Pharmacy and Wellness Review
Volume 5 Issue 1 Article 1
February 2014
A Comparison of Mipomersen (Kynamro®) and Lomitapide (Juxtapid®): Medications for the Treatment of Homozygous Familial Hypercholesterolemia
Ann Marie Ruhe Ohio Northern University
Austin Brown Ohio Northern University
Ginny Daniels Ohio Northern University
Kelsey Fink Ohio Northern University
David Bright Ohio Northern University
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This Article is brought to you for free and open access by the ONU Journals and Publications at DigitalCommons@ONU. It has been accepted for inclusion in Pharmacy and Wellness Review by an authorized editor of DigitalCommons@ONU. For more information, please contact [email protected]. Cardiology A Comparison ofMipomersen (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
Introduction This knowledge-based activity is targeted for all pharmacists As the world's leading cause of death, cardiovascular disease and is acceptable for 1.0 hour (0.1 CEU) of continuing (CVD) is a fairly common diagnosis in patients, although it education credit. This course requires completion can manifest in different ways. There are many factors that of the program evaluation and at least a 70 percent grade contribute to CVD, including poor diet, lack of exercise, hy on the program assessment questions. pertension and dyslipidemia. In a select number of patients, poor cardiovascular outcomes can be attributed to genetic ACPE Universal Activity Number (UA.t~: 0048-0000-14-031-HO 1-P mutations. Homozygous familial hypercholesterolemia, also '------~ known as type II hyperlipoproteinemia, most frequently re sults from mutations in both alleles coding for LDL receptors. Objectives This mutation of the LDL receptors greatly reduces the After completion of this program, the reader should be able amount of serum cholesterol absorbed by cells.1 There are to: several mechanisms by which this occurs, including inability 1. Describe the clinical symptoms of homozygous famil of the receptor to be transported to the cell surface, bind to ial hypercholesterolemia (HoFH). LDL when at the surface or be internalized or released upon 2. Identify conventional and adjunct treatments used for binding the LDL cholesteroJ.2 It is estimated that HoFH af HoFH before the development and FDA approval of fects approximately one in 1 million individuals,3,4 although mipomersen and lomitapide. it is likely that this disease is grossly under diagnosed, given 3. Identify the mechanism of action for both mipomersen the number of diagnosed cases of CVD and the number of and lomitapide. attributable factors. 4 Without proper lipid-lowering treat 4. Identify mipomersen and lomitapide's place in ment, life expectancy is drastically reduced to before age 204 therapy in the treatment of HoFH. or the early 20s3, with a 100 percent mortality rate by age 5. Discuss the common adverse events and appropriate 30.5 The purpose of this paper is to review HoFH and to de monitoring parameters associated with mipomersen scribe two emerging pharmacological treatment options. and lomitapide therapy. Overview of Homozygous Familial Hypercholesterolemia Abstract Homozygous familial hypercholesterolemia presents with Homozygous familial hypercholesterolemia (HoFH) is a rare several characteristic symptoms early in life: total serum disease that involves mutations in the genes coding for low cholesterol of greater than 600mg/dL1 (up to 1,200mg/dL5), density lipoprotein (LDL) receptors, preventing the uptake of coronary artery disease, xanthomas (a yellow-orange, lipid LDL cholesterol from the serum and resulting in extremely filled nodule) on the skin during childhood,1.5 angina of effort high cholesterol levels.1 Between December 2012, and Janu (suffocating chest pain occurring during physical exertion),3,5 ary 2013, two orphan drugs were approved by the U.S. Food aortic stenosis and myocardial infarction (Ml).5 In some pa and Drug Administration (FDA) for the treatment of HoFH. tients, an Ml is known to occur as young as 2 years old.3 In Mipomersen (Kynamro®) is a subcutaneous injection that terestingly, diabetes, hypertension and obesity are not often functions as an antisense oligonucleotide inhibitor and ulti seen in patients with HoFH.5 Patients who are most likely to mately prevents the translation of mRNA coding for apolipo develop HoFH are those who have parents that are ·diag protein B (apoB)-100 which binds to LDL and very low den nosed with or have a positive family history of heterozygous sity lipoprotein (vLDL) cholesterol.7 Lomitapide (Juxtapid®) familial hypercholesterolemia. Clinically, it may be difficult to is an oral drug that inhibits microsomal triglyceride protein distinguish between severe heterozygous and normal (MTP), an enteric and hepatic protein that promotes the lipid presenting HoFH; in homozygous familial hypercholes