- Email: [email protected]
New lipid therapies: PCSK9 inhibitors
Journal of Clinical and Translational Endocrinology: Case Reports 2 (2016) 23–26
Contents lists available at ScienceDirect
Journal of Clinical and Translational Endocrinology: Case Reports j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / j e c r
New lipid therapies: PCSK9 inhibitors Farah Meah, DO a,*, Arshi Basit, MD b, Alaleh Mazhari, DO b, Mary Ann Emanuele, MD b, Nicholas Emanuele, MD a a b
Edward Hines Junior VA Medical Center, IL, USA Loyola University Medical Center, IL, USA
A R T I C L E
I N F O
Article history: Received 29 June 2016 Accepted 25 July 2016
Keywords: LDL LDL receptor Atherothrombosis Familial hyperlipidemia Alirocumab Evolocumab
A B S T R A C T
Pharmacologic therapy reduces cardiovascular risk in a variety of primary and secondary prevention clinical situations in addition to lifestyle modifications. Low density lipoprotein cholesterol (LDL-C) is a key mediator of atherogenesis. Most cholesterol guidelines propose specific LDL-C while recently the ACC/ AHA recommends statin therapy without a specific LDL-C target. Proprotein convertase subtilisin kexin 9 (PCSK9) is a serine protease that leads to LDL receptor degradation. The decreased availability of LDL receptors results in decreased clearance and an increase of circulating LDL-C particles. Monoclonal antibodies that inhibit PCSK9 (PCSK9 abs) reduce LDL-C levels and may be especially helpful in familial hypercholesterolemia and statin-intolerant patients. PCSK9 inhibition is an exciting and promising new therapy for protection against macrovascular events. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).
Abundant data indicate that, in addition to lifestyle modification, pharmacologic lipid-lowering therapy reduces cardiovascular risk in a variety of primary and secondary prevention clinical situations. Though the majority of the randomized controlled trials involve statins, there is some data supporting the efficacy of niacin and gemfibrozil in these situations [1]. Over the years there have been different recommendations regarding treatment of dyslipidemia. Most of the guidelines have proposed specific low density lipoprotein cholesterol (LDL-C) targets [2–4]. Recently, the American College of Cardiology/American Heart Association (ACC/AHA) recommended the use of specific statins for treatment of dyslipidemia without aiming for a specific LDL-C target [1]. While the ACC/AHA did not target a certain LDL-C level, we do not think that this was meant to imply that LDL-C was not important or not atherogenic, just that the many studies showing statin benefit did not show the benefit of statin titration to a certain LDL-C level. Indeed, there is an excellent physiologic basis for believing that LDL-C is very atherogenic and, logically, that lowering LDL-C as much as possible would have incremental benefit. The major carrier of cholesterol in most humans is LDL-C. LDL-C particles are variable in size and contain a hydrophobic cholesterol core lined by a phospholipid coat containing the lipoprotein apolipoprotein B (apoB). Atherosclerotic plaque starts with LDL-C infiltration into arterial walls where LDL-C is able to bind to glycosaminoglycans followed by oxi-
* Corresponding author. E-mail address: [email protected] (F. Meah).
dative processes which lead to a modified apoB recognized and internalized by receptor-mediated macrophage endocytosis. These macrophages transform into cholesterol-laden foam cells that secrete cytokines leading to inflammation, smooth muscle proliferation, and plaque formation within the arterial wall [5]. A fibrous cap forms a barrier between prothrombotic material on the surface of the plaque and platelets which can facilitate thrombus formation [6]. Atherothrombosis can lead to arterial occlusion and end organ damage. Most cells express the LDL-C receptor which recognizes the apoB portion of LDL-C and mediates LDL-C clearance from the circulation [7]. Proprotein convertase subtilisin kexin 9 (PCSK9) is a serine protease produced predominantly in the liver that leads to the degradation of hepatocyte LDL-C receptors and subsequently to increased circulating LDL-C levels. It circulates in three forms: a PCSK9 monomer, LDL-C-bound PCSK9, and a 55 kDa furin-cleaved inactive fragment [8]. The transcription factor sterol regulatory element– binding protein 2 (SREBP2) regulates LDL-C receptor expression and increases PCSK9 synthesis. PCSK9 binds to an epidermal growth factor (EGF)–like repeat located at the extracellular domain of the LDL-C receptor and is subsequently internalized and prevents the recycling of LDL-C receptors to the cell surface. As displayed in Figure 1, the resultant decrease in the number of LDL-C receptors by means of lysosomal degradation leads to an increase of LDL-C particles in circulation which contributes to the generation of atherosclerotic plaque. Sequence variations that cause decreased activity of the PCSK9 gene leading to decreased serum LDL-C is associated with coronary heart disease risk reduction [9].
