A Comparison of Mipomersen (Kynamro®) and Lomitapide (Juxtapid®): Medications for the Treatment of Homozygous Familial Hypercholesterolemia CE Included (2014)

Homozygous familial hypercholesterolemia (HoFH) is a rare disease that involves mutations in the genes coding for low density lipoprotein (LDL) receptors, preventing the uptake of LDL cholesterol from the serum and resulting in extremely high cholesterol levels.1 Between December 2012, and January 2013, two orphan drugs were approved by the U.S. Food and Drug Administration (FDA) for the treatment of HoFH. Mipomersen (Kynamro®) is a subcutaneous injection that functions as an antisense oligonucleotide inhibitor and ultimately prevents the translation of mRNA coding for apolipoprotein B (apoB)-100 which binds to LDL and very low density lipoprotein (vLDL) cholesterol.7 Lomitapide (Juxtapid®) is an oral drug that inhibits microsomal triglyceride protein (MTP), an enteric and hepatic protein that promotes the lipid transfer to apoB and allows a complex to form. Through the inhibition of MTP, vLDL cholesterol and chylomicrons are not formed. Each of these drugs, when combined with a low-fat diet and additional lipid-lowering therapy, which may include statins, resins and LDL-apheresis, can produce a clinically significant reduction in serum LDL cholesterol.7,14 Before the approval of these two drugs, patients faced a greatly shortened lifespan, uncertain and nonspecific treatment options and serious complications secondary to HoFH.1,3-5 Introduction As the world's leading cause of death, cardiovascular disease (CVD) is a fairly common diagnosis in patients, although it can manifest in different ways. There are many factors that contribute to CVD, including poor diet, lack of exercise, hypertension and dyslipidemia. In a select number of patients, poor cardiovascular outcomes can be attributed to genetic mutations. Homozygous familial hypercholesterolemia, also known as type II hyperlipoproteinemia, most frequently results from mutations in both alleles coding for LDL receptors. This mutation of the LDL receptors greatly reduces the amount of serum cholesterol absorbed by cells.1 There are several mechanisms by which this occurs, including inability of the receptor to be transported to the cell surface, bind to LDL when at the surface or be internalized or released upon binding the LDL cholesterol.2 It is estimated that HoFH affects approximately one in 1 million individuals,3,4 although it is likely that this disease is grossly under diagnosed, given the number of diagnosed cases of CVD and the number of attributable factors.4 Without proper lipid-lowering treatment, life expectancy is drastically reduced to before age 204 or the early 20s3, with a 100 percent mortality rate by age 30.5 The purpose of this paper is to review HoFH and to describe two emerging pharmacological treatment options. Overview of Homozygous Familial Hypercholesterolemia Homozygous familial hypercholesterolemia presents with several characteristic symptoms early in life: total serum cholesterol of greater than 600mg/dL1 (up to 1,200mg/dL5), coronary artery disease, xanthomas (a yellow-orange, lipidfilled nodule) on the skin during childhood,1,5 angina of effort (suffocating chest pain occurring during physical exertion),3,5 aortic stenosis and myocardial infarction (MI).5 In some patients, an MI is known to occur as young as 2 years old.3 Interestingly, diabetes, hypertension and obesity are not often seen in patients with HoFH.5 Patients who are most likely to develop HoFH are those who have parents that are diagnosed with or have a positive family history of heterozygous familial hypercholesterolemia. Clinically, it may be difficult to distinguish between severe heterozygous and normalpresenting HoFH; in homozygous familial hypercholesterolemia, the patient's fibroblasts or lymphocytes will show a reduction of LDL receptor activity of 20 percent or more.1 Genetic testing will also provide a conclusive diagnosis and is useful in identifying silent cases, giving health care professionals a better understanding of the disease's clinical presentation and prognosis, as well as providing earlier diagnoses of familial hypercholesterolemia.2 Because HoFH is so rare, the best way to treat it has been with conventional methods used in treating normal or commonly occurring hyperlipidemia. Lifestyle changes, such This knowledge-based activity is targeted for all pharmacists and is acceptable for 1.0 hour (0.1 CEU) of continuing education credit. This course requires completion of the program evaluation and at least a 70 percent grade on the program assessment questions. ACPE Universal Activity Number (UAN): 0048-0000-14-031-H01-P Cardiology A Comparison of Mipomersen (Kynamro®) and Lomitapide (Juxtapid®): Medications for the Treatment of Homozygous Familial Hypercholesterolemia Ann Marie Ruhe, fifth-year pharmacy student from Cincinnati, Ohio; Austin Brown, fourth-year pharmacy student from Forest, Va.; Ginny Daniels, fourth-year pharmacy student from Dover, Ohio; Kelsey Fink, fifth-year pharmacy student from Hudson, Ohio; David Bright, PharmD, BCACP, assistant professor of pharmacy practice