of mipomersen on cardiovascular outcomes (cardiovascular morbidity and mortality) in patients with HoFH have not been established.

∑ Kynamro (mipomersen) for patients with hypercholesterolemia who do not have homozygous familial hypercholesterolemia (HoFH) will not be authorized.

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∑ Kynamro (mipomersen) as an adjunct to LDL apheresis or within 8 weeks after receiving LDL apheresis will not be authorized.2,3,4 ‹ The safety and efficacy of use as an adjunct to LDL apheresis have not been established; therefore, its use as an adjunct to LDL apheresis is not recommended.

∑ There are no head-to-head trials comparing Kynamro (mipomersen) to other treatments. Therefore, there is no evidence that Kynamro (mipomersen) is safer or more effective than other treatments for homozygous familial hypercholesterolemia.

∑ Mipomersen may also be an option for patients who are unable to use lomitapide (Juxtapid) due to its contraindications, including pregnancy category X status, drug interactions with strong and moderate CYP3A4 inhibitors, and additional warnings. Lomitapide (Juxtapid) also carries a black box warning for hepatotoxicity.

FDA INDICATIONS �

∑ Kynamro (mipomersen) is indicated as an adjunct to lipid-lowering medications and diet to reduce low density lipoprotein cholesterol (LDL-C), apolipoprotein B (apo B), total cholesterol (TC), and non-high density lipoprotein- cholesterol (non-HDL-C) in patients with homozygous familial hypercholesterolemia (HoFH).

Limitations of Use • The safety and effectiveness of Kynamro (mipomersen) Injection Solution for Subcutaneous Injection have not been established in patients with hypercholesterolemia who do not have HoFH. • The effect of Kynamro (mipomersen) Injection Solution for Subcutaneous Injection on cardiovascular morbidity and mortality has not been determined. • The use of Kynamro (mipomersen) Injection Solution for Subcutaneous Injection as an adjunct to LDL apheresis is not recommended.

Available as: 200 mg/mL (1 mL) solution for injection

Approved by the FDA: January 2013

RECOMMENDATIONS/COVERAGE CRITERIA

Initiation of therapy with Kynamro (mipomersen) may be authorized for members who meet ALL of the following criteria [ALL]

1. � Prescriber specialty [BOTH]

ß Board-certified clinical lipidologist (achieved certification from the American Board of Clinical Lipidology); specialist in Endocrinology, Diabetes and Metabolism; cardiologist; or hematologist ‹ According to the National Lipid Association (NLA), homozygous FH patients should always be managed by a lipid specialist.B

ß Prescribed by a certified REMS provider demonstrated with supporting documentation (signed attestation) ‹ For more information and Provider enrollment, refer to: http://www.kynamrorems.com/

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2. � Diagnosis/Indication [ALL]

ß Diagnosis of definite homozygous familial hypercholesterolemia confirmed by ONE of the following genetic testing [ONE] û Genetic testing demonstrating mutations in both alleles for LDLR (LDL receptors) û Genetic testing demonstrating gain-of-function mutations in both alleles for PCSK9 û Genetic testing demonstrating mutations in both alleles for apoB (apoprotein B) û Cellular testing demonstrating reduced LDL receptor activity in fibroblasts / lymphocytes equaling 20% or less of the normal activity

NOTE: Molina Healthcare will not authorize coverage for members who do not have homozygous familial hypercholesterolemia (HoFH), such as heterozygous familial hypercholesterolemia

ß Documented diagnosis of definite FH according to the Simon Broome criteria:C [ONE]

û Adult: Cholesterol above 7.5mmol/l or LDL cholesterol above 4.9 mmol/l, or Child under 16: Cholesterol above 6.7mmol/l or LDL cholesterol above 4 mmol/l AND Tendon xanthomas in patient or a 1st degree relative (parent, sibling, child), or in a 2nd degree relative (grandparent, uncle, aunt).

û DNA-based evidence of an LDL receptor mutation, familial defective apoB-100, or a PCSK9 mutation.

ß Laboratory or clinically determined presence of homozygous familial hypercholesterolemia defined by the presence of at least one of the following clinical criteria:2 [ONE]

û History of genetic testing confirming two mutated alleles at the LDL receptor gene locus, or

û Documented history of untreated LDL-C > 500 mg/dL, and at least ONE of the following criteria [ONE] o Tendinous and/or cutaneous xanthoma prior to age 10 years o Documentation of elevated LDL-C > 190 mg/dL prior to lipid-lowering therapy consistent with heterozygous familial hypercholesterolemia (HeFH) in both parents. In case a parent is not available, a history of coronary artery disease in a first degree male relative of the parent younger than 55 years old or first degree female relative of the parent younger than 60 years old was acceptable.

3. � Age/Gender/Other restrictions [ONE]

ß 12 years of age or older2 ‹ The safety and efficacy of Kynamro (mipomersen) have not been established in pediatric patients.a,b

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4. Step/Conservative Therapy/Other condition Requirements [ONE] �

ß Documentation in the medical record that prior to the initiation of therapy, the member has been and will continue to follow a low-fat diet supplying < 20% of energy from fat AND other lipid-lowering therapies including: [ALL]

û Low-fat diet2: Prior to the initiation of Kynamro (mipomersen) therapy, the member has been and will continue to follow a low-fat diet supplying less than 20% of energy from fat a,b

û HMG CoA reductase inhibitor (statin)2: Inadequate clinical response (defined as failure to reach target LDL), intolerance (refer to next criterion) or contraindication to TWO of the following HMG CoA reductase inhibitor (statin) therapy after an adherent trial at maximum therapeutic dose for at least 90 days of consecutive therapy in the past 12 months: [TWO] o pravastatin (Pravachol) 80mg daily o simvastatin (Zocor) 40mg daily o atorvastatin (Lipitor) 80mg daily o rosuvastatin (Crestor) 40mg daily OR For members intolerant to statins: Failure to reach target LDL on fenofibrate, colestipol, or other approved non-formulary LDL lowering medication o Fibrates [Gemfibrozil (Lopid), Tricor, Lofibra] o nicotinic acidD o ezetimibe o bile acid sequestrants (Cholestyramine, Light)

‹ Refer to Appendix 1 for a list of FDA-approved lipid lowering agents

¶ Kynamro (mipomersen) will be used in combination with a standard lipid lowering regimen containing a high potency statin

¶ Kynamro (mipomersen) will not be used concomitantly with Juxtapid (lomitapide) ‹ The safety and effectiveness of mipomersen have not been studied in combination with lomitapide.

