Current Treatment Options in Cardiovascular Medicine (2013) 15:696–705 DOI 10.1007/s11936-013-0272-3
Prevention (L Sperling, Section Editor)
Recent Developments in the Treatment of Familial Hypercholesterolemia: A Review of Several New Drug Classes Michael J. Wilkinson, MD Michael H. Davidson, MD* Address *Department of Medicine, University of Chicago Medicine, 150 E. Huron Street, Suite 900, Chicago, IL 60611, USA Email: [email protected]
Published online: 13 November 2013 * Springer Science+Business Media New York 2013
Keywords Familial hypercholesterolemia I Hyperlipidemia I Low-density lipoprotein cholesterol (LDL-C) I Prevention I Lipidology I Microsomal trigylceride transfer protein (MTP) inhibitor I Apolipoprotein B synthesis inhibitior I Cholesterol ester transfer protein (CETP) inhibitor I Pro-protein convertase subtilisin/kexin 9 (PCSK9) inhibitor
Opinion statement Familial hypercholesterolemia is a genetic disorder of the low-density lipoprotein cholesterol (LDL-c) receptor leading to severe elevations in plasma levels of LDL-c which results in premature atherosclerosis and cardiovascular events. Statins, ezetimibe, and bile acid sequestrants significantly lower LDL-c levels in these patients and subsequently markedly improve survival; however, even with these interventions LDL-c goals often are not met. Several new drug classes are in development and have the potential to make reaching these cholesterol goals easier. In this article we review the most recent trials of several classes of drugs with the potential to change the future of familial hypercholesterolemia management: microsomal triglyceride transfer protein (MTP) inhibitors, apolipoprotein B synthesis inhibitors (mipomersen), cholesterol ester transfer protein (CETP) inhibitors and inhibitors of pro-protein convertase subtilisin/kexin 9 (PCSK9). Each class has shown promise with regard to their effects on the lipid profile. However, the potential side-effects of each drug are also being determined and have limited the development of certain agents. Therefore, the long-term effects of these drug classes, both in terms of side-effects and their effect on clinical outcomes such as cardiovascular events and mortality, continue to be determined.
Introduction Familial hypercholesterolemia (FH) is an autosomal dominant disorder, either heterozygous or homozy-
gous, that results from defects in genes associated with lipid metabolism. The mutations of the low-density li-
Recent Developments in the Treatment of Familial Hypercholesterolemia Wilkinson and Davidson poprotein cholesterol (LDL-c) receptor that lead to the development of familial hypercholesterolemia are diverse and impact the severity of the disease. The disease is characterized by premature atherosclerosis and associated events, such as premature coronary artery disease and myocardial ischemia (Figure 1). Patients with familial hypercholesterolemia are generally not adequately responsive to diet and lifestyle modification, and therefore statins represent the backbone of pharmacotherapy. Other lipid-lowering agents, such as bile-acid sequestrants and ezetimibe, have also been used. Treatment goals include a reduction of LDL-c by 50 % from baseline [1, 2], an LDL-c level G ~100 mg/dL, or an LDL-c level G ~70 mg/dL for those with known CVD [1, 3]. When LDL-c goals cannot be met, attempts should be made to achieve the lowest possible LDL-c level without treatment side effects [3]. Unfortunately, given the severity of LDL-c elevation in this disease, as well as the sometimes limited responses to therapy, LDL-c targets are frequently not
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met with currently available therapies. Patients with homozygous familial hypercholesterolemia (hoFH) have very limited LDL receptor activity and are therefore poorly responsive to existing drug therapy. Therefore, there is a need to develop additional pharmacologic agents for the treatment of familial hypercholesterolemia. Several drug classes are emerging that appear to have great potential to help improve lipid profiles, and thereby cardiovascular disease risk, in patients with hypercholesterolemia. While not all trials of these agents have included patients with familial hypercholesterolemia, the results in these instances are likely largely applicable to the FH population. In this review, we will present each of these drug classes and the recent studies of their effect on lipid levels, particularly LDL-c. The classes of drugs which we will review are: microsomal triglyceride transfer protein (MTP) inhibitors, apolipoprotein B synthesis inhibitors (mipomersen), cholesterol ester transfer protein (CETP) inhibitors and inhibitors of pro-protein convertase subtilisin/kexin 9 (PCSK9).
Microsomal transfer protein (MTP) inhibitors Microsomal transfer protein is critical for the formation and secretion of apolipoprotein B (apoB) containing lipoproteins from cells of the liver and intestine. Mutations in the gene for microsomal transfer protein lead to a rare, autosomal recessive condition known as abetalipoproteinemia. In this disorder, apoB containing lipoproteins that would otherwise arise from the liver and intestine are not present in the bloodstream, including VLDL, the precursor to LDL. Inhibiting MTP through pharmacotherapy was therefore pursued with the hope of developing a way of decreasing circulating VLDL Figure 1. Patients with familial hypercholesterolemia (FH) have an autosomal dominant mutation in the LDL receptor gene resulting in severe elevations of LDL-c. As shown in this figure, tendon xanthomas are one clinical finding associated with high circulating lipid levels in patients with FH.