2214-6245/Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). http://dx.doi.org/10.1016/j.jecr.2016.07.001
24
F. Meah et al. / Journal of Clinical and Translational Endocrinology: Case Reports 2 (2016) 23–26
Figure 1. PCSK9 plays an important role in regulating the number of LDL-C receptors located at the hepatocyte cell surface. In the absence of PCSK9, the LDL particle binds to the LDL receptor followed by internalization. The LDL particle is targeted for degradation by the lysosome and the LDL receptor is recycled to the cell surface. In the presence of PCSK9, PCSK9 binds to the LDL particle-LDL receptor complex. The LDL receptor bound to PCSK9 is unable to recycle to the cell surface and is subject to degradation. A decrease in LDL receptors results in an increase of serum LDL particles.
Therapies that lower circulating PCSK9 levels significantly lower LDL-C levels. This category of lipid lowering therapy offers an important option not previously available and has demonstrated significant efficacy in lowering LDL-C and a large meta-analysis has suggested that this lowering might decrease adverse CV outcomes. Monoclonal antibodies that inhibit PCSK9 (anti-PCSK9 abs) reduce LDL-C by as much as 70% in a dose dependent manner. They have been shown to lower LDL-C by as much as 60% in statin treated patients [10]. A comprehensive meta-analysis of 24 randomized trials (n = 10,159) encompassing a large cohort of clinical situations including familial hypercholesterolemia,
statin-intolerant patients, and those not on any statin therapy found that anti-PCSK9 abs lowered all-cause mortality (odds ratio [OR] 0.45, 95% CI 0.23–0.86), CV mortality (OR 0.50, CI 0.23–1.10), and MI (OR 0.49, CI 0.26–0.93) [11]. The benefits of anti-PCSK9 abs appear to be similar across a wide range of clinical situations and CV risks similar to what has been noted with statin therapy. Therapy with anti-PCSK9 abs appears to result in additional reductions in CV risk even in patients already on intensive or maximal statin therapy. Table 1 displays similarities and differences between the current FDA approved PCSK9 inhibitors in select placebo controlled trials.
Table 1 Comparison of the FDA-approved PCSK9 Inhibitors
Monoclonal Ab Characteristics
Indications for Use LDL-C Reduction Trial Duration Biweekly Therapy Percentage (%) Dosage and Administration
Cost Adverse Effects
Alirocumab
Evolocumab
100% Human 4th generation IgG1 HeFH
100% Human 4th gen IgG2 HoFH, HeFH
Odyssey Long-Term Mendel-2 24 weeks 12 weeks Alirocumab Placebo Evolocumab Placebo −61.0 0.8 −57.0 0.1 1. Injection: Single-dose pre-filled pen/syringe 1. Injection: 140 mg/mL solution in a single-use prefilled syringe 75 mg/mL 2. Injection: 140 mg/mL solution in a single-use prefilled SureClick® autoinjector 150 mg/mL To administer the 420 mg dose, give three 140 mg/dL injections consecutively within 30 minutes ~ $15,000/year ~$14,500/year Nasopharyngitis, Bronchitis, Sinusitis, Influenza, Cough, Myalgia, Urinary tract infections, Diarrhea, Muscle spasms, Musculoskeletal pain, Injection site reactions, Neurocognitive effects
HeFH = Heterozygous Familial Hypercholesterolemia; HoFH = Homozygous Familial Hypercholesterolemia.