¶ Member has not had LDL apheresis within 8 weeks2,3

5. � Contraindications/Exclusions to Kynamro (mipomersen) therapya,b [ANY] Authorization will not be granted if ANY of the following conditions apply [ANY]

ß Non-FDA approved indications

ß Hypersensitivity to Kynamro (mipomersen) or any ingredient in the formulation

ß Moderate or severe hepatic impairment (Child-Pugh class B or C)

ß Active liver disease, including unexplained persistent elevations of serum transaminases

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6. Labs/Reports/Documentation required [ALL] �

ß Diagnosis of definite homozygous familial hypercholesterolemia confirmed by ONE of the following genetic testing [ONE]

û Genetic testing demonstrating mutations in both alleles for LDLR (LDL receptors)

û Genetic testing demonstrating gain-of-function mutations in both alleles for PCSK9

û Genetic testing demonstrating mutations in both alleles for apoB (apoprotein B)

û Cellular testing demonstrating reduced LDL receptor activity in fibroblasts / lymphocytes equaling 20% or less of the normal activity

NOTE: Molina Healthcare will not authorize coverage for members who do not have homozygous familial hypercholesterolemia (HoFH), such as heterozygous familial hypercholesterolemia

ß Documented diagnosis of definite FH according to the Simon Broome criteria:C [ONE]

û Adult: Cholesterol above 7.5mmol/l or LDL cholesterol above 4.9 mmol/l, or � Child under 16: Cholesterol above 6.7mmol/l or LDL cholesterol above 4 mmol/l � AND Tendon xanthomas in patient or a 1st degree relative (parent, sibling, child), or in a 2nd degree relative (grandparent, uncle, aunt).

û DNA-based evidence of an LDL receptor mutation, familial defective apoB-100, or a PCSK9 mutation.

ß Laboratory or clinically determined presence of homozygous familial hypercholesterolemia defined by the presence of at least one of the following clinical criteria:2 [ONE]

û History of genetic testing confirming two mutated alleles at the LDL receptor gene locus, or

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û Low-fat diet: Prior to the initiation of Kynamro (mipomersen) therapy, the member has been and will continue to follow a low-fat diet supplying less than 20% of energy from fat a,b

û HMG CoA reductase inhibitor (statin): Inadequate clinical response (defined as failure to reach target LDL), intolerance (refer to next criterion) or contraindication to TWO of the following HMG CoA reductase inhibitor (statin) therapy after an adherent trial at maximum therapeutic dose for at least 90 days of consecutive therapy in the past 12 months: [TWO] o pravastatin (Pravachol) 80mg daily o simvastatin (Zocor) 40mg daily o atorvastatin (Lipitor) 80mg daily o rosuvastatin (Crestor) 40mg daily OR For members intolerant to statins: Failure to reach target LDL on fenofibrate, colestipol, or other approved non-formulary LDL lowering medication o Fibrates [Gemfibrozil (Lopid), Tricor, Lofibra] o nicotinic acidD o ezetimibe o bile acid sequestrants (Cholestyramine, Light)

‹ Refer to Appendix 1 for a list of FDA-approved lipid lowering agents

ß Recent pre-therapy testing (must be performed only prior to scheduled initiation of treatment) AND is within appropriate limits for treatment, including: [ALL]

û ALT, AST, alkaline phosphatase, total bilirubin ‹ Before beginning treatment with Kynamro, measure alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and total bilirubin. During the first year, conduct liver-related tests monthly (ALT and AST, at a minimum). After the first year, conduct these tests at least every 3 months.

ADMINISTRATION, QUANTITY LIMITATIONS, AND AUTHORIZATION PERIOD

7. � Recommended Dosing Regimen [ALL]

ß Dosage prescribed is within the FDA-approved labeling based on member’s confirmed diagnosis: 200 mg once weekly as a subcutaneous injection. ‹ The safety and effectiveness of higher doses have not been established. ‹ Monitoring • Before treatment, measure ALT, AST, alkaline phosphatase, and total bilirubin and then ALT and AST regularly as recommended. • During treatment, withhold the dose of Kynamro if the ALT or AST is ≥ 3 times the upper limit of normal (ULN) • Discontinue Kynamro for clinically significant liver toxicity.

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8. � Authorization Limita,b [ALL]

ß May authorize up to 7 months of initial therapy ‹ After initiation of Kynamro therapy lipid levels should be monitored at least every 3 months for the first year. Maximal reduction of LDL-C may be seen with Kynamro therapy after approximately 6 months. Health care providers should assess the patient’s LDL-C level after 6 months to determine if the LDL-C reduction achieved with Kynamro is sufficiently robust to warrant the potential risk of liver toxicity.

ß May be authorized in quantities of up to four (4) vials or prefilled syringes per month

9. � Route of Administration [ALL]

ß Medication is considered to be self-administered until information from the manufacturer, scientific literature, practice standards, or governing State or Federal agency indicates otherwise.

ß If member meets all criteria and approval for therapy is granted, medication will be dispensed by a specialty pharmacy vendor at the discretion of Molina Healthcare. Self-administered medications may not be dispensed for self-administration and billed through the medical benefit by a provider; they must be dispensed through a participating pharmacy.

