Medication Policy Manual Policy No: Topic: Date of Origin: Committee Approval Date: Next Review Date: Effective Date: IMPORTANT REMINDER Description

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1 Medication Policy Manual Policy No: dru301 Topic: Kynamro, mipomersen Date of Origin: May 16, 2013 Committee Approval Date: March 13, 2015 Next Review Date: March 2016 Effective Date: April 1, 2015 IMPORTANT REMINDER This Medical Policy has been developed through consideration of medical necessity, generally accepted standards of medical practice, and review of medical literature and government approval status. Benefit determinations should be based in all cases on the applicable contract language. To the extent there are any conflicts between these guidelines and the contract language, the contract language will control. The purpose of medical policy is to provide a guide to coverage. Medical Policy is not intended to dictate to providers how to practice medicine. Providers are expected to exercise their medical judgment in providing the most appropriate care. Description Mipomersen (Kynamro) is a self-administered injectable medication used in the treatment of homozygous familial hypercholesterolemia. It is an oligonucleotide inhibitor of apolipoprotein B- 100, a necessary component in the formation of LDL. dru301.2 Page 1 of 5

2 Policy/Criteria I. Most contracts require prior authorization approval of mipomersen prior to coverage. Mipomersen may be considered medically necessary in patients with homozygous familial hypercholesterolemia. II. Administration, Quantity Limitations, and Authorization Period A. OmedaRx considers mipomersen to be a self-administered medication. B. When prior authorization is approved, mipomersen may be authorized in quantities of four 200mg/ 1 ml pre-filled syringes per month. C. Authorization may be reviewed at least annually to confirm that current medical necessity criteria are met and that the medication is effective. III. Mipomersen is considered investigational when used for all other conditions, including, but not limited to: A. Heterozygous familial hypercholesterolemia B. Non-familial hyperlipidemia/ hypercholesterolemia C. In combination with lomitapide (Juxtapid ) Position Statement Summary - Mipomersen is used for the treatment of homozygous familial hypercholesterolemia (HoFH), a rare genetic disease characterized by abnormally elevated LDL cholesterol levels. - Because mipomersen is linked to uncommon but serious side effects, it should be reserved for conditions where potential benefit outweighs risk, such as HoFH. - The safety and effectiveness of mipomersen in conditions other than HoFH have not been established. Background - HoFH is a rare, genetic disease characterized by abnormally elevated LDL cholesterol levels and an increased risk for early onset coronary heart disease. LDL levels can range from 300 to over 1000 mg/dl. If not treated, affected patients often die in early adulthood. [1-3] - Treatment options include lomitapide, mipomersen, traditional lipid-lowering medications, and LDL-apheresis. - Treatment guidelines for HoFH recommend treatment with high doses statins and LDLapheresis. These guidelines have not been updated since the approval of lomitapide and mipomersen. [4-7] - Diagnosis of HoFH is required as part of the FDA s Risk Evaluation and Mitigation Strategy (REMS) for both lomitapide and mipomersen. Diagnosis may include genetic testing. [15, 16] dru301.2 Page 2 of 5

3 Clinical Efficacy HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA Mipomersen demonstrated LDL reduction is patients with HoFH; however, there is currently no evidence that it improves clinically meaningful outcomes, such as cardiovascular morbidity and mortality. - A single randomized, placebo-controlled trial evaluated mipomersen in 51 patients with HoFH. [8] * Patients were also on maximally tolerated background therapy, including other lipid-lowering medications. * Mipomersen reduced LDL up to 82% (mean 25%) after 26 weeks of treatment. * Due to the number of patients discontinuing treatment early (11%), the precision of these results is uncertain. - It is not known whether LDL is an accurate predictor of clinically meaningful outcomes (e.g. cardiovascular morbidity and mortality) in patients with HoFH. - There are no head-to-head trials comparing mipomersen to other treatments for HoFH. INVESTIGATIONAL CONDITIONS - Heterozygous Familial Hypercholesterolemia Two small-scale trials have evaluated mipomersen in heterozygous familial hypercholesterolemia. [9-10] Mipomersen reduced LDL between 21% and 28%; however, due to differential attrition and small number of subjects, the precision of these results is uncertain. While these two trials were suggestive of an effect, it is not clear that mipomersen results in substantial improvement in clinically meaningful outcomes that outweighs any safety risk. Larger, better designed clinical trials are needed to establish clinical efficacy and safety in this setting. The FDA approved prescribing information for mipomersen states that it should not be used in patients with hypercholesterolemia who do not have homozygous hypercholesterolemia, as safety and effectiveness has not been established in this setting. [11] - Hyperlipidemia / Hypercholesterolemia Several small, randomized, placebo-controlled trials have evaluated mipomersen in patients with hypercholesterolemia. [12-14] Mipomersen reduced LDL between 45% and 52%; however, due to subject disposition and small number of subjects, the precision of these results is uncertain. While suggestive of an effect, it is not clear that mipomersen results in substantial improvement in clinically meaningful outcomes that outweighs any safety risk. Larger, better designed clinical trials are needed to establish clinical efficacy and safety in this setting. The FDA approved prescribing information for mipomersen states that it should not be used in patients with hypercholesterolemia who do not have homozygous hypercholesterolemia, as safety and effectiveness has not been established in this setting. [11] dru301.2 Page 3 of 5