transfer to apoB and allows a complex to form. Through the teroiemia, the patient's fibroblasts or lymphocytes will show inhibition ofMTP, vLDL cholesterol and chylomicrons are not a reduction of LDL receptor activity of 20 percent or more.1 formed. Each of these drugs, when combined with a low-fat Genetic testing will also provide a conclusive diagnosis and is diet and additional lipid-lowering therapy, which may in useful in identifying silent cases, giving health care profes clude statins, resins and LDL-apheresis, can produce a clini sionals a better understanding of the disease's clinical cally significant reduction in serum LDL cholesterol.7,14 Be presentation and prognosis, as well as providing earlier diag fore the approval of these two drugs, patients faced a greatly noses of familial hypercholesterolemia.z shortened lifespan, uncertain and nonspecific treatment op tions and serious complications secondary to HoFH.1,3-5 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
2 THE PHARMACY AND WELLNESS REVIEW February 2014 Volume 5, Issue 1 A Comparison of Mipomersen (Kynamro®) and Lomitapide (Juxtapid®) ... Cardiology as eating a diet low in fat and cholesterol, increasing exercise, ally, the patients met the criteria of a consistent low-fat diet weight control, moderating alcohol intake and smoking ces and maximum lipid-lowering medications that were contin sation are often encouraged. There are several conventional ued throughout the trial. All but one patient were taking choles drug options available to help treat the symptoms of HoFH. terol-lowering medications. More specifically, 76 percent were Statins and resins (such as cholestyramine; also known as taking a statin and an additional lipid-lowering medication. s bile acid sequestrants) can help to reduce serum levels of LDL cholesterol by increasing the activity of the LDL recep Out of patients screened, 51 patients met the inclusion crite tors; however, these drugs will not be effective in removing ria and were randomized in a 2:1 ratio in favor of the experi LDL cholesterol from the blood if the LDL receptor is absent mental group. Patients in the experimental group received or nonfunctionaJ.1 Bile acid resins can also cause undesirable 200 mg (160 mg if patient weighed
Mipomersen (Kynamro®) The safety assessment of mipomersen included the Raal et al. Mipomersen is a Genzyme Corporation orphan drug that has study in a review of four phase III clinical trials in the FDA just recently been approved by the FDA in January 2013. Mi summary review. The Raal et al. study was specific to HoFH, pomersen is formulated as a subcutaneous injection that is but the other phase III trials involved patients with a high indicated as an additional therapy option to supplement risk for CVD, which included heterozygous familial hypercho other lipid-lowering medications and diet in adults with Iesterolemia. Altogether, the trials included a total of 390 HoFH. The clinical ramifications of mipomersen include re patients randomized in a 2:1 ratio in the mipomersen and ductions in low density lipoprotein-cholesterol (LDL-C), placebo groups respectively for six months.9 apoB, total cholesterol (TC), and non-high density lipopro tein-cholesterol (non-HDL-C). These clinical results are at Using the pooled data of the phase III trials, the main safety tributed to mipomersen's antisense oligonucleotide inhibitor issues were hepatic steatosis (fatty liver), injection site reac property that prevents translation of the mRNA strand that tions, elevated serum transaminases, flu-like symptoms, im codes for apoB-100, the primary apolipoprotein in LDL and mune/antibody responses and proteinuria.9 The Raal et al. vLDL. 7 study, specific to HoFH, reported hepatic steatosis, elevated transaminases, injection site reactions and flu-like symp In the FDA approval process, the efficacy of mipomersen was toms, but also mentioned nausea and headache.a assessed primarily using one phase III clinical trial con ducted by Raal et al.B The focus of this particular study is ex In the Raal et al. study, hepatic steatosis was measured by plained, as it was the only mipomersen phase III clinical trial magnetic resonance imaging (MRI) only when a patient's specific to patients with HoFH. The other phase III clinical aminotransferase levels reached three times their upper trials involved patients with a high risk for CVD, which in limit of normal (ULN). Consequently, four patients had an cluded heterozygous familial hypercholesterolemia. 9 The MRI performed, which resulted in one case of an increase in Raal et al. study was a randomized, double-blind, placebo hepatic fat. Because of the few hepatic fat assessments, there controlled trial conducted in nine different lipid clinics in is a chance that other patients experienced undetected he seven different countries for 26 weeks. The inclusion factors patic steatosis.s This possibility is affirmed by two other for patients were an age above 12 years and evidence that phase III clinical trials, conducted by Stein et al. and Thomas pointed to HoFH in the patient. This evidence included either et al., in which the researchers conducted an MRI at baseline genetic confirmation of HoFH, severe LDL-C concentrations and week 2s.10.11 The pooled results for these two studies from an early age or presence of heterozygous familial hy showed 62 percent of the mipomersen group versus 8 per percholesterolemia in both parents of the patient. Addition- cent of the placebo group had hepatic fat increases of;::: 5 per-