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CONTINUATION OF THERAPY Continuation of therapy with Kynamro (mipomersen) may be authorized for members who meet ALL of the following criteria [ALL]

1. Initial Coverage Criteria

ß Member currently meets ALL initial coverage criteria

2. Adherence to Therapy/Compliance

ß Adherence to therapy at least 85% of the time as verified by Prescriber and member’s medication fill history (review Rx history for compliance) NOTE: Therapy may be discontinued due to poor adherence upon recommendation of the Molina Medical Director when adherence < 85% has been demonstrated in at least two months during the course of therapy

ß Review of compliance to recommended liver enzyme laboratory testing as specified in the Kynamro (mipomersen) prescribing informationa,b ‹ Before beginning treatment with Kynamro, measure alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and total bilirubin. ‹ During the first year, conduct liver-related tests monthly (ALT and AST, at a minimum). After the first year, conduct these tests at least every 3 months. ‹ During treatment, withhold the dose of Kynamro if the ALT or AST is ≥ 3 times the upper limit of normal (ULN) ‹ Discontinue Kynamro for clinically significant liver toxicity.

3. Labs/Reports/Documentation required [ALL] Documentation of demonstrated efficacy to Kynamro (mipomersen) treatment as demonstrated by the following: [APPLICABLE]

ß For members who initiated Kynamro therapy within the past 6 months only: Documentation that member’s LDL-C level reduction achieved is sufficiently robust by Week 28 to support continuation of Kynamro therapy

ß For members who have been maintained on Kynamro therapy for longer than 6 months: Documentation of positive clinical response to Kynamro therapy

4. Discontinuation of Treatment

ß Intolerable adverse effects or drug toxicity

ß Persistent or clinically significant elevations of transaminase OR if transaminase elevations are accompanied by clinical symptoms of liver injury or toxicity, increases in bilirubin ≥ 2 times the upper limit of normal (ULN), active liver disease ‹ Discontinue treatment with Kynamro if persistent or clinically significant elevations or if transaminase elevations are accompanied by clinical symptoms of liver injury, increases in bilirubin ≥2x ULN, or active liver disease

ß LDL apheresis within 8 weeks2,3

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ß Contraindications/Exclusions to therapy [ANY] Authorization will not be granted if ANY of the following conditions apply [ANY] û Non-FDA approved in Non-FDA approved indications û Hypersensitivity to Kynamro (mipomersen) or any ingredient in the formulationa,b û Moderate or severe hepatic impairment (Child-Pugh class B or C) a,b û Active liver disease, including unexplained persistent elevations of serum transaminasesa,b

ADMINISTRATION, QUANTITY LIMITATIONS, AND AUTHORIZATION PERIOD

4. Recommended Dosing Regimen [ALL]

ß Dosage prescribed is within the FDA-approved labeling based on member’s confirmed diagnosis: 200 mg once weekly as a subcutaneous injection. ‹ The safety and effectiveness of higher doses have not been established. ‹ Measure ALT, AST, alkaline phosphatase, and total bilirubin before initiating treatment and then ALT, AST regularly as recommended. During treatment, withhold the dose of Kynamro if the ALT or AST are ≥3 x ULN. Discontinue Kynamro for clinically significant liver toxicity.

5. Authorization Limita,b [ALL]

ß May authorize up to 6 months of continuation of therapy ‹ After initiation of Kynamro therapy lipid levels should be monitored at least every 3 months for the first year. Maximal reduction of LDL-C may be seen with Kynamro therapy after approximately 6 months. Health care providers should assess the patient’s LDL-C level after 6 months to determine if the LDL-C reduction achieved with Kynamro is sufficiently robust to warrant the potential risk of liver toxicity.

ß May be authorized in quantities of up to four (4) vials or prefilled syringes per month

6. Route of Administration [ALL]

ß Medication is considered to be self-administered until information from the manufacturer, scientific literature, practice standards, or governing State or Federal agency indicates otherwise.

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COVERAGE EXCLUSIONS All other uses of the mentioned drugs that are not an FDA-approved indication or included in ‘Coverage Criteria’ section above are considered experimental/investigational and is not a covered benefit. The following list may not be all-inclusive and is subject to change based on research and medical literature:

ß Heterozygous familial hypercholesterolemia ‹ The safety and efficacy of Kynamro (mipomersen)have not been established in patients with hypercholesterolemia who do not have homozygous familial hypercholesterolemia.

ß Non-familial hypercholesterolemia ‹ Currently the role of mipomersen in non-familial hypercholesterolemia is unknown. It is not recommended, nor should it be used due to a lack of efficacy and safety data, in patients with only hypercholesterolemia.

ß Drug resistant hypercholesterolemia

ß Members receiving LDL apheresis with the use of Kynamro™

ß Concurrent use with lomitapide (Juxtapid)

WARNINGS/ PRECAUTIONS

A. Adverse Reactions

Black Box Warnings Hepatotoxicity: As seen in clinical trials, may cause hepatic transaminase elevation and increases in hepatic steatosis (with or without concomitant increases in transaminases) which may progress to steatohepatitis and cirrhosis; measure ALT, AST, alkaline phosphatase, and total bilirubin prior to initiation, then ALT and AST on a regular basis as recommended. Withhold dose of mipomersen if ALT or AST is ≥3 x ULN.

Discontinue mipomersen if clinically significant hepatotoxicity occurs. Because mipomersen has a risk of hepatotoxicity, it is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) program (Kynamro™ REMS).

Alcohol consumption during treatment with mipomersen should be limited to ≤1 drink/day due to potential to increase levels of hepatic fat and induce or exacerbate liver injury.

Use caution when used concomitantly with other medications known to cause hepatotoxicity (e.g., isotretinoin, amiodarone, acetaminophen [>4 g/day for ≥3 days/week]).

Use is contraindicated in patients with moderate or severe hepatic impairment or active liver disease including patients with unexplained persistent elevations of hepatic transaminases. If baseline liver function tests are abnormal, consider initiation after an appropriate work up and abnormalities are explained or resolved.

Monitoring Recommendations Measure ALT, AST, alkaline phosphatase, and total bilirubin before initiating treatment and then ALT, AST regularly as recommended. During treatment, withhold the dose of Kynamro if the ALT or AST are ≥ 3 x ULN. Discontinue Kynamro for clinically significant liver toxicity.

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REMS program Due to the risk of hepatotoxicity, Kynamro is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Kynamro REMS.

