Emerging low-density lipoprotein therapies: Microsomal triglyceride transfer protein inhibitors
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1 Journal of Clinical Lipidology (2013) 7, S16 S20 Emerging low-density lipoprotein therapies: Microsomal triglyceride transfer protein inhibitors Anne C. Goldberg, MD, FACP, FAHA, FNLA* Associate Professor of Medicine, Washington University School of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, 660 S. Euclid Avenue, Campus Box 8127, St. Louis, MO 63110, USA KEYWORDS: Familial hypercholesterolemia; Low-density lipoprotein cholesterol; Microsomal triglyceride transfer protein inhibitor Abstract: Microsomal triglyceride transfer protein, which is localized in the endoplasmic reticulum of enterocytes and hepatocytes, is necessary for the formation of chylomicron and very low-density lipoprotein particles. Lomitapide is a small molecule microsomal triglyceride transfer protein inhibitor that was recently approved by the Food and Drug Administration as an adjunct to a low-fat diet and other lipid-lowering therapies for reducing low-density lipoprotein cholesterol (LDL-C) in patients with homozygous familial hypercholesterolemia (FH). Results from clinical trials of lomitapide have demonstrated its ability to reduce atherogenic lipoprotein concentrations in this population. Most recently, in a phase 3 clinical trial of 29 men and women with homozygous FH (mean baseline LDL-C, 336 mg/dl) who were on stable doses of concomitant lipid therapies and a low-fat diet, lomitapide was gradually titrated over 26 weeks (from 5 to 60 mg/d), followed by 52 weeks at the maximum tolerated dose. LDL-C decreased from baseline by 50% at 26 weeks, and reductions were maintained through the end of the study. Gastrointestinal disorders were the most frequent side effects and the most common reason for failure to tolerate lomitapide dose escalation. Few patients had elevated aspartate or alanine aminotransferases; bilirubin and alkaline phosphatase levels were unaffected; and hepatic fat increased by w10 g/100 g. In conclusion, recent data support the LDL-C lowering efficacy of lowdose titrated lomitapide in patients with homozygous FH; however, concerns regarding increased hepatic fat will need to be addressed in long-term safety studies. Ó 2013 National Lipid Association. All rights reserved. Patients with homozygous familial hypercholesterolemia (FH) have extremely elevated levels of low-density lipoprotein cholesterol (LDL-C) and are almost always unable to reach clinical treatment targets with conventional therapies. 1 Individuals with heterozygous FH have milder LDL-C elevations but are also often in need of additional LDL-C lowering beyond that which can be achieved by maximum doses of conventional lipid drug combinations. In addition, some patients do not tolerate statin therapy at * Corresponding author. address: agoldber@dom.wustl.edu Submitted December 5, Accepted for publication March 20, all or at doses sufficient to substantially lower LDL-C. LDL-apheresis is a highly effective method of eliminating LDL particles from the bloodstream and may be prescribed for individuals with homozygous or severe heterozygous FH. 1 3 However, it is costly, time-consuming, and not available to all patients. Novel treatment strategies for the homozygous FH population who are at high risk for cardiovascular disease are needed. 4 One of those potential therapies is the microsomal triglyceride transfer protein (MTP) inhibitor. 5 Lomitapide mesylate (JUXTAPID; N-(2,2,2-trifluoroethyl)- 9-[4-[4-[[[4 0 -(trifluoromethyl)[1,1 0 -biphenyl]-2-yl]carbonyl] amino]-1-piperidinyl]butyl]-9h-fluorene-9-carboxamide, methanesulfonate salt; molecular weight 789.8), hereafter /$ - see front matter Ó 2013 National Lipid Association. All rights reserved.