February 2014 Volume 5, Issue 1 THE PHARMACY AND WELLNESS REVIEW 3 Cardiology A Comparison of Mipomersen (Kynamro®) and Lomitapide (Juxtapid®) ... cent, the study's numerical definition of hepatic steatosis.9 effect is injection site reactions.s.9 Despite higher amounts of MRis utilized in these two phase Ill trials, not all the patients were tested. For instance, in the There are several factors that need to be considered before a Stein et al. study, only 70 percent of patients had MRis com patient undergoes mipomersen treatment. First, as stated pleted. The other 30 percent were not measured for hepatic previously, mipomersen is indicated specifically for adults steatosis because of technical difficulties, timing, metal im with HoFH. Studies have yet to be conducted with a sufficient plants or claustrophobia.10 Almost the exact same statistics number of pediatric or geriatric patients to assess safety. for MRls conducted were found for the Thomas et al. study Additionally, patients should undergo a full liver panel inclu for the same reasons.11 sive of ALT, AST, total bilirubin and alkaline phosphatase before starting mipomersen. Liver panels should be repeated When considering all the pooled data, the most common ad every month for the first year of treatment. After the first verse events were injection site reactions, flu-like symptoms, year, tests should be conducted at a minimum of every three nausea, headache and elevated alanine transaminase (ALT) months.7 Careful monitoring of liver panels is necessary due and aspartate aminotransferase (AST) . These adverse events to the increases in aminotransferases in some mipomersen were assessed by an incidence >10 percent and higher than patients, as noted previously.9 Consequently, contraindica placebo.9 tions exist with moderate to severe hepatic impairment and active liver disease. Furthermore, due to the risk of hepato In the Raal et al. study, the injection site reaction was deter toxicity, the Risk Evaluation and Mitigation Strategy (REMS) mined to be the most common adverse reaction, which program restricts those who can prescribe and dispense mi turned out to be three times more likely in the mipomersen pomersen. Thus, prescribing doctors and dispensing phar group. This adverse event usually manifested itself through macists must be certified in the REMS program.7 mild erythema, but was sometimes accompanied by local pain, tenderness and swelling. These effects caused two pa The REMS program includes a prescriber training module tients to withdraw themselves from the trial.a When all the intended to provide education about appropriate and safe phase III clinical trials of mipomersen were pooled together, prescribing practices. Each pharmacy wishing to dispense 5 percent of patients were forced to discontinue therapy be the medication must also obtain certification and implement cause of injection site reactions.9 strategies to ensure that the prescriber is certified in the REMS program and that the patient has the necessary pre Flu-like symptoms were observed in nearly the same per scription authorization form. 20 The overarching goals of the centage of patients in both groups in the Raal et al. study, but REMS program are the education of prescribers to ensure more events per patient were noted for the mipomersen safe medication utilization and the limitation of therapy to group.a In contrast, the pooled data revealed symptoms in 30 those with a confirmed diagnosis of HoFH. percent of the mipomersen group and 16 percent in the pla cebo.9 Lomitapide (Juxtapid®) Lomitapide (Juxtapid®), an oral alternative to mipomersen A marked difference in ALT and AST elevations between (Kynamro®), is Aegerion Pharmaceutical, lnc.'s FDA groups was noted in the Raal et al. study. An ALT value ~ approved orphan drug serving as an adjunct treatment for three times the ULN was observed in 12 percent of the mi HoFH. Approved in December 2012, it is indicated exclu pomersen group compared to zero in the placebo group. sively as an oral lipid-lowering therapy in patients diagnosed However, no other irregular values in liver tests were ob with HoFH. When supplemented with a low-fat diet, LDL served. Only one patient discontinued