F. Meah et al. / Journal of Clinical and Translational Endocrinology: Case Reports 2 (2016) 23–26
Alirocumab trials Alirocumab (Praluent) is a human monoclonal antibody against PCSK9. In the Efficacy and Safety of Alirocumab SAR236553 (REGN727) Versus Ezetimibe in Patients with Hypercholesterolemia (ODYSSEY MONO) study, alirocumab was evaluated in 103 patients with hypercholesterolemia who were not on lipid-lowering therapy but who had a 1–5% 10-year risk of CV death as assessed by the European Systematic Coronary Risk Estimation. The patients were randomized to ezetimibe 10 mg daily or alirocumab 75 mg every 2 weeks. The alirocumab dose was titrated up to 150 mg if week 8 LDL-C was ≥70 mg/dL. After 24 weeks, alirocumab reduced LDL-C by 47% compared with 16% with ezetimibe. With alirocumab, levels of apo B and non–HDL-C were reduced by 37% and 41%, respectively. There were no differences in treatment-related adverse events between alirocumab and ezetimibe [12]. In the Study of Alirocumab (REGN727/SAR236553) in Patients with Primary Hypercholesterolemia and Moderate, High, or Very High Cardiovascular Risk who are Intolerant to Statins (ODYSSEY ALTERNATIVE) trial, alirocumab was evaluated in patients with statin intolerance who did not have muscle-related adverse events on screening with subcutaneous or oral placebo. Patients (n = 314) were randomized to alirocumab 75 mg every 2 weeks, ezetimibe 10 mg daily, or atorvastatin 20 mg daily. At 24 weeks of treatment, alirocumab reduced LDL-C by 45% compared with 15% with ezetimibe. Treatment-emergent adverse events were similar in the 2 groups, with rates of skeletal muscle-related events being lower in the alirocumab than in the atorvastatin group [13,14]. The Efficacy and Safety of Alirocumab (SAR236553/REGN727) Versus Ezetimibe on Top of Statin in High Cardiovascular Risk Patients with Hypercholesterolemia (ODYSSEY COMBO) I and II trials tested alirocumab as add-on therapy to maximally tolerated statin in high-CV disease-risk patients with suboptimal cholesterol control. In ODYSSEY COMBO I, patients (n = 316) were randomized to 75 mg every 2 weeks or placebo. After 24 weeks, alirocumab reduced LDL-C by 48% compared with 2% with placebo [15]. In Efficacy and Safety of Alirocumab (SAR236553/REGN727) Versus Ezetimibe on Top of Statin in High Cardiovascular Risk Patients with Hypercholesterolemia (ODYSSEY COMBO II), patients (n = 720) were randomized to 75 mg every 2 weeks or ezetimibe 10 mg daily. After 24 weeks, alirocumab reduced LDL-C by 51% compared with 21% with ezetimibe [16]. The Long-term Safety and Tolerability of Alirocumab (SAR236553/ REGN727) Versus Placebo on Top of Lipid-Modifying Therapy in High Cardiovascular Risk Patients With Hypercholesterolemia (ODYSSEY LONG-TERM) trial evaluated the efficacy and safety of treatment with alirocumab for 78 weeks in patients with heterozygous familial hypercholesterolemia with established CHD or CHD equivalent with LDL-C ≥70 mg/dL on maximal tolerated statin dose (47% of patients were on high-dose statin) or other lipid-lowering therapy. Patients (n = 2341) were randomized to alirocumab 150 mg or placebo every 2 weeks. Alirocumab decreased LDL-C by 61% from baseline at 24 weeks and by 52% at 78 weeks. Reductions in non– HDL-C of 52%, apo B of 54%, and Lp (a) of 26% were observed with alirocumab therapy. In addition to evaluating safety and efficacy, the trial collected data on prespecified adjudicated CV disease outcomes. Notably, a post hoc analysis showed that treatment with alirocumab was associated with a lower rate of major adverse cardiovascular outcomes [17]. In addition to the already completed safety and efficacy trials, there is a large ongoing outcome trial evaluating the impact of PCSK9 inhibition with alirocumab on CVD end points. The ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment with Alirocumab SAR236553 (REGN727; ODYSSEY OUTCOMES) trial will randomize 18,000
25
patients to alirocumab every 2 weeks or placebo who have had recent hospitalization for acute myocardial infarction or unstable angina and are on a background of statin therapy. The primary outcome is time to first occurrence of CHD death, acute myocardial infarction, hospitalization for unstable angina, or ischemic stroke. The estimated study completion date is January 2018 [18]. Evolucumab trials Evolucumab (Repatha) is another human monoclonal antibody against PCSK9. The MENDEL studies in 2012 and 2014 proved the significant reduction in LDL-C by 55–57% from baseline compared to placebo and 38–40% more than ezetimibe with both biweekly and monthly doses of Evolucumab [19,20]. Significant increase in HDL-C and decrease in triglycerides and VLDL-C levels was also observed. Three hundred seven patients intolerant to at least 2 statins were randomized in the GAUSS-2 placebo and ezetimibe controlled study [21]. Similar reduction in LDL-C was noted (55–56%). More than 75% achieved LDL-C less than 100 mg/dL in 12 weeks. The drug was well tolerated with very low incidence of myalgia, 7% and 9% in the weekly and monthly doses respectively. Patients with primary hypercholesterolemia and mixed dyslipidemia on moderate or high intensity statins, when given a trial of evolocumab either biweekly or monthly, showed equal reductions in LDL-C by 65–75% over a 12-week trial, compared to