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Prevention (L Sperling, Section Editor) and LDL, with an ultimate goal of reducing cardiovascular risk [4]. Early studies of MTP inhibitors, such as implitapide, were found to reduce LDL-c. However, further development of most of these drugs was discontinued due to concerns related to GI side-effects and hepatic fat accumulation. An MTP inhibitor called lomitapide has therefore become the only MTP inhibitor to be developed beyond a phase 2 clinical trial [4]. BMS-201038, later called lomitapide, was tested in a proof of concept study in patients with homozygous familial hypercholesterolemia [5]. This study, by Cuchel et al. in 2007, enrolled six patients with homozygous familial hypercholesterolemia. All other lipid agents were held, including apheresis. Dose escalation was pursued to the highest dose, four weeks per dose. All patients were found to tolerate the highest dose and treatment at the highest dose led to LDL-c being reduced by 50.9 % and apolipoprotein B levels being reduced by 55.6 %, from baseline. The frequency and severity of side-effects were variable but included increased stool frequency (associated with eating a high fat meal), elevated transaminases and increased accumulation of liver fat. Liver fat was monitored with MRI of the liver at baseline, after each 4 week period on a particular dose, and 4 weeks after discontinuing the drug. More severe transaminase elevations and accumulation of hepatic fat were potentially confounded by a patient with hypertriglyceridemia and another patient who admitted to significant alcohol use during the study. There was no significant change in HDL-c, apolipoprotein A-I or Lp(a) lipoprotein [5]. Based on the positive effects on LDL-c and apoB in this study, as well as the relatively limited adverse effects compared with prior studies of MTP inhibitors, lomitapide would be developed further. Cuchel et al. carried out a phase 3 study of lomitapide involving 29 patients with homozygous familial hypercholesterolemia from multiple centers and four countries. On lomitapide, the dose was escalated up to 60 mg per day, and the effect on LDL-c was measured at 26 weeks (efficacy phase), week 56, and week 78 (weeks 26–78 were considered the safety phase). The mean LDL-c was decreased by 50 % from baseline at week 26. At 56 weeks LDL-c continued to be reduced at 44 % from baseline, and at week 78 LDL-c was reduced 38 % from baseline (Fig. 2). The most common symptoms were GI related. Ten patients experienced elevated levels of AST, ALT or both to greater than three times the upper limit of normal. Only four patients had transaminase levels that reached 95 times the upper limit of normal which resolved with decreasing the drug dose or temporarily stopping the medication. Three of these patients admitted to having consumed alcohol at levels higher than allowed by the protocol. Patients continued other lipid-lowering therapies during the trial, including apheresis. Mean hepatic fat was elevated above baseline in the patients (20 total) who were able to undergo NMRS (nuclear magnetic resonance spectroscopy) [6••]. Based on these additional findings, lomitapide has been approved as an orphan drug in the treatment of homozygous familial hypercholesterolemia. Lomitapide is therefore an effective LDL-c lowering agent for patients with FH that do not respond adequately to existing therapies and clinical trials have demonstrated that the initiation of very low doses with gradual titration of the dose generally results in tolerability and liver safety [5, 6••]. Even so, the long term health consequences of mild to moderate hepatic steatosis are uncertain and therefore continued monitoring for potential safety issues is important.
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Figure 2. In a long-term efficacy study in patients with homozygous familial hypercholesterolemia, lomitapide with gradual dose titration significantly reduced LDL-c by approximately 40 % with a reasonable safety and tolerability profile.
Apo-B synthesis inhibitors (mipomersen) Another target of recently tested lipid-lowering drugs is apolipoprotein B synthesis. Mipomersen is an oligonucleotide antisense inhibitor that targets the apoB mRNA. Mipomersen binds to the mRNA sequence which then results in the degradation of the mRNA, preventing translation of the mRNA and thereby inhibiting production of apoB. Apolipoprotein B is a critical component of the VLDL lipoprotein and without this protein VLDL levels, and thereby LDL levels, would be expected to fall [7, 8••]. Raal and colleagues completed a randomized, double-blind, placebo controlled phase 3 study of mipomersen. A total of 34 patients with homozygous familial hypercholesterolemia received mipomersen and 17 received placebo. Mipomersen was given at a 200-mg dose, subcutaneously, once a week. There was a 26-week treatment period. The mean percent change in LDL-c with mipomersen was -24.7 % (versus placebo, which produced a -3.3 % change). Patients were continued on other lipid-lowering agents. Mipomersen was also associated with a significant reduction in non-HDL cholesterol, VLDL, apolipoprotein B, and lipoprotein(a). Mipomersen was also associated with an elevation in HDL cholesterol (p=0.0326) [8••]. The most common adverse reaction was localized reaction at the injection site. Four patients experienced significant elevations in ALT to three or more times the upper limit of normal. MRI was used to measure hepatic fat at baseline for all participants (unless contraindicated). MRI was repeated if
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Prevention (L Sperling, Section Editor) ALT increased to three times or more above the upper limit of normal. A total of four patients met criteria for MRI, and three underwent repeat scan. Of these three, only one had an elevation in hepatic fat content [8••]. Another study of mipomersen was performed by Akdim and colleagues. It was similar to the Raal study, but was a phase 2 study and enrolled patients with heterozygous familial hypercholesterolemia. It was a randomized, double-blind, placebo-controlled, dose escalation study. There were 44 participants, and a range of mipomersen doses were tested, from 50 mg to 300 mg during a six-week treatment period. The primary end point was LDLc reduction from baseline. Other lipid lowering agents were continued during the study. At the highest doses of mipomersen, LDL-c was significantly reduced from baseline by 21–34 %. At the highest doses of mipomersen, apolipoprotein B, non-HDL, and total cholesterol levels were also significantly reduced [9]. Local injection site reaction was the most common adverse event. Significant transaminase elevation (9 or equal to 3 times upper limit of normal) occurred in only four patients receiving treatment. Three patients had more persistent transaminase elevations, and these patients were receiving the highest-dose mipomersen. Upon evaluation with CT scan, two had a steatotic liver and one had hepatomegaly without steatosis; there were no baseline scans to compare to so any kind of causal relationship was not clear [9].
Cholesterol ester transfer protein (CETP) inhibitors CETP (cholesterol ester transfer protein) is an enzyme, bound to HDL, that facilitates transfer of cholesterol esters from HDL to pro-atherogenic lipoproteins such as those containing ApoB. Therefore, inhibition of this protein might be expected to raise HDL-c levels. Based on the anti-atherogenic role of HDL, a drug which causes HDL-c levels to increase might reduce cardiovascular risk [7]. Early on in the development of CETP inhibitors, Barter and colleagues performed a randomized, double-blind study of a CETP inhibitor called torcetrapib. The team enrolled 15,067 patients and tested torcetrapib and atorvastatin versus atorvastatin alone in patients with known cardiovascular disease or type 2 diabetes. Primary outcome was time to first major cardiovascular event (death from CHD, non-fatal MI, stroke, or hospitalization for UA). At 12 months in the torcetrapib group, HDL-c had increased 72.1 %, and LDL-c had decreased 24.9 %. However, systolic blood pressure had also increased, serum potassium had decreased, and serum sodium, bicarbonate and aldosterone had increased. There was also a significantly increased risk of cardiovascular events and death from any cause. Therefore, the trial was discontinued early. The authors speculate that the higher rate of adverse cardiovascular events and death from any cause might be either related to an off-target effect of torcetrapib (such as effects related to increased aldosterone levels), or an adverse effect of CETP inhibition (possibly leading to abnormal and detrimental HDL function) [10]. Another early study of torcetrapib enrolled 850 patients with heterozygous familial hypercholesterolemia and measured carotid intima-media thickness at baseline and then after two years of torcetrapib plus atorvastatin versus atorvastatin alone [11].
