Page 14 - Delaware Medical Journal August 2015

Pharmacogenetics in the Development
of Lipid Lowering Medications:
Lomitapide & Mipomersen in Clinical Practice
Jeffrey A. Marbach, MBBS; Jhapat Thapa, MD; Edward Goldenberg, MD, FACC; Danielle Duffy, MD, FACC
Introduction: The familial hypercholesterolemias (FH) are a group of undertreated genetically inherited disorders of lipid metabolism that lead to severely elevated cholesterol levels and early onset cardiovascular disease. Aggressive lifestyle modifications and lipid-lowering medications such as statins and bile acid sequestrants are the backbone of current treatment. Despite these interventions, homozygous FH (HoFH) patients are unable to reach LDL-C targets and remain at significantly increased risk of cardiovascular disease. Recently, two novel lipid-lowering medications, lomitapide and mipomersen, have been approved for the treatment of HoFH.
Case Descriptions: We present two patients with HoFH who have been unable to reach target LDL-C goals on standard therapy. Patient A is a 41-year-old male and patient B is a 64-year-old female, both of whom have complex histories of multi-vessel coronary artery disease. In attempt to improve their LDL-C levels and lower their cardiovascular risk, lomitapide and mipomersen were initiated in patient A and B, respectively.
Discussion/Conclusion: Through inhibition of the microsomal triglyceride transfer protein, lomitapide prevents the formation of triglyceride rich lipoproteins. Mipomersen is an antisense oligonucleotide that inhibits the translation of apolipoprotein B-100. Both medications employ novel mechanisms developed through advances in pharmacogenetic technology and achieve unprecedented LDL-C reductions.
IntroductionHomozygous familial hypercholesterolemia
(HoFH) is an autosomal dominant or co-dominant disorder resulting in severely elevated total and low-density lipoprotein cholesterol (LDL-C) levels.1 Although relatively rare in
the general population with a prevalence of approximately 1/1,000,000, HoFH causes early onset coronary artery disease leading to substantial morbidity and mortality.2 Despite currently available medical therapies, patients are often unable to reach their LDL targets and consequently nearly 50 percent of men and more than 30 percent of women have myocardial infarctions by 60 years of age.3,4

such as statins, bile acid sequestrants, cholesterol absorption inhibitors, and niacin have helped patients lower their LDL-C and total cholesterol (TC), the end result is often inadequate and progressive coronary heart disease continues. Until
recently, the only alternative therapy has been LDL-C apheresis, a costly, time consuming method of physically removing lipid particles from the bloodstream similar to dialysis.5,6 The pressing need for alternative medical therapies is being addressed by two recently approved medications with novel mechanisms of action.
Lomitapide (JuxtapidTM, Aegerion, Cambridge, MA),7 a microsomal triglyceride transfer protein (MTP) inhibitor
and Mipomersen (Kynamro, Genzyme, Cambridge, MA),8
a second-generation antisense oligonucleotide (ASO) to the human apolipoprotein (apo) B RNA have received orphan
drug status as add-on therapy for HoFH patients unable to reach lipid targets on standard lipid lowering therapy. Through inhibition of production of apo B-containing lipoproteins both LDL-C and lipoprotein(a) [Lp(a)]. Lomitapide has the added advantage of decreasing chylomicron production.
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Del Med J | August 2015 | Vol. 87 | No. 8
Abstract