placebo (LAPLACE-2) [22]. The reduction in LDL-C observed was significantly greater (66%) with evolocumab when compared to ezetimibe (24%). About 86–94% of patients achieved LDL-C <70 mg/dL in 12 weeks with evolocumab and background statin therapy, in contrast to 17–62% achieving the same goal in the ezetimibe group. Subsequent to 12 weeks, analysis of effects on other lipids demonstrated 12% and 6–16% reduction in the triglycerides with the biweekly and monthly doses respectively. HDL-C levels were modestly elevated by 5–10% in both dose groups. Evolocumab was well tolerated, with an uncommon incidence of neurocognitive events ≤1% in this study. In January 2015, Lancet published the TESLA Part B (a randomized, double-blinded, placebo controlled, phase 3 trial) [23] conducted at 17 sites in 10 countries (North America, Europe, the Middle East, and South Africa) on 50 patients with homozygous familial hypercholesterolemia (HoFH) ≥12 years of age. After 4 weeks of a stable lipid lowering agent (statin with or without ezetimibe) without receiving apheresis, patients randomized to the evolocumab group (420 mg subcutaneous monthly) significantly reduced the LDL-C at 12 weeks by 30.9% compared to placebo. Upper respiratory tract infections and influenza were the most common adverse events noted in the evolocumab group with no serious adverse events noted. The RUTHERFORD-2, a multicenter randomized 12 week study of 331 participants with heterozygous familial hypercholesterolemia (HeFH) age 18–80 years showed a robust 60% reduction in LDL-C compared to placebo [24]. Nasopharyngitis and musclerelated adverse events were the most commonly reported side effects. The year 2015 also introduced the OSLER studies: OSLER 1 (comprising of patients completing phase 2 trials in 190 centers) and OSLER 2 (comprising of patients completing phase 3 trials in 305 centers); 2 open labeled randomized trials with more than 4000 patients, studied the efficacy and safety of evolocumab in reducing lipids and cardiovascular events [25]. Evolocumab reduced cholesterol levels by 61% in 12 weeks compared to the standard therapy alone, by reducing the pretreatment median of 120 mg/ dL to 48 mg/dL and, sustaining the reduction through 48 weeks. Evolocumab was reported to have nonspecific adverse events (arthralgia, headache, limb pain, and fatigue) and some neurocognitive adverse events like dementia, delirium, confusion, amnesia, attention
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F. Meah et al. / Journal of Clinical and Translational Endocrinology: Case Reports 2 (2016) 23–26
deficits, disturbance in mental thinking and perception, more frequently than the standard therapy group. The cardiovascular benefits are yet to be established. Though the analysis was exploratory, the modest reduction in LDL-C showed consistency with the one-year reduction in cardiovascular events in the OSLER trials. However, larger randomized placebo controlled trials are underway with the intention of providing a more conclusive assessment of the cardiovascular benefit of evolocumab [Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) study] [26]. Evolocumab is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with HeFH or clinical atherosclerotic CV disease and HoFH in conjunction with diet and other lipid-lowering therapies (e.g. statins, ezetimibe, LDL-C apheresis), who require additional lowering of LDL-C. Two dose formulations are available, 140 mg subcutaneous every 2 weeks or 420 mg monthly. Nasopharyngitis, upper respiratory tract infections, injection site reactions, myalgias, headaches and, rarely, neurocognitive effects were among the noted adverse effects. The role of PCSK9 and statin in lowering LDL-C is additive, 70% when combined as compared to 50% when used alone, with maximum lowering effect seen within 2 weeks of therapy [27]. Summary PCSK9 inhibition is an exciting and promising new therapy for protection against macrovascular events. However, for now, use should be restricted to those with familial hypercholesterolemia or patients with clinical atherosclerotic cardiovascular disease, who require additional lowering of LDL-C. Prospective trials examining CV outcomes are underway and the results are eagerly awaited. Conflict of interest The authors declare they have no conflicts of interest. References [1] Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;129(25 Suppl. 2):S1–45. [2] Reiner Z, Catapano AL, De Backer G, Graham I, Taskinen MR, Wiklund O, 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(14):1769– 818. [3] Jellinger PS, Smith DA, Mehta AE, Ganda O, Handelsman Y, Rodbard HW, et al. American Association of Clinical Endocrinologists’ guidelines for management of dyslipidemia and prevention of atherosclerosis. Endocr Pract 2012;18(Suppl. 1):1–78. [4] Standards of medical care in diabetes – 2016: summary of revisions. Diabetes Care 2016;39(Suppl. 1):S4–5. [5] Tabas I, Garcia-Cardena G, Owens GK. Recent insights into the cellular biology of atherosclerosis. J Cell Biol 2015;209(1):13–22. [6] Libby P, Tabas I, Fredman G, Fisher EA. Inflammation and its resolution as determinants of acute coronary syndromes. Circ Res 2014;114(12):1867–79. [7] Goldstein JL, Brown MS. A century of cholesterol and coronaries: from plaques to genes to statins. Cell 2015;161(1):161–72.