Contraindicationsa,b ß Hypersensitivity to mipomersen or any component of the formulation ß Moderate or severe hepatic impairment (Child-Pugh class B or C) ß Patients with active liver disease, including unexplained persistent elevations of serum transaminases

The most common adverse reactions reported injection site reactions, flu-like symptoms, nausea, headache and elevations in liver enzymes. a,b

Severe adverse reactions: Mipomersen can cause severe injection site reactions, flu-like symptoms, nausea, headache and elevations in transaminases. Hepatic steatosis, which is a risk factor for progressive liver disease, including steatohepatitis and cirrhosis, has occurred. Because of the risk of hepatotoxicity, mipomersen is only available through a restricted access program.

B. Special Populationsa,b

ß Pregnancy: Category B. There are no adequate and well-controlled studies in pregnant women. Females of reproductive potential should use effective contraception during mipomersen therapy. According to the manufacturer, the drug should be used during pregnancy only if clearly needed and females who become pregnant during mipomersen therapy should be instructed to notify their healthcare provider. ß Lactation: It is not known if mipomersen is excreted in breast milk. Consider the benefits of breast- feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. Breast-feeding is not recommended by the manufacturer. ß Pediatric: Safety and efficacy have not been established in pediatric patients. ß Geriatric: Elderly: In clinical trials, patients ≥65 years of age (n=59) experienced a higher incidence of hepatic steatosis, hypertension, and peripheral edema; use with caution in the elderly. ß Renal Impairment: No dosage adjustment provided in manufacturer’s labeling (has not been studied); use is not recommended in patients with severe renal impairment, clinically significant proteinuria, or receiving hemodialysis. ß Hepatic Impairment: No dosage adjustment provided in manufacturer’s labeling (has not been studied); use is contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh class B or C), active liver disease, or unexplained persistent elevations of hepatic transaminases.

C. Drug Interactionsa,b Mipomersen is not metabolized by CYP450 enzymes. No clinically relevant pharmacokinetic interactions were reported with simvastatin, ezetimibe or warfarin. Drug/Food Interactionsa,b ß Alcohol (Ethyl): May enhance the hepatotoxic effect of Mipomersen. Management: Patients being treated with mipomersen should limit their consumption of alcohol to a maximum of 1 drink (or equivalent) per day. Risk D: Consider therapy modification

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DESCRIPTION OF PROCEDURE/SERVICE/PHARMACEUTICAL Kynamro (mipomersen sodium) is indicated as an adjunct to lipid-lowering medications and diet to reduce low density lipoproteincholesterol (LDL-C), apolipoprotein B (apo B), total cholesterol (TC), and non-high density lipoprotein- cholesterol (non HDL-C) in patients with homozygous familial hypercholesterolemia (HoFH).

Mipomersen is a first-in-class apolipoprotein B synthesis inhibitor, which binds to a specific segment of the mRNA coding region for apo B, thus inhibiting the synthesis of this target. In humans, apo B-100 is the principal apolipoprotein associated with very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and low density lipoprotein (LDL), comprising approximately 30% to 95% of the proteins in these lipoproteins. Apo B-100 is also a principal component of lipoprotein (a) (Lp[a]), which consists of apolipoprotein (a) covalently bound to the apo B component of an LDL-like particle. Low density lipoprotein cholesterol (LDL-C), apo B and Lp(a) are key risk factors for atherosclerosis.

The safety and efficacy of mipomersen has not been established in patients with hypercholesterolemia who do not have HoFH. In addition, the effect of this agent on cardiovascular morbidity and mortality has not been established. Furthermore, the use of mipomersen as an adjunctive treatment to low density lipoprotein apheresis is not recommended. The prescribing information for mipomersen includes a Black Box Warning regarding the risk of elevations in transaminases, increases in hepatic fat content and risk of hepatotoxicity. Due to the risk of hepatotoxicity, Kynamro® is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS). With the Kynamro® REMS, only certified providers and pharmacies may prescribe and distribute Kynamro.

Familial hypercholesterolemia (FH) is genetic autosomal dominant disorder involving the LDL receptor gene, more specifically, FH involves lipid metabolism that is characterized by a significant elevation in levels of low-density lipoprotein cholesterol (LDL-C) receptor, apo B, or proprotein convertase subtilisin kexin type 9 (PCSK9), all of which are involved in the normal processing and trafficking of LDL-C.

Homozygous FH (HoFH) is rare and is characterized by severe elevations of total and LDL cholesterol. HoFH leads to accumulation of LDL particles in plasma and premature cardiovascular disease. Patients with HoFH carry two of the same defective genes, while patients with the heterozygous form of the condition carry one defective gene. Individuals with familial hypercholesterolemia (FH) are at significantly increased risk for premature cardiovascular disease (CVD).

HoFH is prevalent in approximately one out of a million individuals.D Most patients with HoFH have LDL levels that are four times the normal levels (between 400-1,000 mg/dL). Patients with HoFH will form xanthelasmas (yellowish collection of cholesterol under the skin) and cutaneous xanthomas (larger, nodular xanthelasmas) within the first few months of years of life. Tendon xanthomas (papules found in tendons of hands, feet and achilles) and tuberous xanthomas (xanthomas over the joints) tend to develop in HoFH patients later on in life. Generally, treating patients with HoFH has been challenging because the patient expresses little or no LDL-receptor activity and therefore is resistant to diet modifications and most medications indicated for lowering cholesterol.

