Mipomersen and Lomitapide Background

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Drug Use Research & Management Program Oregon State University, 500 Summer Street NE, E35 Salem, Oregon 97301-1079 Phone 503-947-5220 | Fax 503-947-1119

Prior Authorization Review: mipomersen and lomitapide

Background: Familial hypercholesterolemia is a genetic disorder which results in extremely high levels of low‐density lipoprotein cholesterol (LDL‐C) and increased risk of premature cardiovascular disease. 1 Homozygous familial hypercholesterolemia (HoFH) is caused by mutations in the low density lipoprotein receptor (LDLR) gene. Patients with HoFH present with severe hypercholesterolemia and accelerated atherosclerosis within the first two decades of life. 2 Clinical diagnosis includes appearance of xanthomas at an early age, untreated LDL >500 mg/dL, treated LDL ≥300 mg/dL, or non high‐density lipoprotein cholesterol (HDL‐C) ≥330 mg/dL. 2 Available treatments to lower LDL include high‐intensity statin therapy, ezetimibe, PCSK‐9 inhibitors, bile acid sequestrants, niacin, and lomitapide, mipomersen, and LDL apheresis.3

Mipomersen (Kynamro®) is an oligonucleotide inhibitor of apolipoprotein B synthesis. Apo B is the principal precursor of LDL‐C and VLDL‐C. Mipomersen is indicated as an adjunct to lipid lowering medications and diet to reduce LDL‐C, apo B, total cholesterol, and non HDL‐C in patients with HoFH.4 It was approved by the U.S. Food and Drug Administration (FDA) in 2013 to reduce hypercholesterolemia only for HoFH patients. The Pharmacy & Therapeutics Committee reviewed this drug previously and approved Prior Authorization (PA) for its use (see Appendix 1). The safety and effectiveness of mipomersen was evaluated in a randomized, double blind, placebo‐controlled Phase 3 trial conducted in 51 adult HoFH patients. Mipomersen was administered as 200 mcg subcutaneously once a week for 26 weeks. The primary efficacy endpoint was percent change in LDL‐C from baseline. At week 26 the mean percent reduction in LDL‐C from baseline was 25% (p<0.001) in the mipomersen arm.5 Four patients (12%) in the mipomersen group had increases in ALT 3‐times the upper limit of normal (ULN). The drug carries a “black box” warning regarding the risk of hepatotoxicity and is only available through a restricted risk evaluation and mitigation strategies (REMS) program. The efficacy and safety of mipomersen was evaluated in a post marketing open‐label extension trial. 6 Thirty eight patients with HoFH and 103 patients with heterozygous familial hypercholesterolemia (HeFH) were recruited for the study. At 104 weeks, a 28% decrease in mean LDL‐C was noted from baseline in the 53 patients that were still actively participating in the study. Almost all patients experienced one adverse event including injection site reactions (98%) or flu‐like symptoms (65%). Changes in ALT greater than 3‐times ULN were noted in 18 (13%) of patients. The transaminase elevations were reversible upon drug discontinuation.

Lomitapide (Juxtapid®) is an oral microsomal triglyceride transfer (MTP) protein inhibitor indicated as an adjunct to a low‐fat diet and other lipid lowering treatments, including LDL apheresis where available, to reduce LDL‐C, total cholesterol, apolipoprotein B and non‐HDL‐C in patients with HoFH. 7 It was approved by the FDA in 2012 to reduce hypercholesterolemia only for HoFH patients. The Pharmacy & Therapeutics Committee reviewed this drug previously and approved Prior Authorization (PA) for its use (see Appendix 1). The Phase 3 trial that led to FDA approval was conducted in 29 adults HoFH patients in an international, multicenter, open‐label, and 26‐week study sponsored by the manufacturer.8 The primary endpoint was reduction in LDL‐C from baseline to week 26. The study was continued for an additional 52 weeks to assess safety. At the week 26, researchers noted a 50% mean reduction in LDL‐C. By the end of the 78 weeks, a mean LDL‐C reduction of 38% was noted in the 23 patients that completed the trial. Ten patients in the study (34%) had increased ALT or AST levels greater than 3‐times ULN. Four patients (14%) experienced ALT or AST elevations greater than 5‐times ULN. Due to the incidence of elevated LFTs, lomitapide received a “black box” warning regarding the incidence of hepatotoxicity. Because of this risk, lomitapide is only available through a restricted REMS program.