[8] Latimer J, Batty JA, Neely DD, Kunadian V. PCSK9 inhibitors in the prevention of cardiovascular disease. J Thromb Thrombolysis 2016;doi:10.1007/s11239016-1364-1. [9] Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006;354(12):1264–72. [10] Roth EM, McKenney JM, Hanotin C, Asset G, Stein EA. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N Engl J Med 2012;367(20):1891–900. [11] Navarese EP, Kolodziejczak M, Schulze V, Gurbel PA, Tantry U, Lin Y, et al. Effects of proprotein convertase Subtilisin/Kexin type 9 antibodies in adults with hypercholesterolemia: a systematic review and meta-analysis. Ann Intern Med 2015;163(1):40–51. [12] Roth EM, Taskinen MR, Ginsberg HN, Kastelein JJ, Colhoun HM, Robinson JG, et al. Monotherapy with the PCSK9 inhibitor alirocumab versus ezetimibe in patients with hypercholesterolemia: results of a 24 week, double-blind, randomized Phase 3 trial. Int J Cardiol 2014;176(1):55–61. [13] Moriarty PM, Jacobson TA, Bruckert E, Thompson PD, Guyton JR, Baccara-Dinet MT, et al. Efficacy and safety of alirocumab, a monoclonal antibody to PCSK9, in statin-intolerant patients: design and rationale of ODYSSEY ALTERNATIVE, a randomized phase 3 trial. J Clin Lipidol 2014;8(6):554–61. [14] Moriarty PMTP, Cannon CP, Guyton JR, Bergeron J, Zieve FJ, Bruckert E, et al. Late-Breaking Clinical Trial Abstracts: ODYSSEY ALTERNATIVE: efficacy and safety of the proprotein convertase subtilisin/kexin type 9 monoclonal antibody, alirocumab, versus ezetimibe, in patients with statin intolerance as defined by a placebo run-in and statin rechallenge arm. Circulation 2014;2105–26. [15] Kereiakes DJ, Robinson JG, Cannon CP, Lorenzato C, Pordy R, Chaudhari U, et al. Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: The ODYSSEY COMBO I study. Am Heart J 2015;169(6): 906–15, e13. [16] Cannon CP, Cariou B, Blom D, McKenney JM, Lorenzato C, Pordy R, et al. Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial. Eur Heart J 2015;36(19):1186– 94. [17] Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372(16):1489–99. [18] ODYSSEY outcomes: evaluation of cardiovascular outcomes after an acute coronary syndrome during treatment with alirocumab.. [19] Koren MJ, Scott R, Kim JB, Knusel B, Liu T, Lei L, 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(9858):1995–2006. [20] Koren MJ, Lundqvist P, Bolognese M, Neutel JM, Monsalvo ML, Yang J, et al. Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab. J Am Coll Cardiol 2014;63(23):2531–40. [21] Stroes E, Colquhoun D, Sullivan D, Civeira F, Rosenson RS, Watts GF, et al. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol 2014;63(23):2541–8. [22] Robinson JG, Nedergaard BS, Rogers WJ, Fialkow J, Neutel JM, Ramstad D, et al. Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial. JAMA 2014;311(18):1870–82. [23] Raal FJ, Honarpour N, Blom DJ, Hovingh GK, Xu F, Scott R, et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet 2015;385(9965):341–50. [24] Raal FJ, Stein EA, Dufour R, Turner T, Civeira F, Burgess L, et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet 2015;385(9965):331–40. [25] Sabatine MS, Giugliano RP, Wiviott SD, Raal FJ, Blom DJ, Robinson J, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372(16):1500–9. [26] Further cardiovascular outcomes research with PCSK9 inhibition in subjects with elevated risk (FOURIER).