2 Goldberg Emerging LDL therapies: MTP inhibitors S17 referred to as lomitapide, is an MTP inhibitor that was recently approved by the Food and Drug Administration as an adjunct to a low-fat diet and other lipid-lowering therapies, including LDL apheresis where available, to reduce LDL-C, total-c, apolipoprotein (Apo) B, and non highdensity lipoprotein-c in patients with homozygous FH. 6 clearance of LDL particles from the circulation, and many are refractory to drugs that depend mainly on up-regulation of hepatic LDL receptors. 12,13 Therefore, homozygous FH patients almost always fail to achieve the magnitude of LDL-C reduction that is needed with statins and other conventional lipid-lowering therapies. MTP inhibitors MTP is a lipid transfer protein localized in the endoplasmic reticulum of hepatocytes and enterocytes, where it initiates the incorporation of lipids into Apo B, acting as a chaperone to assist in Apo B folding. 5 MTP is necessary for the formation of very-low-density lipoprotein (VLDL) particles in hepatocytes and chylomicron particles in enterocytes. Because MTP is highly expressed in the intestine, its inhibition may result in gastrointestinal disturbances, including diarrhea and steatorrhea, among others. Mutations in MTP leading to its deficiency result in inadequate formation of VLDL and chylomicrons, and increased degradation of Apo B-48 and Apo B-100, creating a rare condition called abetalipoproteinemia. 5,7,8 Some individuals with abetalipoproteinemia have almost no circulating LDL and VLDL lipoproteins. As a result of an understanding of the role of MTP in the formation of VLDL from the study of this rare genetic disorder, a small molecule inhibitor of MTP was created (originally BMS , now called AEGR-733/ lomitapide) as a possible strategy for reducing hepatic VLDL formation to lower circulating VLDL-C and LDL-C concentrations in individuals with FH. 9 In addition to gastrointestinal side effects, another major challenge in the development of this agent has been that there is the potential for the neutral lipid that is not used in the creation of lipoproteins to accumulate in the liver, producing hepatic steatosis. 10 Early investigations with compound In the mid-to-late 1990s, the MTP inhibitor BMS (Bristol-Myers Squibb) was reported to lower LDL-C by.50% in hypercholesterolemic subjects. 9 The time course of this effect was relatively rapid about 4 weeks. However, many participants discontinued from the early BMS studies because of a high rate of gastrointestinal side effects. Furthermore, hepatic fat as estimated from nuclear magnetic resonance spectroscopy was increased by 10 to 30 g/100 g but appeared to decrease during a washout period. The pharmaceutical development program of BMS was officially discontinued, but other investigators continued to examine the possible use of this compound in homozygous FH. FH is a disease caused by autosomal-dominant defects in the genes coding for the LDL receptor, Apo B, or proprotein convertase subtilisin/ kexin type Although many patients with heterozygous FH respond well to high-dose statins, ezetimibe, and bile acid sequestrants, patients with homozygous FH have little or no LDL receptor activity, which prevents hepatic Proof-of-concept study in homozygous FH In a phase 2 proof-of-concept study published by Cuchel et al, 14 six patients with homozygous FH were administered four escalating doses (0.03, 0.1, 0.3, 1.0 mg/kg body weight) of BMS for 4 weeks each dose (mean dose of 67 mg/d at 16 weeks). Total-C, LDL-C, and Apo B decreased by w50% at the greatest dose. The dose escalation protocol was selected because of the frequency of gastrointestinal side effects reported in the original development program. Even with dose escalation, there were a large number of possibly or probably drug-related gastrointestinal side effects (increased stool frequency, nausea, vomiting, heartburn, stomach pain), but the adverse event profile was improved compared with previous fixed-dose studies. This improvement was also partly attributed to the use of a low-fat diet (an average of 17% energy from fat). There were some instances of alanine aminotransferase (ALT) levels greater than five times the upper limit of normal (.5! ULN); however, these returned to normal with continued therapy and were not associated with greater levels of bilirubin or alkaline phosphatase. Hepatic fat, measured by chemical-shift magnetic resonance imaging techniques, was also increased in a dose-dependent manner, although the effect was variable from patient to patient and began to decrease during the washout period. In two patients, potential contributing factors to the increase in hepatic fat were identified as significant ethanol consumption (which was a protocol violation) and high baseline triglycerides (605 mg/dl). A high triglyceride concentration is unusual and not representative of the typical patient with homozygous FH, and is suggestive of the presence of a secondary cause and/or additional metabolic error. Phase 2 trial of lomitapide Further work using BMS (now called AEGR- 733/lomitapide; Aegerion Pharmaceuticals, Inc., Cambridge, MA) focused on a controlled-dose approach through titration, and used lower doses in combination with other lipid-lowering treatments as an adjunct to a low-fat diet. In a phase 2, randomized, double-blind, multicenter trial, 84 patients with moderate hypercholesterolemia (baseline LDL-C between 160 and 250 mg/dl in patients with 0-1 risk factors and between 130 mg/dl and 250 mg/dl in patients with 21 risk factors) were randomized to receive either 10 mg/d ezetimibe (n 5 29), AEGR-733 with forced up-titration (4 weeks 5 mg/d, 4 weeks 7.5 mg/d, 4 weeks 10 mg/d) (n 5 28), or 10 mg/d ezetimibe 1 AEGR-733 with