treatment due to ele apheresis, and other lipid-lowering therapies, lomitapide has vated ALT.B Similar results were found in the pooled studies demonstrated reduction in LDL-C, total cholesterol, apoB, with 16 percent in the mipomersen versus 1 percent in the and non-HDL-C. 13 Its mechanism entails the small-molecule placebo.9 inhibition of the microsomal triglyceride protein (MTP). This enteric and hepatic endoplasmic reticular protein is respon Antibody response was an adverse event not measured in sible for the transfer of lipids to apoB to form a complex. Mi the Raal et al. study, but observed in the other phase III trials crosomal triglyceride protein inhibition ultimately precludes and an open-label extension study. Compiled data showed the synthesis and secretion ofvLDL cholesterol and chylomi mipomersen to be very immunogenic. The percentage of mi crons, which require apoB for assembly and subsequent pomersen patients who developed antibodies to mipomersen function.13 Patients can expect a clinically significant reduc increased from 4 percent in week 13 to 33 percent in week tion in serum LDL cholesterol when combining lomitapide 50 of treatment. Proteinuria was also observed in 0.8 percent therapy with both a low-fat diet and lipid-lowering therapy, of the placebo group and 2.3 percent of the mipomersen as demonstrated by the clinical trials utilized for FDA ap group. According to the FDA summary review, clinical signifi proval in the subsequent discussion. cance of this adverse event has yet to be determined.9 The phase II clinical trial conducted to assess the safety, tol Based upon the safety and efficacy studies noted earlier, mi erability and efficacy of the novel MTP inhibitor was pub pomersen should be taken 200 mg subcutaneously once a lished in the New England Journal of Medicine in 2007.14 This week.B.9 Patients should also be informed that each weekly interventional, open-label, single-group assessment of lomi dose is priced at $4,860.4612 and that the most common side tapide treatment in patients with HoFH was sponsored by
4 THE PHARMACY AND WELLNESS REVIEW February 2014 Volume 5, Issue 1 A Comparison ofMipomersen (Kynamro®) and Lomitapide (Juxtapid®) ... Cardiology Aegerion.1s Owing to the low incidence of the disease, six triglycerides were 36.4 ± 28.2 percent, 39.4 ± 30.01 percent, patients (three men and three women, ranging 18 to 40 and 29.0 ± 55.72 percent, respectively.16 Both the primary years of age) comprised the study group, which was con and secondary outcomes lack statistical analysis due to the ducted at a single medical facility. 14 A diet of less than 10 per trial information not yet having reached publication. cent of daily caloric intake from fat was initiated for each patient, and any other lipid-lowering therapies were held Six of the 29 initial participants failed to complete the study, during the course of the study. Investigators initiated dosing and four of these discontinuations are attributed to adverse at 0.03 mg/kg/day for four weeks with a successive titration events. Both serious and more common adverse events asso to 0.1 mg/kg/day, 0.3 mg/kg/day, and 1.0 mg/mg/day every ciated with lomitapide therapy have been observed from the four weeks over the course of the 16-week study period.14 first dose until 28 days post-treatment. Rare yet serious ad verse events included cardiac disorders (angina pectoris: Percent reduction in LDL cholesterol was chosen as the pri chest pain secondary to ischemic cardiac muscle, coronary mary outcome, followed by a number of secondary consid artery atherosclerosis: plaque accumulation in the coronary erations including the change from baseline in triglycerides, artery and acute coronary syndrome: an emergent situation apoB, ALT, AST, total bilirubin, vitamins A, E and D, among in which blood supply to heart muscle is interrupted), lower others.14 Statistical analysis was performed using paired respiratory tract infections and menorrhagia.16 More notable t-tests or the Wilcoxon signed-rank test for continuous vari common adverse events, at least one of which affected 23 of ables and the chi-squared test for percentages.14 Clinically the 29 participants, included gastrointestinal disorders, pain, significant reductions (p<0.001) were seen in LDL choles fatigue, pyrexia, increased infection incidence and diverse terol levels, as well as both apoB and triglycerides. After four pain complaints. Elevations in ALT, AST and transaminases weeks of the 0.03 mg/kg/day dose, LDL decreased 24.7 per are also under investigation for a potential patient safety cent from a baseline of 614 mg/dL. An additional four weeks risk. of therapy with a 1.0 mg/kg/day dose demonstrated a total reduction from baseline of 50.9 percent. Triglycerides saw a After analysis of available lomitapide safety information, the decrease of 34.1 percent from baseline after four weeks