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Patients receiving torcetrapib had higher average HDL levels as well as a lower average LDL level compared to the atorvastatin-only group; however, annualized change in maximum carotid intima-media thickness was not significantly different between the two groups. Annualized change in mean carotid intima-media thickness for the common carotid segment was in fact increased in the torcetrapib group, but was decreased in the atorvastatin alone group. Authors suggest that this discrepancy may be related to the increase in systolic blood pressure seen in the torcetrapib group [11]. More recently, Cannon and colleagues tested a different CETP inhibitor (anacetrapib) in a randomized, double-blind, placebo-controlled trial in patients on statin therapy with CHD or who were considered to be at high risk for CHD. Anacetrapib was tested against placebo for 18 months. The primary end point was LDL-c at 24 weeks, as well as determining the safety and side-effects of anacetrapib [12]. At 24 weeks, LDL-c was reduced in the anacetrapib group 39.8 % beyond the reduction seen in the placebo group. HDL-c also significantly increased in the anacetrapib group (a rise 138.1 % beyond that seen in the placebo group). Importantly, anacetrapib was not associated with changes in blood pressure, electrolytes or aldosterone levels and the rate of cardiovascular events was not significantly different between the two groups. The authors suggest that the HDL particles in patients treated with anacetrapib (and torcetrapib) actually have a normal to enhanced ability to facilitate off-loading of cholesterol from macrophages (observed in vitro) [12].
Pro-protein convertase subtilisin/kexin 9 (PCSK9) inhibitors Pro-protein convertase subtilisin/kexin 9 (PCSK9) is a protein which helps to regulate low density lipoprotein receptor (LDL-R) expression on hepatocytes. As part of LDL-R mediated cholesterol metabolism, once bound to ApoB (as part of an ApoB associated lipoprotein), the LDL-R is internalized into the hepatocyte. The ApoB lipoprotein is degraded and the LDL-R either returns to the surface of the hepatocyte to bind additional lipoprotein or is targeted for lysosomal degradation by PCSK9 [13]. Therefore, it might be expected that a reduction in PCSK9 activity would lead to increased LDL-R expression on the hepatocyte, and thereby promote removal of pro-atherogenic lipoproteins from the circulation (Fig. 3). Indeed, early studies have shown that naturally occurring sequence variations in PCSK9 are associated with reduced LDL levels and are also linked with reductions in the risk of CHD [14]. There have therefore been several recent studies testing agents which inhibit PCSK9. Stein and colleagues recently described three phase 1 studies of REGN727/SAR236553 (REGN727), a monoclonal antibody against PCSK9. Two were randomized, single ascending-dose studies of REGN727 (intravenous or subcutaneous administration) in healthy volunteers with a serum LDL-c of 9100 mg/dl. The third study was a randomized, placebo-controlled trial of various doses of REGN727 in patients with heterozygous familial hypercholesterolemia and in patients with non-familial hypercholesterol-
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Figure 3. The activity of an antibody directed against pro-protein convertase subtilisin/kexin 9 (PCSK9) reduces PCSK9 mediated degradation of internalized low-density lipoprotein receptor (LDL-R), thereby promoting the return of LDL-R to the cell surface. The subsequent increase in LDL-R expression would be expected to increase removal of LDL particles from the circulation.
emia (both groups were also on atorvastatin); the primary outcome was frequency of adverse events with effects on lipids as a secondary outcome. There was also a group in this part of the study with non-familial hypercholesterolemia whose participants had LDL 9130 mg/dl and were treated with modified diet rather than atorvastatin. PCSK9 was well-tolerated and associated with reductions in LDL-c, as well as reductions in total cholesterol, non-HDL cholesterol, apolipoprotein B, and Lp(a) (however, the reduction in Lp(a) was not always significant) [15]. McKenney and colleagues performed a double-blind, placebo-controlled phase 2 trial intended to measure the effect of REGN727/SAR236553 (SAR236553) versus placebo on LDL cholesterol after 12 weeks of treatment in 183 patients already taking a statin but with baseline levels of LDL that were still greater than or equal to 100 mg/dl [16•]. They found that SAR236553 reduced LDL-c levels in a dose and frequency dependent manner. Specifically, with doses of 50, 100, and 150 mg administered every 2 weeks, the mean reduction of LDL from baseline was 40 %, 64 %, and 72 %, respectively (Fig. 4). When administered at doses of 200 and 300 mg every 4 weeks, LDL-c was reduced 43 % and 48 %, respectively. Non-HDL cholesterol, Lp(a), and apolipoprotein B were also reduced. In terms of side-effects SAR236553 was generally well-tolerated; however, one patient did experience leukocytoclastic vasculitis that may have been related to the study drug. Local injection site reaction was the most common adverse event [16•].
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Figure 4. Change in LDL-C from baseline in a study of pro-protein convertase subtilisin/kexin 9 (PCSK9) inhibitor SAR236553 in a double-blind, placebo-controlled phase 2 trial by McKenney and colleagues [16•].
AMG 145 is another monoclonal antibody directed against PCSK9, and is currently in phase 1 and 2 trials. Two recent phase 2 trials have found AMG 145 to reduce LDL-c. In one trial, in which AMG 145 was administered in patients with hypercholesterolemia not on other lipid-lowering agents, LDL was significantly reduced by approximately 40–50 % in all dose groups [17]. In another phase 2 trial involving patients with hypercholesterolemia who were also on a statin (with or without ezetimibe), LDL cholesterol was reduced by 42–66 % in the groups receiving AMG 145 every 2 weeks, and by 42-50 % in the groups receiving the drug every 4 weeks [18]. In both studies, the drug was generally well tolerated [13].