3 S18 Journal of Clinical Lipidology, Vol 7, No 3S, June 2013 Figure 1 Mean percent change from baseline lipids after four doses of BMS for 4 weeks each in patients with homozygous FH. Reprinted with permission from Cuchel et al. 14 forced up-titration (n 5 28). 15 In the ezetimibe-only group, LDL-C decreased by 20% compared with escalated doses of AEGR-733 alone, which lowered LDL-C by 19%, 26%, and 30%, respectively (Fig. 1). The combination of AEGR ezetimibe showed an additive effect producing decreases in LDL-C of 35%, 38%, and 46%, respectively, with 5, 7.5, and 10 mg/d AEGR-733 doses. The main gastrointestinal side effects were nausea and diarrhea, which were severe in some cases. However, the predominant reason cited for discontinuation was elevated liver transaminases, which were experienced by 9 of 56 patients in the two groups that received AEGR-733. Phase 3 trial of lomitapide A phase 3 clinical trial designed to evaluate the efficacy and long-term safety of open-label, ascending-dose lomitapide in patients with homozygous FH was recently completed. 16 Study participants included men (n 5 16) and women (n 5 13) 18 to 55 years of age (average age of 30.7 years) with a diagnosis of homozygous FH (ie, clinical criteria, fibroblast activity, or mutations in genes affecting LDL receptor functionality) and on stable doses of concomitant lipid therapies. The dose of lomitapide was titrated over the course of 26 weeks: 5 mg/d for 2 weeks, followed by 10, 20, 40, and 60 mg/d for 4 weeks up to their maximally tolerated dose and continued for the remainder of the 26 weeks. After the initial treatment period, participants continued on a stable regimen of their maximally tolerated dose of lomitapide for an additional year. Patients were also instructed to eat a low-fat diet. In addition to lipid assessments, liver enzymes were carefully monitored, and hepatic fat was periodically evaluated by nuclear magnetic resonance spectroscopy. Twenty-three patients completed 26 weeks and completed the full 78-week study. The median lomitapide dose was 40 mg/d. The maximum dose in the subjects who completed the study was 5 mg (n 5 1), 20 mg (n 5 5), 40 mg (n 5 6), and 60 mg (n 5 11); the dose distribution remained similar at week 78. From a baseline average LDL-C concentration of mg/dl, LDL-C had dropped by 50% to an average level of mg/dl at 26 weeks (Fig. 2). Notably, eight patients had an LDL-C concentration,100 mg/dl and one patient achieved an LDL-C level,70 mg/dl. These levels were maintained throughout the remainder of the 78-week study. One of the concomitant lipid-lowering therapies administered to some patients during the trial was LDL apheresis, a process in which Apo B-containing particles are removed from circulation through extracorporeal precipitation. 2,3 Where available, LDL apheresis can be performed in homozygous FH patients either every two weeks or once per week; however, LDL apheresis is not available at most health care centers. Of the 13 patients who were being treated by LDL apheresis at week 26, seven patients remained unchanged in their schedules during the 52 weeks of maximum stable-dose lomitapide, three patients reduced the frequency of apheresis, and three patients discontinued apheresis completely. Figure 2 Mean percent changes in LDL cholesterol, total cholesterol, and Apo B levels from baseline to week 26 (end of efficacy phase) in phase 3 homozygous FH trial. Data available at each time point are expressed as mean (SD). Reprinted with permission from Cuchel et al. 16
4 Goldberg Emerging LDL therapies: MTP inhibitors S19 Figure 3 Panel A: Alanine transaminase and aspartate transaminase levels in phase 3 homozygous FH trial; Panel B: Percentage of hepatic fat (g/100 g) in the liver in phase 3 homozygous FH trial. Reprinted with permission from Cuchel et al. 16 At least one adverse event was experienced by 93% of subjects during the first 26 weeks of lomitapide treatment, and 91% of subjects had an adverse event during weeks Mild-to-moderate gastrointestinal disorders (diarrhea, nausea, abdominal discomfort, vomiting) were the most frequent side effects, reported by 93% of subjects during the first 26 weeks, and decreased slightly to 74% of subjects during the last 52 weeks. Gastrointestinal adverse events were the most common reason