of primary concern during the course of therapy is the risk of 0.03 mg/kg/day, with a total reduction of 65.2 percent after hepatotoxicity. This is manifested through an increase in an additional four weeks of therapy with 1.0 mg/kg/day. both AST and ALT ::?: three times the ULN. Hepatic fat in After a similar dosing regimen, apoB levels were diminished creases were also noted, augmenting a patient's risk of devel 55.6 percent from baseline.14 oping steatohepatitis and cirrhosis.17 Therapy should be dis continued if a patient experiences transaminase elevations During the course of the study, patients experienced both an concomitantly with clinical symptoms of liver injury. Eleva elevation in liver transaminases and accumulation of liver tions resolve within one to four weeks of stopping therapy in fat.14 This hepatic lipid accumulation is hypothesized to be a most patients.18 direct result of the mechanism and initiates potential progression to fibrotic liver disease. Although additional Lomitapide therapy is contraindicated in moderate to severe long-term studies are indicated to further assess these impli hepatic impairment, active liver disease, pregnancy and con cations, patients should be monitored for increases in ami current therapy with moderate or strong CYP3A4 inhibitors, notransferase levels and hepatic steatosis during therapy. such as clarithromycin, ritonavir and telithromycin.19 A num This study further suggests that the adverse hepatic effects ber of dose adjustments should also be considered where may impair the clinical utility of lomitapide. applicable. Dose-related myopathy has been noted with con comitant use of simvastatin (also suspected with lovastatin), The phase III clinical assessment of the safety and efficacy of and a reduction of the simvastatin dose by 50 percent is rec lomitapide was verified by the FDA in January 2013.16 It was ommended upon lomitapide initiation.19 A maximum daily also an interventional, open-label, intention to treat, single dose of 40 mg is recommended in patients with end stage group assessment conducted in 29 patients at 11 medical renal disease (ESRD) or mild hepatic impairment (Child facilities. For six weeks prior to initiation of lomitapide ther Pugh A).18 apy, patients entered a 'run-in' phase, during which current lipid-lowering therapies were stabilized and a low-fat diet The target population for lomitapide therapy includes those (less than 20 percent) was initiated. Dosing was titrated from with a clinical or laboratory diagnosis of HoFH, excluding an initial oral dose of 5 mg/day for two weeks to an eventual those with routine dyslipidemia. The study was a once daily 60 mg/day at four-week intervals. oral therapy available in 5 mg, 10 mg and 20 mg capsules with an average cost per a 28 capsule bottle of $27,156. Percentage reduction in LDL cholesterol was again pro Therapy is initiated at 5 mg once daily and increased to a 10 nounced as the primary outcome and was assessed through mg daily dose after two weeks of patient tolerance. The dose week 26 of therapy. Secondary outcomes were very similar may then be increased to 20 mg, 40 mg and a maximum of 60 to phase II and included percent change from baseline in to mg at four-week intervals for peak therapeutic efficacy.18 tal cholesterol, apoB, triglycerides, HDL, AST, ALT, and nu Each capsule should be swallowed whole with a glass of wa merous others. In the 29 patients evaluated, a 40.1 ± 31.25 ter two hours following the evening meal. percent reduction was observed in LDL cholesterol levels. Reductions from baseline in total cholesterol, apoB, and
February 2014 Volume 5, Issue 1 THE PHARMACY AND WELLNESS REVIEW 5 A Comparison ofMipomersen (Kynamro®) and Lomitapide (Juxtapid®) ... Cardiology
Table 1. Clinical Comparison of Mipomersen and Lomitapide?,12
Mipomersen Lomitapide Basis of Comparison (Kynamro®) (Juxtapid®)
Cost $4,860.46 per weekly dose $27,156.00 per 28 capsules
Route and Frequency subQ, Qweek oral, QD of Administration
GI upset, blood and lymphatic disorders, Injection site reactions, flu-like symptoms, cardiac palpitations, chest pain, fatigue, Side Effects nausea, headache and elevated pyrexia, headache, dizziness, weight loss transaminases and diverse musculoskeletal pain
Hepatotoxicity, hepatic steatosis, elevated Hepatotoxicity, cardiac disorders, lower Adverse Effects ALT and AST, immunogenicity respiratory tract infections and and proteinuria reproductive system disorders
Baseline: ALT, AST, total bilirubin and Baseline: ALT, AST, total bilirubin, alka- alkaline phosphatase line phosphatase, and pregnancy testing Test liver transaminases levels monthly Test liver transaminases levels monthly Monitoring for the first year and subsequently every for the first year and subsequently every three months. three months. Also test before dosage increases. Also test before dosage increases.