Author: D. Moretz, PharmD, BCPS Date: April 2016

The effect of both of these agents on cardiovascular morbidity and mortality has not been evaluated. There was no utilization for either one of these drugs in the Oregon Health Plan fee‐for‐service population in 2015.

Recommendations: No changes to the current PA criteria are recommended. No further review or research needed at this time.

References: 1. Bouhairie VE, Goldberg AC. Familial Hypercholesterolemia. Endocrinol Metab Clin North Am. 2016;45(1):1‐16. doi:10.1016/j.ecl.2015.09.001. 2. Raal FJ, Santos RD. Homozygous familial hypercholesterolemia: current perspectives on diagnosis and treatment. Atherosclerosis. 2012;223(2):262‐268. doi:10.1016/j.atherosclerosis.2012.02.019. 3. Gidding SS, Champagne MA, de Ferranti SD, et al. The Agenda for Familial Hypercholesterolemia: A Scientific Statement From the American Heart Association. Circulation. 2015;132(22):2167‐2192. doi:10.1161/CIR.0000000000000297. 4. Kynamro (Mipomersen) [Prescribing Information]. Cambridge, MA: Genzyme Corporation. March, 2015. 5. 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. 2010;375(9719):998‐1006. doi:10.1016/S0140‐ 6736(10)60284‐X. 6. Santos RD, Duell PB, East C, et al. Long‐term efficacy and safety of mipomersen in patients with familial hypercholesterolaemia: 2‐year interim results of an open‐label extension. Eur Heart J. 2015;36(9):566‐575. doi:10.1093/eurheartj/eht549. 7. Juxtapid (Lomitapide). [Prescribing Information]. Cambridge, MA: Aegerion Pharmaceuticals. March 2016. 8. Cuchel M, Meagher EA, du Toit Theron H, et al. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single‐arm, open‐label, phase 3 study. Lancet. 2013;381(9860):40‐46. doi:10.1016/S0140‐6736(12)61731‐0.

Author: D. Moretz, PharmD, BCPS Date: April 2016

Appendix 1: Current Prior Authorization Criteria.

Mipomersen (Kynamro®) and Lomitapide (Juxtapid®) Goal(s):  To ensure appropriate drug use and limit to patient populations in which mipomersen or lomitapide has been shown to be effective and safe.

Length of Authorization: Up to 6 months

Covered Alternatives:  Current PMPDP preferred drug list per OAR 410-121-0030 at www.orpdl.org  Searchable site for Oregon FFS Drug Class listed at www.orpdl.org/drugs/

Approval Criteria

1. What diagnosis is being treated? Record ICD10 code.

2. Is the drug prescribed by or in consultation with a specialist Yes: Go to #3 No: Pass to RPh. Deny; medical in lipid disorders? appropriateness

3. Is the diagnosis homozygous familial hypercholesterolemia? Yes: Go to #4 No: Pass to RPh. Deny; medical appropriateness

4. Has the patient tried and failed or does the patient have a Yes: Go to #5 No: Pass to RPh. Deny; medical medical contraindication to maximum lipid lowering therapy appropriateness with a combination of traditional drugs (high-intensity statin with ezetimibe; see Table 1)?

5. Has the patient failed or are they not appropriate for LDL-C Yes: Approve for 1 year No: Pass to RPh. Deny; medical apheresis OR appropriateness Is LDL-C apheresis not available to them?

Table 1. High-intensity Statins. High-intensity Statins

Author: D. Moretz, PharmD, BCPS Date: April 2016

(50% LDL-C Reduction) Atorvastatin 40-80 mg Rosuvastatin 20-40 mg Ref. Stone NJ, et al. 2013 ACC/AHA Blood Cholesterol Guideline.

P&T Review: 5/16 (DM); 9/13; 7/13; 5/13 Implementation: 1/1/14; 11/21/2013

Author: D. Moretz, PharmD, BCPS Date: April 2016