The diagnosis of both homozygous and heterozygous FH is based primarily on the finding of severe LDLc elevations in the absence of secondary causes of hypercholesterolemia with triglyceride levels that are within the reference range or mildly elevated and HDL cholesterol (HDLc) levels that are within the reference range or slightly low. Definitive diagnosis can be made only with gene or receptor analysis. 3,4 Homozygous FH can be distinguished from heterozygous FH clinically by the much more extreme elevations in LDL and can be confirmed by either genetic characterization of the LDL receptor mutations (from leukocytes) or by quantification of LDL receptor activity (from skin fibroblasts).H

Children with homozygous FH usually present within the first decade of life, most commonly after investigation of physical findings related to cholesterol deposition, such as tendon xanthomata, cutaneous xanthelasma, or corneal arcus, or with clinical manifestations of atherosclerotic cardiovascular disease.H,3,4 Individuals with the more severe homozygous form of FH (HoFH) develop clinically significant cardiovascular disease in early childhood and, if untreated, they rarely survive beyond the age of 30 years, whereas in those with the less severe heterozygous form (HeFH) the onset of significant cardiovascular disease is generally delayed until the fourth or fifth decade.J It is noted by the American Heart

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AssociationH that familial hypercholesterolemia (FH) is the most common of the primary hyperlipidemias, and the most clearly documented to have important cardiovascular consequences beginning in childhood. Hence, the identification and management of FH in children is of significant consequence.

NICE (2008) guidelines recommend “a diagnosis of FH should be made using the Simon Broome criteria, which include a combination of family history, clinical signs (specifically tendon xanthomata), cholesterol concentration and DNA testing.”C ‹ Refer to Appendix E of NICE Clinical Guideline 71 (2008) Simon Broome criteria

TREATMENT OPTIONS The goal of FH treatment is to reduce the risk of CHD or risk of a CHD-equivalent condition (e.g., carotid artery disease, diabetes, peripheral arterial disease).

Management of homozygous FH:A,B • Lifestyle changes: Recommended for cardiovascular benefits • High doses of HMG-CoA reductase inhibitors (statins) combined with bile acid sequestrants, ezetimibe, and niacin • Estrogen replacement therapy in postmenopausal women • LDL apheresis for selective removal of lipoproteins that contain apo-B (when the LDL receptors are absent or non-functional) NOTE: The use of Kynamro as an adjunct to LDL apheresis is not recommended. • Surgical procedures: Portacaval anastomosis or Liver transplantation (rarely)

Other FDA-approved pharmacological therapies indicated for the treatment of HoFH include certain statins (atorvastatin, rosuvastatin and simvastatin), ezetimibe/simvastatin and ezetimibe in combination with either atorvastatin or simvastatin. The 2002 Adult Treatment Panel (ATP) III guidelines from the National Cholesterol Education Program (NCEP) lists statins and nicotinic acid as an adjunct to other lipid-lowering treatments such as LDL aphresis (process which removes VLDL and LDL from the plasma) or when such treatments are unavailable as therapeutic considerations in patients with HoFH.

The Medical Letter noted “The standard treatment for patients with homozygous familial hypercholesterolemia includes a low-fat diet, high doses of a statin such as atorvastatin or rosuvastatin combined with ezetimibe (and often with bile acid sequestrants and niacin in addition), and LDL apheresis.”E

UpToDateG recommends “For homozygous FH patients without cardiovascular disease who do not achieve LDL-C <200 mg/dL (5.17 mmol/L) or those with established disease who do not achieve an LDL-C <160 mg/dL (4.10 mmol/L) after optimal drug therapy and either LDL-apheresis or liver transplantation, we suggest adding lomitapide or mipomersen (Grade 2C). For patients who are not candidates for or refuse LDL-apheresis or liver transplantation, lomitapide or mipomersen should be considered as additional pharmacologic therapy.”

‹ It should be noted that the safety and efficacy of Kynamro (mipomersen) in children have not been established.a,b

‹ American Heart AssociationH recommendations for pediatric patients regarding homozygous familial hypercholesterolemia patients are as follows: • complete cardiovascular assessment at diagnosis along with ongoing surveillance for cardiovascular disease • treatment should be instituted as soon as possible • therapy for most patients is weekly or biweekly plasmapheresis, preferably LDL apheresis • high-dose statins recommended in combination with a cholesterol absorption inhibitor • low-dose anticoagulation may also be indicated

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PUBLISHED CLINICAL TRIALS The three randomized placebo-controlled phase III trials (discussed below) were only 26 weeks long and did not evaluate CHD outcomes. LDL-C goal was achieved only in the HeFH study. There is insufficient evidence to determine if mipomersen lowers the incidence of CHD events in patients with HoFH, HeFH or drug resistant hypercholesterolemia.

∑ Mipomersen in HoFH patients2 Mipomersen was approved based upon a single phase III trial of 51 patients who were genetically or clinically confirmed with HoFH.2 The safety and efficacy of Kynamro (mipomersen) as an adjunct to lipid-lowering medications in individuals with homozygous familial hypercholesterolemia (HoFH) were evaluated in a multinational, randomized, placebo-controlled, 26-week trial (N=51).

The approval of Kynamro was based on a pivotal Phase III trial that showed that the medication lowered LDL-C by 25%.2 • Diagnosis of HoFH was determined by: û history of genetic testing confirming two mutated alleles at the LDL receptor gene locus, or û documented history of untreated LDL-C > 500 mg/dL, and at least one of the following criteria o tendinous and/or cutaneous xanthoma prior to age 10 years o documentation of elevated LDL-C > 190 mg/dL prior to lipid-lowering therapy consistent with heterozygous familial hypercholesterolemia (HeFH) in both parents. In case a parent is not available, a history of coronary artery disease in a first degree male relative of the parent younger than 55 years old or first degree female relative of the parent younger than 60 years old was acceptable. • Forty-four of the 51 individuals (86%) in the trial had genetic confirmation of HoFH: 29 were true homozygotes and 13 were compound heterozygoes.

• Patients with HoFH already on lipid-lowering treatment. Patients were maintained on maximum tolerated prior lipid lowering drugs (high-dose statins, cholesterol absorption inhibitors, bile acid sequestrants or nicotinic acid) throughout the study.

• LDL-C apheresis was not allowed.

• Kynamro was given as 200 mg weekly subcutaneous injections, as an adjunct to lipid-lowering medications. Raal et al.2 randomized 34 patients to 200mg of subcutaneous mipomersen per week and 17 patients to a matching volume of placebo subcutaneously per week.