Moderate to severe hepatic impairment, Moderate to severe hepatic impairment active liver disease, pregnancy and Contraindications and active liver disease concurrent therapy with moderate or strong CYP3A4 inhibitors
Prescriber and pharmacy Prescriber and pharmacy Additional Considerations require REMS certification require REMS certification
Pharmacists need to be cognizant of both common and seri nases should subsequently be measured monthly during the ous adverse events that may impact patients during the first year, every three months thereafter and prior to any course of therapy. During the escalation of treatment doses increase in dose.rn in the safety and efficacy trial, 10.34 percent of patients ex Due to the specificity of its indication, risk of hepatotoxicity perienced a serious adverse event that included cardiac dis and continuous monitoring associated with therapy, lomi orders, lower respiratory tract infections and reproductive tapide may only be prescribed and dispensed by health care system disorders. More commonly, patients were at risk for a professionals and pharmacies that are certified in the REMS number of mild adverse effects. Gastrointestinal upset, blood program.20 and lymphatic disorders, cardiac palpitations, chest pain, fatigue, pyrexia, headache, dizziness, weight loss and diverse Conclusion musculoskeletal pain are among the most notable.16 As an orphan disease, HoFH has long been treated using the standardized treatments indicated for hyperlipidemia, de Additional counseling points may be appropriate for certain spite its greatly increased severity and treatment challenges. patient populations. Because lomitapide is formulated with With the approval of mipomersen and lomitapide as more lactose, diarrhea and intestinal malabsorption may be ex targeted and specialized treatments for HoFH, patients can perienced in patients with hereditary galactose intolerance, experience greater convenience in taking an oral medication Lapp lactase deficiency or glucose-galactose malabsorption. or administering a subcutaneous injection than they would It would be appropriate to suggest supplementation with fat experience with LDL-apheresis, an expensive and time soluble vitamins to all patients due to decreased absorp consuming procedure that has long been the best treatment tion.ls option. These orphan drugs have been shown to improve serum cholesterol levels and may promote favorable clinical Upon initiation of therapy, baseline AST, ALT, total bilirubin, outcomes for patients with HoFH. alkaline phosphatase and pregnancy testing in females of reproductive age should be recommended. Liver transami-
6 THE PHARMACY AND WELLNESS REVIEW February 2014 Volume 5, Issue 1 A Comparison ofMipomersen (Kynamro®) and Lomitapide (Juxtapid®) ... Cardiology References 20. www.fda.gov/ downloads/Drugs/DrugSafety / PostmarketDrug 1. Harada-Shiba M, Arai H, Oikawa S, Ohta T, Okada T, Okamura T, et al. SafetylnforrnationforPatientsandProviders/UCM333438.pdf}uxtapid. Guidelines for the management of familial hypercholesterolemia. j Risk Evaluation and Mitigation Strategy (REMS). Food and Drug Ad Atheroscler Thromb. 2012;19(12):1043-1060. ministration. 2013 August. 2. Fahed AC, Nemer GM. Familial hypercholesterolernia: the lipids or the genes? Nutr Metab. 2011;8(1):23-34. 3. Pottle A. Familial hypercholesterolaernia: clinical features and manage ment. Nurs Stand. 2005;20(14-16):55-65. 4. Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart]. 2013 Aug 15. 5. Engler MB. Familial hypercholesterolemia: genetic predisposition to atherosclerosis. Medsurg Nurs. 2004;13(4):253-257. 6. University of Michigan Cardiovascular Center. LDL apheresis: treating familial hypercholesterolemia with LDL apheresis. 2013. Retrieved from www.med.umich.edu/cvc/services/site_Iipid/ldl.html. 7. Kynamro (mipomersen sodium) injection solution [package insert on the Internet]. Bethesda (MD): U.S. National Library of Medicine; 2013 Jan [updated 2013 Jan; cited 2013 Nov 13]. Available from: daily med.nlm.nih.gov / dailymed/looku p.cfm ?setid=34de6 5 be -fl 10-40 OO a0fl-cb00ec98658f. 8. Raal FJ, Santos RD, Blom DJ, Marais AD, Charng MJ, Cromwell WC, et al. Mipomersen, an apolipoprotein 8 synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: A randomised, double-blind, placebo-controlled trial. lancet [Internet]. 