Conclusion Familial hypercholesterolemia is a genetic disease that is difficult to treat with currently available pharmacotherapies, particularly in patients with the homozygous form of the disease. LDL-c goals are often not met, despite dietary and lifestyle modifications and use of high dose statins and other currently available therapies such as ezetimibe and bile-acid sequestrants. Therefore, the development of agents such as MTP inhibitors, apolipoprotein B synthesis inhibitors (mipomersen), CETP inhibitors, and PCSK9 inhibitors holds great promise for the future of lipid-lowering and cardiovascular risk reduction in this population. All of the agents described herein have proven their effectiveness at altering the lipid profile in a beneficial way, by lowering levels of pro-atherogenic mol-
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Prevention (L Sperling, Section Editor) ecules, such as LDL, and sometimes by increasing levels of anti-atherogenic molecules, such as HDL. Safety concerns have limited the development of certain classes of drugs, such as the MTP inhibitors and mipomerson. However, with drugs such as the MTP inhibitor lomitapide, a role has been found for utilization in patients with homozygous familial hypercholesterolemia. While these emerging agents have proven their efficacy with regard to positively lowering LDL-c, additional research should help to further explore the safety of these agents and define the effect of these agents on clinical outcomes, such as cardiovascular event rates and mortality.
Compliance with Ethics Guidelines Conflict of Interest Dr. Michael J. Wilkinson and Dr. Michael H. Davidson both reported no potential conflicts of interest relevant to this article. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.
2.
3.
4.
5.
Goldberg AC, Hopkins PN, Toth PP, et al. 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 Lipid. 2011;5:133–40. National Institute for Health and Care Excellence (NICE). 2008. Familial Hypercholesterolaemia (CG71). (Accessed September 11, 2013, at http:// www.nice.org.uk/cg71.) Reiner Z et al. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J. 2011;32:1769–818. Cuchel M, Rader DJ. Microsomal transfer protein inhibition in humans. Curr Opin Lipidol. 2013;24:246–50. Cuchel M, Bloedon LT, Szapary PO, Kolansy DM, Wolfe ML, Sarkis A, et al. Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia. N Engl J Med. 2007;356:148–56.
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Cuchel M, Meagher EA, du Toit Theron H, Blom DJ, Marais AD, Hegele RA, 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;381:40–6. This study showed that lomitapide, a microsomal triglyceride transfer protein inhibitor, produces significant reductions in LDL cholesterol in patients with homozygous familial hypercholesterolemia, and found that elevations in transaminase levels could be corrected with dose reduction or temporary cessation of the medication. These findings help to establish a role for the use of lomitapide in clinical practice, and provide guidance for addressing the potential side effect of transaminase elevation. 7. Hovingh GK, Davidson MH, Kastelein JJ, O'Connor AM. Diagnosis and treatment of familial hypercholesterolaemia. Eur Heart J. 2013;34:962–71. 8.•• Raal FJ, Santos RD, Blom DJ, Marais AD, Charng M, Cromwell WC, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous famililal hypercholesterolaemia: a randomised,
Recent Developments in the Treatment of Familial Hypercholesterolemia Wilkinson and Davidson double-blind, placebo-controlled trial. Lancet. 2010;375:998–1006. This study demonstrated that mipomersen, an apolipoprotein B synthesis inhibitor, has beneficial effects on the lipid profile of patients with homozygous familial hypercholesterolemia, including a reduction in LDL cholesterol, and that it is generally safe to use. 9. Akdim F, Visser ME, Tribble DL, et al. Effect of mipomersen, an apolipoprotein B synthesis inhibitor, on low-density lipoprotein cholesterol in patients with familial hypercholesterolemia. Am J Cardiol. 2010;105:1413–9. 10. Barter PJ, Caulfield, M., Eriksson, M., Grundy, S. M., Kastelein, J. J. P., Komajda, M., Lopez-Sendon, J., Mosca, L., Tardif, J., Waters, D. D., Shear, C. L., Revkin, J. H., Buhr, K. A., Fisher, M. R., Tall, A. R., and B. Brewer Effects of Torcetrapib in Patients at High Risk for Coronary Events. N Engl J Med 2007;357. 11. Kastelein JJP, van Leuven S. I., Burgess, L., Evans, G. W., Kuivenhoven, J. A., Barter, P. J., Revkin, J. H., Grobbee, D. E., Riley, W. A., Shear, C. L., Duggan, W. T., and M. L. Bots. Effect of Torcetrapib on Carotid Atherosclerosis in Familial Hypercholesterolemia. N Engl J Med 2007;356. 12. Cannon CP, Shah, S., Dansky, H. M., Davidson, M., Brinton, E. A., Gotto, A. M., Stepanavage, M., Xueyu Liu, S., Gibbons, P., Ashraf, T. B., Zafarino, J., Mitchel, Y., Barter, P. Safety of Anacetrapib in Patients with or at High Risk for Coronary Heart Disease. N Engl J Med 2010;363. 13. Davidson MH. Emerging low-density lipoprotein therapies: Targeting PCSK9 for low-density lipoprotein reduction. Journal of Clinical Lipidology. 2013;7:S11–5. 14. Cohen JC, Boerwinkle, E., Mosley, T. H., and H. H. Hobbs. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006;354.
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Stein EA, Mellis, S., Yancopoulos, G. D., Stahl, N., Logan, D., Smith, W. B., Lisbon, E., Gutierrez, M., Webb, C., Wu, R., Du, Y., Kranz, T., Gasparino, E., and G. D. Swergold. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N Engl J Med 2012;366. 16.• McKenney JM, Koren MJ, Kereiakes DJ, Hanotin C, Ferrand AC, Stein EA. Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/ REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. J Am Coll Cardiol. 2012;59:2344–53. This study showed that SAR236553, a monoclonal antibody against PCSK9, was generally well-tolerated and reduced LDL cholesterol in a dose and frequency dependent manner in patients on atorvastatin, but with baseline LDL cholesterol levels still ≥100 mg/dl. Although this was not a study of the treatment of familial hypercholesterolemia, the significance of these findings suggests that antibodies against PCSK9 should be tested further and considered among the potential emerging therapies for familial hypercholesterolemia. 17. Koren MJ, Scott R, Kim JB, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo-controlled, phase 2 study. Lancet. 2012;380:1995–2006. 18. Giugliano RP, Desai NR, Kohli P, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase 2 study. Lancet. 2012;380:2007–17.