• Mean baseline LDL cholesterol concentrations were 439 mg/dL among patients randomized to mipomersen and 400 mg/dL in the placebo group.

• The primary efficacy endpoint was the percent change from baseline to 28 weeks in low density lipoprotein cholesterol (LDL-C). The mean treatment time was 25 weeks and follow-up was two weeks after the last dose. ° At 28 weeks, there was a significantly greater reduction from baseline with mipomersen compared to placebo with regard to LDL (-25 vs -3%; P=0.0003), apolipoprotein B (-27 vs -3%; P<0.0001), total cholesterol (-21 vs -2%; P<0.05), non-high density lipoprotein-cholesterol (HDL-C) (-25 vs -3%; P=0.0002), triglycerides (-18 vs 1%; P=0.013) and HDL-C (15 vs 4%; P<0.001).

• Primary efficacy endpoint: At week-28, there was a significantly greater improvement from baseline in LDL-C for patients treated with mipomersen compared to patients treated with placebo (-25 vs -3%; P=0.0003).

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• Secondary efficacy endpoint:: At 28 weeks, there was a significantly greater reduction from baseline with mipomersen compared to placebo with regard to LDL (-25 vs -3%; P=0.0003), apolipoprotein B (-27 vs -3%; P<0.0001), total cholesterol (-21 vs -2%; P<0.05), non-high density lipoprotein-cholesterol (HDL-C) (-25 vs -3%; P=0.0002), triglycerides (- 18 vs 1%; P=0.013) and HDL-C (15 vs 4%; P<0.001).

• The most common adverse event was injection-site reaction, which was three-times more common in the mipomersen group than in the placebo group. Three serious adverse events were reported.

∑ Mipomersen in heterozygous familial hypercholesterolemia3 Mipomersen in adults with HeFH and CAD on maximally tolerated lipid-lowering therapies:

Stein et al.3 randomized 83 patients to self-administered subcutaneous mipomersen 200mg and 41 patients to an un- described, but self-administered placebo. Both were given weekly for 26 weeks. All patients were genetically or clinically confirmed with HeFH on a stable, maximally tolerated lipid-lowering drug regimen for 12 weeks. LDL-C apheresis was not allowed. There were slightly more patients with cardiovascular history and who smoked in the mipomersen group. Risks for selection, performance and attrition biases were identified. There was inadequate description of randomization, allocation concealment and blinding. Three mipomersen patients were lost to follow-up and nine mipomersen patients withdrew due to ADEs. Again CHD outcomes were not assessed and the percent change from baseline to 28 weeks in LDL-C was the primary outcome. The mean difference in LDL-C between groups was a decrease of 33% favoring mipomersen (p <0.001) to final LDL-C levels of: mipomersen 104 mg/dL and placebo 143 mg/dL.

∑ Drug resistant hypercholesterolemia1 Mipomersen in adults with severe hypercholesterolemia on maximum lipid-lowering therapy and excluded from apheresis:

MCPowan et al.1 randomized 39 patients to self-administered mipomersen 200mg subcutaneously per week to and 19 patients to a self-administered similarly appearing placebo for 26 weeks. It included adults with severe hypercholesterolemia on maximum lipid-lowering therapy and excluded from apheresis.

The groups differed in that there was more alcohol use and metabolic syndrome in the mipomersen group but more tobacco use in the placebo group. The mipomersen group experienced more loss to follow-up (13%) and total attrition (36%) than the placebo group (5% and 16% respectively). Blinding may have been broken due to all mipomersen patients experiencing an ADE, most of which were injection site reactions. CHD outcomes were not assessed. The mean difference in the primary outcome, percent change in LDL-C at 28 weeks, was 48% favoring mipomersen (0.001). The final LDL-C for both groups remained high: mipomersen 174mg/dL versus placebo 263mg/dL.

HAYES DIRECTORY A Hayes Directory report was not available for Kynamro® (mipomersen) and/or for the homozygous familial hypercholesterolemia at the time of this writing in September 2013.

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GUIDELINES Available treatment guidelines support the use of high-dose statins, low density lipoprotein apheresis and other cholesterol lowering agents (e.g., ezetimibe), often as part of combination regimens to reach cholesterol goals.B,D,F

AMERICAN HEART ASSOCIATION The 2006 American Heart Association scientific statement H on cardiovascular risk reduction in high-risk pediatric patients recommends that children with homozygous FH receive early initiation of combined therapy including LDL apheresis, high dose statin therapy, and a cholesterol absorption inhibitor. UpToDateG experts on homozygous FH also recommend this approach for both children and adults.

Drug Therapy of High-Risk Lipid Abnormalities in Children and Adolescents: a Scientific Statement from the American Heart Association (2007)L may be given as necessary, although compliance with these agents tends to be challenging. • For children meeting criteria for lipid-lowering drug therapy, a statin is recommended as first-line treatment. The choice of statin is dependent upon preference but should be initiated at the lowest dose once daily, usually at bedtime. • For patients with high-risk lipid abnormalities, the presence of additional risk factors or high-risk conditions may reduce the recommended LDL level for initiation of drug therapy and the desired target LDL levels. Therapy may also be considered for initiation in patients <10 years of age. • Additional research regarding drug therapy of high-risk lipid abnormalities in children is needed to evaluate the long-term efficacy and safety and impact on the atherosclerotic disease process.

NATIONAL HEART LUNG AND BLOOD INSTITUTE Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk (2011)K

Specific recommendations regarding the management of familial hypercholesterolemia include: • Children with homozygous familial hypercholesterolemia and extremely elevated LDL-C levels (>500 mg/dL) have undergone effective LDL-C lowering therapy with biweekly LDL apheresis under the care of lipid specialists in academic medical centers. • Statins have been shown to reduce LDL-C in children and adolescents with marked LDL-C elevation or familial hypercholesterolemia. • Plant sterol esters and/or plant stanol esters up to 2 g/day as replacement for usual fat sources can be used after two years of age in children with familial hypercholesterolemia

NATIONAL CHOLESTEROL EDUCATION PROGRAM (NCEP)D The 2002 Adult Treatment Panel (ATP) III guidelines from the National Cholesterol Education Program (NCEP) lists statins and nicotinic acid as an adjunct to other lipid-lowering treatments such as LDL aphresis (process which removes VLDL and LDL from the plasma) or when such treatments are unavailable as therapeutic considerations in patients with HoFH.