2010 [cited 2013 Nov 13]; 375(9719), 998- 1006. 9. U.S. Food and Drug Administration [Internet]. Silver Spring (MD): U.S. Food and Drug Administration. Drug Approval Package; 2013 Jan 29 [cited 2013 Nov 13]; [1 screen]. Available from: www.access data.fda.gov/ drugsatfda_docs/nda/2013 /203 5680riglsOOOTOC.cfm. 10. Stein EA, Dufour R, Gagne C, Gaudet D, East C, Donovan JM, et al. Apoli poprotein 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 [Internet] 2012 [cited 2013Nov14] 126(19), 2283-2292. 11. Thomas GS, Cromwell WC, Ali S, Chin W, Flaim JD, Davidson M. Mi pomersen, an apolipoprotein 8 synthesis inhibitor, reduces athero genic lipoproteins in patients with severe hypercholesterolemia at high cardiovascular risk: a randomized, double-blind, placebo-controlled trial.] Am Coll ofCardiol. (2013). [Accepted manuscript]. 12. Lexicomp [Internet]. Hudson (OH): Lexicomp Inc. cl 978-2013. Mi pomersen; [updated 2013 Nov 12; cited 2013 Nov 13]; [1 screen]. Available from: online.lexi.com. 13. Nguyen, CP. Center for Drug Evaluation and Research Summary Re view. Application number 2038580rigls000. Food and Drug Admini stration. 2012 Feb 29. Submitted by Aegerion Pharmaceuticals, Inc. 14. Cuchel M, Bloedon L, Rader D, et al. Inhibition of microsomal triglyc eride transfer protein in Familial Hypercholesterolemia. New England journal Of Medicine [serial online]. January 11, 2007;356(2):148-156. Available from: Academic Search Complete. Accessed October 8, 2013. 15. Aegerion Pharmaceuticals, Inc. Safety, tolerability and efficacy of Mi crosomal Triglyceride Protein (MTP) Inhibitor. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- 2013. Available from: clinicaltrials.gov/ct2/show/NCT01556906? term=NCT01556906&rank=l. NLM Identifier: NCT01556906. 16. Aegerion Pharmaceuticals, Inc. A safety and efficacy study of AEGR-733 to treat Homozygous Familial Hypercholesterolemia (FH). In: Clinical Trials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- 2013. Available from: clinicaltrials.gov/ct2/show/NCT 00730236?term=NCT00730236&rank=l. NLM Identifier: CT00730236. 17. 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 hypercholesterolemia: a single-arm, open-label, phase 3 study. lancet. 2013;381(9860):40-6. Available from: PubMed. Accessed October 14, 2013. 18. Lexi-Drugs Online [Internet]. Hudson (OH): Lexi-Comp, Inc. 1978-2013. Juxtapid; [cited 2013 October 7]. Available from: online.lexi.com. 19. Juxtapid [moqograph on the internet]. Bethesda (MD): U.S. National Library of Medicine; 2013 (cited 2013 November 3]. Available from: dai lymed.n Im. nih .gov/ dailymed/looku p. cfm ?setid=e4c45b b 5-15 f4- 437e-ab98-a649b3676d 14#nlm43685-7. A Comparison ofMipomersen (Kynamro®) and Lomitapide (Juxtapid®) ... Infectious Disease
Assessment Questions 8. After initiation of mipomersen or lomitapide treatment, 1. Mild adverse events associated with administration of how frequently should a patient have ALT/ AST tests lomitapide include all of the following EXCEPT: conducted? A. Blood and lymphatic disorders A. Every six months B. Chest pain B. Every month for the first year, then discontinue C. GI upset tests D. Hyperkalemia C. Every month during the course of treatment D. Every month for the first year, then every 2. Which of the following are appropriate baseline three months monitoring parameters for a patient initiating lomitapide therapy? 9. Which of the following are characteristic symptoms of A. AST/ALT HoFH? B. Total bilirubin A. Xanthomas C. Pregnancy testing B. Total serum cholesterol of greater than D. Two of the above 1,300 mg/dL E. All of the above C. Early-onset cardiovascular diseases, including coronary artery disease, angina of effort, aortic 3. In which of the following patient populations is stenosis and myocardial infarction lomitapide therapy most appropriately indicated? D. A and C only A. Monotherapy in patients diagnosed with HoFH E. All of the above B. Lipid-lowering therapy in patients with hyperlipidemia unresponsive to statin therapy 10. Which of the following conventional treatments