Prevention (L Sperling, Section Editor)
Recent Developments in the Treatment of Familial Hypercholesterolemia: A Review of Several New Drug Classes Michael J. Wilkinson, MD Michael H. Davidson, MD* Address *Department of Medicine, University of Chicago Medicine, 150 E. Huron Street, Suite 900, Chicago, IL 60611, USA Email: [email protected]
Published online: 13 November 2013 * Springer Science+Business Media New York 2013
Keywords Familial hypercholesterolemia I Hyperlipidemia I Low-density lipoprotein cholesterol (LDL-C) I Prevention I Lipidology I Microsomal trigylceride transfer protein (MTP) inhibitor I Apolipoprotein B synthesis inhibitior I Cholesterol ester transfer protein (CETP) inhibitor I Pro-protein convertase subtilisin/kexin 9 (PCSK9) inhibitor
Opinion statement Familial hypercholesterolemia is a genetic disorder of the low-density lipoprotein cholesterol (LDL-c) receptor leading to severe elevations in plasma levels of LDL-c which results in premature atherosclerosis and cardiovascular events. Statins, ezetimibe, and bile acid sequestrants significantly lower LDL-c levels in these patients and subsequently markedly improve survival; however, even with these interventions LDL-c goals often are not met. Several new drug classes are in development and have the potential to make reaching these cholesterol goals easier. In this article we review the most recent trials of several classes of drugs with the potential to change the future of familial hypercholesterolemia management: microsomal triglyceride transfer protein (MTP) inhibitors, apolipoprotein B synthesis inhibitors (mipomersen), cholesterol ester transfer protein (CETP) inhibitors and inhibitors of pro-protein convertase subtilisin/kexin 9 (PCSK9). Each class has shown promise with regard to their effects on the lipid profile. However, the potential side-effects of each drug are also being determined and have limited the development of certain agents. Therefore, the long-term effects of these drug classes, both in terms of side-effects and their effect on clinical outcomes such as cardiovascular events and mortality, continue to be determined.
Introduction Familial hypercholesterolemia (FH) is an autosomal dominant disorder, either heterozygous or homozy-
gous, that results from defects in genes associated with lipid metabolism. The mutations of the low-density li-
Recent Developments in the Treatment of Familial Hypercholesterolemia Wilkinson and Davidson poprotein cholesterol (LDL-c) receptor that lead to the development of familial hypercholesterolemia are diverse and impact the severity of the disease. The disease is characterized by premature atherosclerosis and associated events, such as premature coronary artery disease and myocardial ischemia (Figure 1). Patients with familial hypercholesterolemia are generally not adequately responsive to diet and lifestyle modification, and therefore statins represent the backbone of pharmacotherapy. Other lipid-lowering agents, such as bile-acid sequestrants and ezetimibe, have also been used. Treatment goals include a reduction of LDL-c by 50 % from baseline [1, 2], an LDL-c level G ~100 mg/dL, or an LDL-c level G ~70 mg/dL for those with known CVD [1, 3]. When LDL-c goals cannot be met, attempts should be made to achieve the lowest possible LDL-c level without treatment side effects [3]. Unfortunately, given the severity of LDL-c elevation in this disease, as well as the sometimes limited responses to therapy, LDL-c targets are frequently not
697
met with currently available therapies. Patients with homozygous familial hypercholesterolemia (hoFH) have very limited LDL receptor activity and are therefore poorly responsive to existing drug therapy. Therefore, there is a need to develop additional pharmacologic agents for the treatment of familial hypercholesterolemia. Several drug classes are emerging that appear to have great potential to help improve lipid profiles, and thereby cardiovascular disease risk, in patients with hypercholesterolemia. While not all trials of these agents have included patients with familial hypercholesterolemia, the results in these instances are likely largely applicable to the FH population. In this review, we will present each of these drug classes and the recent studies of their effect on lipid levels, particularly LDL-c. The classes of drugs which we will review are: microsomal triglyceride transfer protein (MTP) inhibitors, apolipoprotein B synthesis inhibitors (mipomersen), cholesterol ester transfer protein (CETP) inhibitors and inhibitors of pro-protein convertase subtilisin/kexin 9 (PCSK9).
Microsomal transfer protein (MTP) inhibitors Microsomal transfer protein is critical for the formation and secretion of apolipoprotein B (apoB) containing lipoproteins from cells of the liver and intestine. Mutations in the gene for microsomal transfer protein lead to a rare, autosomal recessive condition known as abetalipoproteinemia. In this disorder, apoB containing lipoproteins that would otherwise arise from the liver and intestine are not present in the bloodstream, including VLDL, the precursor to LDL. Inhibiting MTP through pharmacotherapy was therefore pursued with the hope of developing a way of decreasing circulating VLDL Figure 1. Patients with familial hypercholesterolemia (FH) have an autosomal dominant mutation in the LDL receptor gene resulting in severe elevations of LDL-c. As shown in this figure, tendon xanthomas are one clinical finding associated with high circulating lipid levels in patients with FH.