for failure to tolerate a higher dose of lomitapide, causing three subjects to discontinue the study. Aspartate aminotransferase (AST) was increased in 7% of patients during the first 26 weeks and no patients during the last 52 weeks of treatment, and ALT was increased in 17 and 4% of patients in the first and second periods of treatment, respectively. Transient elevations in ALT.5! ULN were experienced by four of the 29 patients, leading to temporary lomitapide dose reductions. There were no changes in bilirubin or alkaline phosphatase levels, and no subjects discontinued from the study based on results from liver function tests. Hepatic fat content at 26 weeks of treatment had increased from 1.0 g/100 g at baseline to 8.6 g/100 g, and either stabilized or decreased at 56 and 78 weeks (Fig. 3). Conclusion In conclusion, results from recent phase 2 and 3 studies of lomitapide (previously known as BMS and AEGR-733; now FDA-approved as JUXTAPID) demonstrate its efficacy as an add-on therapy for lowering LDL- C, total-c, and Apo B in homozygous FH patients. Lomitapide was tolerable when administered as part of a low-dose titration scheme along with a low-fat diet. There were some concerns regarding the effect of lomitapide to produce elevations in liver enzymes and increase hepatic fat. Because of the risk of liver toxicity, lomitapide is available only through a restricted program called the JUXTAPID Risk Evaluation and Mitigation Strategy Program, which will require certification of all health care providers who prescribe it and pharmacies that dispense it. Monitoring should include measurement of ALT, AST, alkaline phosphatase, and total bilirubin before initiating treatment and then ALT and AST regularly, as recommended. During treatment, the dose should be adjusted if ALT or AST are $3! ULN, and drug should be discontinued for clinically significant liver toxicity. Combination with cytochrome P450 3A4 (CYP3A4) inhibitors increases exposure to lomitapide, thus lomitapide should not be used with strong and moderate CYP3A4 inhibitors, and dosage limitation (not exceeding 30 mg/d) is also required when administering concomitantly with weak CYP3A4 inhibitors. Financial disclosures Dr. Goldberg has received research grants from Amarin, Abbott Laboratories, Merck & Co., Novartis Pharmaceuticals, GlaxoSmithKline, Regeneron Pharmaceuticals/Sanofi, Genzyme/Isis Pharmaceuticals, and Genentech. References 1. Goldberg AC, Hopkins PN, Toth PP, 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. 2011;5(3 Suppl):S1 S8. 2. Moriarty PM. LDL-apheresis therapy. Curr Treat Options Cardiovasc Med. 2006;8: Thompson GR, Barbir M, Davies D, et al. Efficacy criteria and cholesterol targets for LDL apheresis. Atherosclerosis. 2010;208: Goldberg AC. Novel therapies and new targets of treatment for familial hypercholesterolemia. J Clin Lipidol. 2010;4: Stein EA. Other therapies for reducing low-density lipoprotein cholesterol: medications in development. Endocrinol Metab Clin North Am. 2009;38: Aegerion Pharmaceuticals, Inc. December 24, FDA approves Aegerion Pharmaceuticals JUXTAPID(TM) (lomitapide) capsules for homozygous familial hypercholesterolemia (HoFH). Available at: Accessed March 28, Wetterau JR, Aggerbeck LP, Bouma ME, et al. Absence of microsomal triglyceride transfer protein in individuals with abetalipoproteinemia. Science. 1992;258: Zamel R, Khan R, Pollex RL, Hegele RA. Abetalipoproteinemia: two case reports and literature review. Orphanet J Rare Dis. 2008;3: Burnett JR, Watts GF. MTP inhibition as a treatment for dyslipidaemias; time to deliver or empty promises? Expert Opin Ther Targets. 2007;11:
5 S20 Journal of Clinical Lipidology, Vol 7, No 3S, June Rizzo M, Wierzbicki AS. New lipid modulating drugs: the role of microsomal transport protein inhibitors. Curr Pharm Des. 2011;17: Hopkins PN, Toth PP, Ballantyne CM, Rader DJ, National Lipid Association Expert Panel on Familial Hypercholesterolemia. Familial hypercholesterolemias: prevalence, genetics, diagnosis and screening recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011;5(3 Suppl):S9 S Marais AD, Naoumova RP, Firth JC, Penny C, Neuwirth CK, Thompson GR. Decreased production of low density lipoprotein by atorvastatin after apheresis in homozygous familial hypercholesterolemia. J Lipid Res. 1997;38: Gagne C, Gaudet D, Bruckert E, Ezetimibe Study Group. Efficacy and safety of ezetimibe coadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia. Circulation. 2002;105: Cuchel M, Bloedon LT, Szapary PO, et al. Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia. N Engl J Med. 2007;356: Samaha FF, McKenney J, Bloedon LT, Sasiela WJ, Rader DJ. Inhibition of microsomal triglyceride transfer protein alone or with ezetimibe in patients with moderate hypercholesterolemia. Nat Clin Pract Cardiovasc Med. 2008;5: Cuchel M, Meagher EA, du Toit Theron H, et al, Phase 3 HoFH Lomitapide Study investigators. 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;381:40 46.
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