C. As an adjunct to low-fat diet and lipid-lowering (nonspecific for HoFH) can be used in the treatment of therapy in patients with HoFH diagnosis HoFH? D. Monotherapy in patients diagnosed with A. Lifestyle modifications including low-fat, heterozygous familial hypercholesterolemia low-cholesterol diet, weight control, moderation of alcohol intake and smoking cessation 4. Health care professionals and pharmacists must be en B. Pharmacological therapy including statins, rolled in the Risk Evaluation and Mitigation Strategy resins (also known as bile acid sequestrants), (REMS) program for which of the following reasons? fibrates, nicotinic acid (also known as niacin) A. Risk ofhepatotoxicity and cholesterol absorption inhibitors B. Specificity of indication C. LDL-apheresis C. Need for continuous monitoring D. A and 8 only D. All of the above E. All of the above
5. What is the most common side effect associated with mipomersen treatment? A. Flu-like symptoms Ohio Northern University is accredited by the B. Nausea Accreditation Council for Pharmacy Education as a C. Injection site reactions provider of continuing pharmacy education. This D. Headache ~. program is eligible for credit until 02/25/2017. 6. Baseline monitoring for mipomersen is the same as lomitapide EXCEPT for: To receive continuing education credit for this program, you A. ALT/AST must answer the above questions and fill out the evaluation B. Pregnancy testing form. Please visit www.onu.edu/pharmacy to enter the C. Total bilirubin required information. Please allow two to three weeks for D. Alkaline phosphatase electronic distribution of your continuing education certifi cate, which will be sent to your valid email address in PDF 7. What is the mechanism of action associated with format. mipomersen? A. Small-molecule inhibition of microsomal triglyceride protein (MTP) B. Antisense oligonucleotide inhibitor C. HMG-CoA reductase inhibitor D. NPC1L1 antagonist To receive continuing education credit for this program, visit www.onu.edu/pharmacy/CE OR fill out the form below including your indicated answers to the assessment questions and return to: Office of Continuing Education at the Raabe College of Pharmacy Ohio Northern University 525 South Main Street Ada, Ohio 45810
Program Title: A Comparison ofMipomersen (Kynamro®) and Lomitapide (Juxtapid®): Medications for the Treatment of Homozygous Familial Hypercholesterolemia UAN: 0048-0000-14-031-HOl-P CEUs: 0.1 All information must be printed CLEARLY to ensure accurate record keeping for attendance and the awarding of continuing education credit. Certificates will be distributed as a PDF document to a valid email address. Name: Address: City: State: Zip: Phone: Email:
Pharmacy License #: State: ONU Alumni? y N
The program objectives were clear. 1 2 3 4 5 The program met the stated goals and objectives: Describe the clinical symptoms of homozygous familial hypercholes 1 2 terolemia (HoFH). 3 4 5 Identify conventional and adjunct treatments used for HoFH before 1 2 the development and FDA approval ofmipomersen and lomitapide. 3 4 5 Identify the mechanism of action for both mipomersen and lomitapide. 1 2 3 4 5 Identify mipomersen and lomitapide's place in therapy in the treatment 1 2 4 ofHoFH. 3 5 Discuss the common adverse events and appropriate monitoring 1 2 3 4 parameters associated with mipomersen and lomitapide therapy. 5 The program met your educational needs. 1 2 3 4 5 Content of the program was interesting. 1 2 3 4 5 Material presented was relevant to my practice. 1 2 3 4 5 Comments/Suggestions for future programs:
Thank you! Answers to Assessment Questions-Please Circle Your Answer 1. A B C D 4. A B C D 7. A B C D 10. A B C D E
2. A B C D E 5. A B C D 8. A B C D
3. A B C D 6. ABCD 9. A B C D E
Any questions/comments regarding this continuing education program can Ohio Northern University is accredited by the be directed to Lauren Hamman, Advanced Administrative Assistant for the Accreditation Council for Pharmacy Education as a Office of Continuing Education (email: [email protected], phone 419- provider of continuing pharmacy education. This ,.,,.,,, ')")~U\\ nrncrr<1Tn io PlicrihlP f"nr r.rPrlit 11ntil ()?/?<;/'.)(117