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Prevention (L Sperling, Section Editor) and LDL, with an ultimate goal of reducing cardiovascular risk [4]. Early studies of MTP inhibitors, such as implitapide, were found to reduce LDL-c. However, further development of most of these drugs was discontinued due to concerns related to GI side-effects and hepatic fat accumulation. An MTP inhibitor called lomitapide has therefore become the only MTP inhibitor to be developed beyond a phase 2 clinical trial [4]. BMS-201038, later called lomitapide, was tested in a proof of concept study in patients with homozygous familial hypercholesterolemia [5]. This study, by Cuchel et al. in 2007, enrolled six patients with homozygous familial hypercholesterolemia. All other lipid agents were held, including apheresis. Dose escalation was pursued to the highest dose, four weeks per dose. All patients were found to tolerate the highest dose and treatment at the highest dose led to LDL-c being reduced by 50.9 % and apolipoprotein B levels being reduced by 55.6 %, from baseline. The frequency and severity of side-effects were variable but included increased stool frequency (associated with eating a high fat meal), elevated transaminases and increased accumulation of liver fat. Liver fat was monitored with MRI of the liver at baseline, after each 4 week period on a particular dose, and 4 weeks after discontinuing the drug. More severe transaminase elevations and accumulation of hepatic fat were potentially confounded by a patient with hypertriglyceridemia and another patient who admitted to significant alcohol use during the study. There was no significant change in HDL-c, apolipoprotein A-I or Lp(a) lipoprotein [5]. Based on the positive effects on LDL-c and apoB in this study, as well as the relatively limited adverse effects compared with prior studies of MTP inhibitors, lomitapide would be developed further. Cuchel et al. carried out a phase 3 study of lomitapide involving 29 patients with homozygous familial hypercholesterolemia from multiple centers and four countries. On lomitapide, the dose was escalated up to 60 mg per day, and the effect on LDL-c was measured at 26 weeks (efficacy phase), week 56, and week 78 (weeks 26–78 were considered the safety phase). The mean LDL-c was decreased by 50 % from baseline at week 26. At 56 weeks LDL-c continued to be reduced at 44 % from baseline, and at week 78 LDL-c was reduced 38 % from baseline (Fig. 2). The most common symptoms were GI related. Ten patients experienced elevated levels of AST, ALT or both to greater than three times the upper limit of normal. Only four patients had transaminase levels that reached 95 times the upper limit of normal which resolved with decreasing the drug dose or temporarily stopping the medication. Three of these patients admitted to having consumed alcohol at levels higher than allowed by the protocol. Patients continued other lipid-lowering therapies during the trial, including apheresis. Mean hepatic fat was elevated above baseline in the patients (20 total) who were able to undergo NMRS (nuclear magnetic resonance spectroscopy) [6••]. Based on these additional findings, lomitapide has been approved as an orphan drug in the treatment of homozygous familial hypercholesterolemia. Lomitapide is therefore an effective LDL-c lowering agent for patients with FH that do not respond adequately to existing therapies and clinical trials have demonstrated that the initiation of very low doses with gradual titration of the dose generally results in tolerability and liver safety [5, 6••]. Even so, the long term health consequences of mild to moderate hepatic steatosis are uncertain and therefore continued monitoring for potential safety issues is important.
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Figure 2. In a long-term efficacy study in patients with homozygous familial hypercholesterolemia, lomitapide with gradual dose titration significantly reduced LDL-c by approximately 40 % with a reasonable safety and tolerability profile.
Apo-B synthesis inhibitors (mipomersen) Another target of recently tested lipid-lowering drugs is apolipoprotein B synthesis. Mipomersen is an oligonucleotide antisense inhibitor that targets the apoB mRNA. Mipomersen binds to the mRNA sequence which then results in the degradation of the mRNA, preventing translation of the mRNA and thereby inhibiting production of apoB. Apolipoprotein B is a critical component of the VLDL lipoprotein and without this protein VLDL levels, and thereby LDL levels, would be expected to fall [7, 8••]. Raal and colleagues completed a randomized, double-blind, placebo controlled phase 3 study of mipomersen. A total of 34 patients with homozygous familial hypercholesterolemia received mipomersen and 17 received placebo. Mipomersen was given at a 200-mg dose, subcutaneously, once a week. There was a 26-week treatment period. The mean percent change in LDL-c with mipomersen was -24.7 % (versus placebo, which produced a -3.3 % change). Patients were continued on other lipid-lowering agents. Mipomersen was also associated with a significant reduction in non-HDL cholesterol, VLDL, apolipoprotein B, and lipoprotein(a). Mipomersen was also associated with an elevation in HDL cholesterol (p=0.0326) [8••]. The most common adverse reaction was localized reaction at the injection site. Four patients experienced significant elevations in ALT to three or more times the upper limit of normal. MRI was used to measure hepatic fat at baseline for all participants (unless contraindicated). MRI was repeated if
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Prevention (L Sperling, Section Editor) ALT increased to three times or more above the upper limit of normal. A total of four patients met criteria for MRI, and three underwent repeat scan. Of these three, only one had an elevation in hepatic fat content [8••]. Another study of mipomersen was performed by Akdim and colleagues. It was similar to the Raal study, but was a phase 2 study and enrolled patients with heterozygous familial hypercholesterolemia. It was a randomized, double-blind, placebo-controlled, dose escalation study. There were 44 participants, and a range of mipomersen doses were tested, from 50 mg to 300 mg during a six-week treatment period. The primary end point was LDLc reduction from baseline. Other lipid lowering agents were continued during the study. At the highest doses of mipomersen, LDL-c was significantly reduced from baseline by 21–34 %. At the highest doses of mipomersen, apolipoprotein B, non-HDL, and total cholesterol levels were also significantly reduced [9]. Local injection site reaction was the most common adverse event. Significant transaminase elevation (9 or equal to 3 times upper limit of normal) occurred in only four patients receiving treatment. Three patients had more persistent transaminase elevations, and these patients were receiving the highest-dose mipomersen. Upon evaluation with CT scan, two had a steatotic liver and one had hepatomegaly without steatosis; there were no baseline scans to compare to so any kind of causal relationship was not clear [9].
Cholesterol ester transfer protein (CETP) inhibitors CETP (cholesterol ester transfer protein) is an enzyme, bound to HDL, that facilitates transfer of cholesterol esters from HDL to pro-atherogenic lipoproteins such as those containing ApoB. Therefore, inhibition of this protein might be expected to raise HDL-c levels. Based on the anti-atherogenic role of HDL, a drug which causes HDL-c levels to increase might reduce cardiovascular risk [7]. Early on in the development of CETP inhibitors, Barter and colleagues performed a randomized, double-blind study of a CETP inhibitor called torcetrapib. The team enrolled 15,067 patients and tested torcetrapib and atorvastatin versus atorvastatin alone in patients with known cardiovascular disease or type 2 diabetes. Primary outcome was time to first major cardiovascular event (death from CHD, non-fatal MI, stroke, or hospitalization for UA). At 12 months in the torcetrapib group, HDL-c had increased 72.1 %, and LDL-c had decreased 24.9 %. However, systolic blood pressure had also increased, serum potassium had decreased, and serum sodium, bicarbonate and aldosterone had increased. There was also a significantly increased risk of cardiovascular events and death from any cause. Therefore, the trial was discontinued early. The authors speculate that the higher rate of adverse cardiovascular events and death from any cause might be either related to an off-target effect of torcetrapib (such as effects related to increased aldosterone levels), or an adverse effect of CETP inhibition (possibly leading to abnormal and detrimental HDL function) [10]. Another early study of torcetrapib enrolled 850 patients with heterozygous familial hypercholesterolemia and measured carotid intima-media thickness at baseline and then after two years of torcetrapib plus atorvastatin versus atorvastatin alone [11].