4 - In combination with lomitapide (Juxtapid) Safety The safety and effectiveness of mipomersen have not been studied in combination with lomitapide. - The most common adverse reactions reported with an incidence of at least 10% include: injection site reactions, flu-like symptoms, nausea, headache, and elevations in liver transaminases. [11] - Mipomersen has a boxed warning for risk of elevated transaminases and hepatic steatosis. Liver transaminases should be monitored prior to initiation of mipomersen and monthly thereafter. Mipomersen should be discontinued is persistent or significant elevations are observed. [11] - Because of potential serious side effects, the FDA has initiation a Risk Evaluation and Mitigation (REMS) program to ensure mipomersen is only used in homozygous familial hypercholesterolemia. [15] Dosing - The recommended dose of mipomersen is 200 mg subcutaneously once weekly. [11] - The safety and effectiveness of higher doses have not been established. Cross References Branded Lipid-Modifying Medications, dru336 Juxtapid, lomitapide, dru302 Codes Number Description N/A References 1. Raal FJ, Santos RD. Homozygous familial hypercholesterolemia: current perspectives on diagnosis and treatment. Atherosclerosis Aug;223(2): doi: /j.atherosclerosis Epub 2012 Feb 16. Review. PubMed PMID: Rosenson RS, de Ferranti SD, et al. Primary disorders of LDL-cholesterol metabolism. In: UpToDate, Freeman MW (ed), UpToDate, Waltham, MA, Rosenson RS, de Ferranti SD, et al. Treatment of drug resistant hypercholesterolemia. In: UpToDate, Freeman MW (ed), UpToDate, Waltham, MA, DeMott K, Nherera L, et al. Clinical Guidelines and Evidence Review for Familial hypercholesterolaemia: the identification and management of adults and children with familial hypercholesterolaemia London: National Collaborating Centre for Primary Care and Royal College of General Practitioners. dru301.2 Page 4 of 5

5 5. National Heart, Lung, and Blood Institute. Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents. [cited 4/10/2013]; Available from: 6. American Heart Association. Cardiovascular risk reduction in high-risk pediatric patients: endorsed by the American Academy of Pediatrics. Circulation Dec 12;114(24): Epub 2006 Nov 27. Review. PubMed PMID: Goldberg AC, Hopkins PN, et al. National Lipid Association Expert Panel on Familial Hypercholesterolemia. Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol Jun;5(3 Suppl):S1-8. doi: / j.jacl Epub 2011 Apr 12. PubMed PMID: Raal FJ, Santos RD, Blom DJ, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet Mar 20;375(9719): doi: /S (10)60284-X. PubMed PMID: Stein EA, Dufour R, Gagne C, 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 Nov 6;126(19): doi: /CIRCULATIONAHA Epub 2012 Oct 11. PubMed PMID: Akdim F, Visser ME, Tribble DL, et al. Effect of mipomersen, an apolipoprotein B synthesis inhibitor, on low-density lipoprotein cholesterol in patients with familial hypercholesterolemia. Am J Cardiol May 15;105(10): doi: /j.amjcard Epub 2010 Mar 30. PubMed PMID: Kynamro [package insert]. Cambridge, MA: Genzyme Corporation; January Visser ME, Wagener G, Baker BF, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, lowers low-density lipoprotein cholesterol in high-risk statin-intolerant patients: a randomized, double-blind, placebo-controlled trial. Eur Heart J May;33(9): doi: /eurheartj/ehs023. Epub 2012 Apr 16. PubMed PMID: Akdim F, Tribble DL, Flaim JD, et al. Efficacy of apolipoprotein B synthesis inhibition in subjects with mild-to-moderate hyperlipidaemia. Eur Heart J Nov;32(21): doi: /eurheartj/ehr148. Epub 2011 May 18. PubMed PMID: Akdim F, Stroes ES, Sijbrands EJ, et al. Efficacy and safety of mipomersen, an antisense inhibitor of apolipoprotein B, in hypercholesterolemic subjects receiving stable statin therapy. J Am Coll Cardiol Apr 13;55(15): doi: /j.jacc PubMed PMID: Kynamro Risk Evaluation and Mitigation Strategy [cited 4/10/2013]; Available from: ntsandproviders/ucm pdf. 16. TEC Assessment March "Speciality Pharmacy Report #3-2011; mipomersen (Kynamro)." BlueCross and BlueShield Association Technology Evaluation Center. dru301.2 Page 5 of 5