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NATIONAL LIPID ASSOCIATION (NLA) EXPERT PANEL Management of familial hypercholesterolemias in adult patients: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia (2011)F

‹ Low-fat, low-cholesterol diet and tobacco cessation, physical activity and maintenance of a healthy body weight are recommended.

‹ For adult familial hypercholesterolemia patients, initial treatment is the use of moderate to high doses of high- potency statin are recommended to reduce LDL-C at least 50% from baseline. Low potency statins are generally inadequate for familial hypercholesterolemia patients. If a patient is not able to meet the LDL-C goal with statin, additional agents such as ezetimibe, bile acid sequestrants, or niacin may be added to statin therapy.

• If the initial statin is not tolerated, consider changing to an alternative statin, or every-other-day statin therapy.

• If initial statin therapy is contraindicated or poorly tolerated, ezetimibe, a bile acid sequestrant (colesevelam) or niacin may be considered.

• For patients who cannot use a statin, most will require combination drug therapy.

• If the patient is not at LDL-C treatment goal with the maximum available and tolerable dose of statin, then combine with ezetimibe, niacin, or a bile acid sequestrant (colesevelam preferred).

‹ Decisions regarding selection of additional drug combinations should be based on concomitant risk factors for myopathy, concomitant medications, and the presence of other disease conditions and lipid abnormalities.

‹ In patients who, after six months, do not have an adequate response to maximum tolerated drug therapy, LDL apheresis is indicated according to these guidelines: ° Functional homozygous familial hypercholesterolemia patients with LDL-C ≥300 mg/dL (or non-HDL-C ≥330 mg/dL). ° Functional heterozygous familial hypercholesterolemia patients with LDL-C ≥300 mg/dL (or non-HDL-C ≥330 mg/dL) and one or fewer risk factors. ° Functional heterozygous familial hypercholesterolemia patients with LDL-C ≥200 mg/dL (or non-HDL-C ≥230 mg/dL) and high risk characteristics such as two or more risk factors or high lipoprotein (a) ≥50 mg/dL using an isoform insensitive assay. ° Functional heterozygotes with LDL-C ≥160 mg/dL (or non-HDL-C ≥190 mg/dL) and very high-risk characteristics (established CHD, other cardiovascular disease, or diabetes). LDL-C apheresis is recommended for patients with HoFH who have an LDL-C level of at least 300 mg/dL despite maximal drug therapy for at least six months.

‹ Liver transplantation is rarely utilized due to its risks, but it may be beneficial in patients who fail to respond to all other therapies because it provides normal LDL-C receptors and often leads to a significant lowering of LDL cholesterol.

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NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE Identification and Management of Familial Hypercholesterolemia (2008)C

• LDL cholesterol apheresis and liver transplantation are treatment options for individuals with homozygous familial hypercholesterolemia

• LDL cholesterol apheresis occasionally used for heterozygous individuals refractory to conventional lipid-lowering therapy

• Healthcare professionals should consider prescribing a high-intensity statin to achieve a recommended reduction in LDL-C concentration of greater than 50% from baseline.

• The dose of statin should be increased to the maximum licensed or tolerated dose to achieve a recommended reduction in LDL-C concentration of greater than 50% from baseline.

• Healthcare professionals should offer treatment with a statin with a low acquisition cost for adults with familial hypercholesterolemia in whom the diagnosis is made after the 60 years of age and who do not have coronary heart disease.

• Prescribing of drug therapy for adults with homozygous familial hypercholesterolemia should be undertaken within a specialist center.

• Healthcare professionals should offer adults with familial hypercholesterolemia a referral to a specialist with expertise in familial hypercholesterolemia if treatment with the maximum tolerated dose of a high-intensity statin and ezetimibe does not achieve a recommended reduction in LDL-C concentration of greater than 50% from baseline.

• Adults with familial hypercholesterolemia with intolerance or contraindications to statins or ezetimibe should be offered a referral to a specialist with expertise in familial hypercholesterolemia for consideration for treatment with either a bile acid sequestrant (resin), nicotinic acid, or a fibrate to reduce their LDL-C concentration.

• Lipid-modifying drug therapy for a child or young person with familial hypercholesterolemia should usually be considered by 10 years of age. Statins should be considered as initial treatment.

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DEFINITIONS

N/A

APPENDIX Appendix 1

List of FDA-approved lipid lowering medications or pharmaceutical agents

Generic Name U.S. Trade Name Route Class

Abbreviations: FDA = U.S. Food and Drug Administration; HMG-CoA = 3-hydroxy-3-methyl-glutaryl- coenzyme A reductase; N/A = not applicable; XL = extended release

Atorvastatin Lipitor® Oral HMG-CoA reductase inhibitor (statin)

Fluvastatin Lescol® Oral HMG-CoA reductase inhibitor (statin)

Fluvastatin XL Lescol XL® Oral HMG-CoA reductase inhibitor (statin)

Lovastatin Mevacor® Oral HMG-CoA reductase inhibitor (statin)

Pitavastatin Livalo® Oral HMG-CoA reductase inhibitor (statin)

Pravastatin Pravachol® Oral HMG-CoA reductase inhibitor (statin)

Rosuvastatin Crestor® Oral HMG-CoA reductase inhibitor (statin)

Simvastatin Zocor® Oral HMG-CoA reductase inhibitor (statin)