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Patients receiving torcetrapib had higher average HDL levels as well as a lower average LDL level compared to the atorvastatin-only group; however, annualized change in maximum carotid intima-media thickness was not significantly different between the two groups. Annualized change in mean carotid intima-media thickness for the common carotid segment was in fact increased in the torcetrapib group, but was decreased in the atorvastatin alone group. Authors suggest that this discrepancy may be related to the increase in systolic blood pressure seen in the torcetrapib group [11]. More recently, Cannon and colleagues tested a different CETP inhibitor (anacetrapib) in a randomized, double-blind, placebo-controlled trial in patients on statin therapy with CHD or who were considered to be at high risk for CHD. Anacetrapib was tested against placebo for 18 months. The primary end point was LDL-c at 24 weeks, as well as determining the safety and side-effects of anacetrapib [12]. At 24 weeks, LDL-c was reduced in the anacetrapib group 39.8 % beyond the reduction seen in the placebo group. HDL-c also significantly increased in the anacetrapib group (a rise 138.1 % beyond that seen in the placebo group). Importantly, anacetrapib was not associated with changes in blood pressure, electrolytes or aldosterone levels and the rate of cardiovascular events was not significantly different between the two groups. The authors suggest that the HDL particles in patients treated with anacetrapib (and torcetrapib) actually have a normal to enhanced ability to facilitate off-loading of cholesterol from macrophages (observed in vitro) [12].
Pro-protein convertase subtilisin/kexin 9 (PCSK9) inhibitors Pro-protein convertase subtilisin/kexin 9 (PCSK9) is a protein which helps to regulate low density lipoprotein receptor (LDL-R) expression on hepatocytes. As part of LDL-R mediated cholesterol metabolism, once bound to ApoB (as part of an ApoB associated lipoprotein), the LDL-R is internalized into the hepatocyte. The ApoB lipoprotein is degraded and the LDL-R either returns to the surface of the hepatocyte to bind additional lipoprotein or is targeted for lysosomal degradation by PCSK9 [13]. Therefore, it might be expected that a reduction in PCSK9 activity would lead to increased LDL-R expression on the hepatocyte, and thereby promote removal of pro-atherogenic lipoproteins from the circulation (Fig. 3). Indeed, early studies have shown that naturally occurring sequence variations in PCSK9 are associated with reduced LDL levels and are also linked with reductions in the risk of CHD [14]. There have therefore been several recent studies testing agents which inhibit PCSK9. Stein and colleagues recently described three phase 1 studies of REGN727/SAR236553 (REGN727), a monoclonal antibody against PCSK9. Two were randomized, single ascending-dose studies of REGN727 (intravenous or subcutaneous administration) in healthy volunteers with a serum LDL-c of 9100 mg/dl. The third study was a randomized, placebo-controlled trial of various doses of REGN727 in patients with heterozygous familial hypercholesterolemia and in patients with non-familial hypercholesterol-
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Figure 3. The activity of an antibody directed against pro-protein convertase subtilisin/kexin 9 (PCSK9) reduces PCSK9 mediated degradation of internalized low-density lipoprotein receptor (LDL-R), thereby promoting the return of LDL-R to the cell surface. The subsequent increase in LDL-R expression would be expected to increase removal of LDL particles from the circulation.
emia (both groups were also on atorvastatin); the primary outcome was frequency of adverse events with effects on lipids as a secondary outcome. There was also a group in this part of the study with non-familial hypercholesterolemia whose participants had LDL 9130 mg/dl and were treated with modified diet rather than atorvastatin. PCSK9 was well-tolerated and associated with reductions in LDL-c, as well as reductions in total cholesterol, non-HDL cholesterol, apolipoprotein B, and Lp(a) (however, the reduction in Lp(a) was not always significant) [15]. McKenney and colleagues performed a double-blind, placebo-controlled phase 2 trial intended to measure the effect of REGN727/SAR236553 (SAR236553) versus placebo on LDL cholesterol after 12 weeks of treatment in 183 patients already taking a statin but with baseline levels of LDL that were still greater than or equal to 100 mg/dl [16•]. They found that SAR236553 reduced LDL-c levels in a dose and frequency dependent manner. Specifically, with doses of 50, 100, and 150 mg administered every 2 weeks, the mean reduction of LDL from baseline was 40 %, 64 %, and 72 %, respectively (Fig. 4). When administered at doses of 200 and 300 mg every 4 weeks, LDL-c was reduced 43 % and 48 %, respectively. Non-HDL cholesterol, Lp(a), and apolipoprotein B were also reduced. In terms of side-effects SAR236553 was generally well-tolerated; however, one patient did experience leukocytoclastic vasculitis that may have been related to the study drug. Local injection site reaction was the most common adverse event [16•].
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Figure 4. Change in LDL-C from baseline in a study of pro-protein convertase subtilisin/kexin 9 (PCSK9) inhibitor SAR236553 in a double-blind, placebo-controlled phase 2 trial by McKenney and colleagues [16•].
AMG 145 is another monoclonal antibody directed against PCSK9, and is currently in phase 1 and 2 trials. Two recent phase 2 trials have found AMG 145 to reduce LDL-c. In one trial, in which AMG 145 was administered in patients with hypercholesterolemia not on other lipid-lowering agents, LDL was significantly reduced by approximately 40–50 % in all dose groups [17]. In another phase 2 trial involving patients with hypercholesterolemia who were also on a statin (with or without ezetimibe), LDL cholesterol was reduced by 42–66 % in the groups receiving AMG 145 every 2 weeks, and by 42-50 % in the groups receiving the drug every 4 weeks [18]. In both studies, the drug was generally well tolerated [13].