Cholestyramine Prevalite® Oral Bile acid sequestrant

Colesevelam Welchol® Oral Bile acid sequestrant

Colestipol Colestid®; Flavored Colestid® Oral Bile acid sequestrant

Ezetimibe Zetia® Oral Cholesterol absorption inhibitor

Tricor®; Triglide®; Lipofen®; Fenofibrate Oral Fibric acid Fenoglide®

Fenofibric acid Fibricor®; Trilipix® Oral Fibric acid

Gemfibrozil Lopid® Oral Fibric acid

Niacin Niaspan®; Niacor® Oral Nicotinic acid

Omega-3-acid ethyl Lovaza®; Omacor® Oral Omega-3-acid ethyl ester ester

Icosapent ethyl Vascepa® Oral Omega-3-acid ethyl ester

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List of FDA-approved lipid lowering medications or pharmaceutical agents

Generic Name U.S. Trade Name Route Class

Atorvastatin + HMG-CoA reductase inhibitor (statin) + N/A – Under FDA review Oral ezetimibe ezetimibe

HMG-CoA reductase inhibitor (statin) + Lovastatin + niacin Advicor® Oral nicotinic acid

HMG-CoA reductase inhibitor (statin) + Simvastatin + ezetimibe Vytorin® Oral ezetimibe

HMG-CoA reductase inhibitor (statin) + Simvastatin + niacin Simcor® Oral nicotinic acid Reference: Agency for Health Research and Quality (AHRQ) Effective Healthcare Program. Update of Comparative Effectiveness of Lipid-Modifying Agents. Published online: May 16, 2013. Available at: www.effectivehealthcare.ahrq.gov

CODING INFORMATION CPT Description 96372 Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular

HCPCS Description J2212 Injection, methylnaltrexone, 0.1 mg

The drug is given as a subcutaneous injection every other day. It should not be administered more than once every 24-hour period

ICD-9 Description [For dates of service prior to 10/01/2015] 272.0 Pure hypercholesterolemia; Familial hypercholesterolemia ICD-10 Description [For dates of service on or after 10/01/2015] E78.0 Pure hypercholesterolemia; Familial hypercholesterolemia

REFERENCES Package Insert and FDA a. Kynamro [package insert]. Cambridge, MA: Genzyme Corporation; January 2013. b. Kynamro. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2012. URL: http://www.clinicalpharmacology.com. Accessed

Clinical Trials, Definitions, Peer-Reviewed Publications 1. MCPowan MP, et al. Randomized, placebo-controlled trial of mipomersen in patients with severe hypercholesterolemia receiving maximally tolerated lipid-lowering therapy. Public Library of Science one PLoS 1 2012;7(11):e49006. doi: 10.1371/journal.pone.0049006. Epub 2012 Nov 13. 2. Raal FJ, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolemia: a randomized, double-blind, placebo-controlled trial. Lancet 2010 Mar 20;375(9719):998-1006 3. Stein EA et al. Apolipoprotein B synthesis inhibition with mipomersen in heterozygous familial hypercholesterolemia: results of a randomized, double-blind, placebo-controlled trial to assess efficacy and safety as add-on therapy in patients with coronary artery disease. Circulation 2012; 126:2283.

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Government Agencies, Professional Societies, and Other Authoritative Publications A. Robinson JG. et al, Treatment of adults with Familial Hypercholesterolemia and evidence for treatment: Recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia; Journal of Clinical Lipidology (2011) 5, S18–S29 B. Goldberg AC, Hopkins PN, Toth PP, et al. Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical Policy from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. Journal of Clinical Lipidology. 2011;5(3):133-140. Goldberg AC, Hopkins PN, Toth PP et al. Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical Policy from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol 2011;5(3 suppl):S1–8. C. National Institute for Health and Clinical Excellence. Identification and management of familial hypercholesterolemia. Clinical Policy 71 2008. London: NICE 2008. Available at: http://Policy.nice.org.uk/CG71/Policy/pdf/English. Accessed September 2013 D. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002; 106:3143–3421. Available at: http://www.nhlbi.nih.gov/guidelines/cholesterol/index.htm. Accessed September 2013. E. Two New Drugs for Homozygous Familial Hypercholesterolemia. The Medical Letter on Drugs and Therapeutics. April 1, 2013 (1413):25 F. Ito MK, MCPowan MP, Moriarty PM; National Lipid Association Expert Panel on Familial Hypercholesterolemia. Management of familial hypercholesterolemias in adult patients: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011 Jun;5(3 Suppl):S38- 45. G. Rosenson, RS. Treatment of drug-resistant hypercholesterolemia. In: UpToDate [Internet Database]. Freeman, MW ed. Waltham, MA: UpToDate. Updated 2013 May 29. H. Kavey REW, et al. Cardiovascular risk reduction in high-risk pediatric patients: a scientific statement from the American Heart Association expert panel on population and prevention science; the councils on cardiovascular disease in the young, epidemiology and prevention, nutrition, physical activity and metabolism, high blood pressure research, cardiovascular nursing, and the kidney in heart disease. Circulation. 2006;114(24):2710–2738. Available at: http://circ.ahajournals.org/content/114/24/2710.full#TBL2 Accessed September 2013. I. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA. May 16 2001;285(19):2486-97. J. Raal, Frederick et al. Elevated PCSK9 Levels in Untreated Patients With Heterozygous or Homozygous Familial Hypercholesterolemia and the Response to High‐Dose Statin Therapy. Journal of American Heart Association. 2013; Apr 24, 2013; 2:28-28. doi: 10.1161/JAHA.112.000028 K. Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents; National Heart, Lung, and Blood Institute. Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report. Pediatrics. 2011 Dec;128 Suppl 5:S213-56. L. McCrindle BW, et al. Circulation. 2007 Apr 10;115(14):1948-67. Drug therapy of high-risk lipid abnormalities in children and adolescents: a scientific statement from the American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee, Council of Cardiovascular Disease in the Young, with the Council on Cardiovascular Nursing. M. Jellinger PS, Smith DA, Mehta AE, et al. American Association of Clinical Endocrinologists’ Guidelines for Management of Dyslipidemia and Prevention of Atherosclerosis. Endocrine Practice. 2012;16(S1):1-78. Available at: https://www.aace.com/publications/guidelines.

AMR Peer Review Network AMR Peer Review Network. Board certified in Internal Medicine, Endocrinology, Diabetes and Metabolism. Date completed: 9/24/2013.

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