Conclusion Familial hypercholesterolemia is a genetic disease that is difficult to treat with currently available pharmacotherapies, particularly in patients with the homozygous form of the disease. LDL-c goals are often not met, despite dietary and lifestyle modifications and use of high dose statins and other currently available therapies such as ezetimibe and bile-acid sequestrants. Therefore, the development of agents such as MTP inhibitors, apolipoprotein B synthesis inhibitors (mipomersen), CETP inhibitors, and PCSK9 inhibitors holds great promise for the future of lipid-lowering and cardiovascular risk reduction in this population. All of the agents described herein have proven their effectiveness at altering the lipid profile in a beneficial way, by lowering levels of pro-atherogenic mol-
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Prevention (L Sperling, Section Editor) ecules, such as LDL, and sometimes by increasing levels of anti-atherogenic molecules, such as HDL. Safety concerns have limited the development of certain classes of drugs, such as the MTP inhibitors and mipomerson. However, with drugs such as the MTP inhibitor lomitapide, a role has been found for utilization in patients with homozygous familial hypercholesterolemia. While these emerging agents have proven their efficacy with regard to positively lowering LDL-c, additional research should help to further explore the safety of these agents and define the effect of these agents on clinical outcomes, such as cardiovascular event rates and mortality.
Compliance with Ethics Guidelines Conflict of Interest Dr. Michael J. Wilkinson and Dr. Michael H. Davidson both reported no potential conflicts of interest relevant to this article. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.
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Goldberg AC, Hopkins PN, Toth PP, et al. 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 Lipid. 2011;5:133–40. National Institute for Health and Care Excellence (NICE). 2008. Familial Hypercholesterolaemia (CG71). (Accessed September 11, 2013, at http:// www.nice.org.uk/cg71.) Reiner Z et al. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J. 2011;32:1769–818. Cuchel M, Rader DJ. Microsomal transfer protein inhibition in humans. Curr Opin Lipidol. 2013;24:246–50. Cuchel M, Bloedon LT, Szapary PO, Kolansy DM, Wolfe ML, Sarkis A, et al. Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia. N Engl J Med. 2007;356:148–56.
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Cuchel M, Meagher EA, du Toit Theron H, Blom DJ, Marais AD, Hegele RA, 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;381:40–6. This study showed that lomitapide, a microsomal triglyceride transfer protein inhibitor, produces significant reductions in LDL cholesterol in patients with homozygous familial hypercholesterolemia, and found that elevations in transaminase levels could be corrected with dose reduction or temporary cessation of the medication. These findings help to establish a role for the use of lomitapide in clinical practice, and provide guidance for addressing the potential side effect of transaminase elevation. 7. Hovingh GK, Davidson MH, Kastelein JJ, O'Connor AM. Diagnosis and treatment of familial hypercholesterolaemia. Eur Heart J. 2013;34:962–71. 8.•• Raal FJ, Santos RD, Blom DJ, Marais AD, Charng M, Cromwell WC, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous famililal hypercholesterolaemia: a randomised,
Recent Developments in the Treatment of Familial Hypercholesterolemia Wilkinson and Davidson double-blind, placebo-controlled trial. Lancet. 2010;375:998–1006. This study demonstrated that mipomersen, an apolipoprotein B synthesis inhibitor, has beneficial effects on the lipid profile of patients with homozygous familial hypercholesterolemia, including a reduction in LDL cholesterol, and that it is generally safe to use. 9. Akdim F, Visser ME, Tribble DL, et al. Effect of mipomersen, an apolipoprotein B synthesis inhibitor, on low-density lipoprotein cholesterol in patients with familial hypercholesterolemia. Am J Cardiol. 2010;105:1413–9. 10. Barter PJ, Caulfield, M., Eriksson, M., Grundy, S. M., Kastelein, J. J. P., Komajda, M., Lopez-Sendon, J., Mosca, L., Tardif, J., Waters, D. D., Shear, C. L., Revkin, J. H., Buhr, K. A., Fisher, M. R., Tall, A. R., and B. Brewer Effects of Torcetrapib in Patients at High Risk for Coronary Events. N Engl J Med 2007;357. 11. Kastelein JJP, van Leuven S. I., Burgess, L., Evans, G. W., Kuivenhoven, J. A., Barter, P. J., Revkin, J. H., Grobbee, D. E., Riley, W. A., Shear, C. L., Duggan, W. T., and M. L. Bots. Effect of Torcetrapib on Carotid Atherosclerosis in Familial Hypercholesterolemia. N Engl J Med 2007;356. 12. Cannon CP, Shah, S., Dansky, H. M., Davidson, M., Brinton, E. A., Gotto, A. M., Stepanavage, M., Xueyu Liu, S., Gibbons, P., Ashraf, T. B., Zafarino, J., Mitchel, Y., Barter, P. Safety of Anacetrapib in Patients with or at High Risk for Coronary Heart Disease. N Engl J Med 2010;363. 13. Davidson MH. Emerging low-density lipoprotein therapies: Targeting PCSK9 for low-density lipoprotein reduction. Journal of Clinical Lipidology. 2013;7:S11–5. 14. Cohen JC, Boerwinkle, E., Mosley, T. H., and H. H. Hobbs. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006;354.
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Stein EA, Mellis, S., Yancopoulos, G. D., Stahl, N., Logan, D., Smith, W. B., Lisbon, E., Gutierrez, M., Webb, C., Wu, R., Du, Y., Kranz, T., Gasparino, E., and G. D. Swergold. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N Engl J Med 2012;366. 16.• McKenney JM, Koren MJ, Kereiakes DJ, Hanotin C, Ferrand AC, Stein EA. Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/ REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. J Am Coll Cardiol. 2012;59:2344–53. This study showed that SAR236553, a monoclonal antibody against PCSK9, was generally well-tolerated and reduced LDL cholesterol in a dose and frequency dependent manner in patients on atorvastatin, but with baseline LDL cholesterol levels still ≥100 mg/dl. Although this was not a study of the treatment of familial hypercholesterolemia, the significance of these findings suggests that antibodies against PCSK9 should be tested further and considered among the potential emerging therapies for familial hypercholesterolemia. 17. Koren MJ, Scott R, Kim JB, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo-controlled, phase 2 study. Lancet. 2012;380:1995–2006. 18. Giugliano RP, Desai NR, Kohli P, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase 2 study. Lancet. 2012;380:2007–17.