Contents lists available at ScienceDirect
Journal of Clinical and Translational Endocrinology: Case Reports j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / j e c r
New lipid therapies: PCSK9 inhibitors Farah Meah, DO a,*, Arshi Basit, MD b, Alaleh Mazhari, DO b, Mary Ann Emanuele, MD b, Nicholas Emanuele, MD a a b
Edward Hines Junior VA Medical Center, IL, USA Loyola University Medical Center, IL, USA
A R T I C L E
I N F O
Article history: Received 29 June 2016 Accepted 25 July 2016
Keywords: LDL LDL receptor Atherothrombosis Familial hyperlipidemia Alirocumab Evolocumab
A B S T R A C T
Pharmacologic therapy reduces cardiovascular risk in a variety of primary and secondary prevention clinical situations in addition to lifestyle modifications. Low density lipoprotein cholesterol (LDL-C) is a key mediator of atherogenesis. Most cholesterol guidelines propose specific LDL-C while recently the ACC/ AHA recommends statin therapy without a specific LDL-C target. Proprotein convertase subtilisin kexin 9 (PCSK9) is a serine protease that leads to LDL receptor degradation. The decreased availability of LDL receptors results in decreased clearance and an increase of circulating LDL-C particles. Monoclonal antibodies that inhibit PCSK9 (PCSK9 abs) reduce LDL-C levels and may be especially helpful in familial hypercholesterolemia and statin-intolerant patients. PCSK9 inhibition is an exciting and promising new therapy for protection against macrovascular events. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).
Abundant data indicate that, in addition to lifestyle modification, pharmacologic lipid-lowering therapy reduces cardiovascular risk in a variety of primary and secondary prevention clinical situations. Though the majority of the randomized controlled trials involve statins, there is some data supporting the efficacy of niacin and gemfibrozil in these situations [1]. Over the years there have been different recommendations regarding treatment of dyslipidemia. Most of the guidelines have proposed specific low density lipoprotein cholesterol (LDL-C) targets [2–4]. Recently, the American College of Cardiology/American Heart Association (ACC/AHA) recommended the use of specific statins for treatment of dyslipidemia without aiming for a specific LDL-C target [1]. While the ACC/AHA did not target a certain LDL-C level, we do not think that this was meant to imply that LDL-C was not important or not atherogenic, just that the many studies showing statin benefit did not show the benefit of statin titration to a certain LDL-C level. Indeed, there is an excellent physiologic basis for believing that LDL-C is very atherogenic and, logically, that lowering LDL-C as much as possible would have incremental benefit. The major carrier of cholesterol in most humans is LDL-C. LDL-C particles are variable in size and contain a hydrophobic cholesterol core lined by a phospholipid coat containing the lipoprotein apolipoprotein B (apoB). Atherosclerotic plaque starts with LDL-C infiltration into arterial walls where LDL-C is able to bind to glycosaminoglycans followed by oxi-
* Corresponding author. E-mail address: [email protected] (F. Meah).
dative processes which lead to a modified apoB recognized and internalized by receptor-mediated macrophage endocytosis. These macrophages transform into cholesterol-laden foam cells that secrete cytokines leading to inflammation, smooth muscle proliferation, and plaque formation within the arterial wall [5]. A fibrous cap forms a barrier between prothrombotic material on the surface of the plaque and platelets which can facilitate thrombus formation [6]. Atherothrombosis can lead to arterial occlusion and end organ damage. Most cells express the LDL-C receptor which recognizes the apoB portion of LDL-C and mediates LDL-C clearance from the circulation [7]. Proprotein convertase subtilisin kexin 9 (PCSK9) is a serine protease produced predominantly in the liver that leads to the degradation of hepatocyte LDL-C receptors and subsequently to increased circulating LDL-C levels. It circulates in three forms: a PCSK9 monomer, LDL-C-bound PCSK9, and a 55 kDa furin-cleaved inactive fragment [8]. The transcription factor sterol regulatory element– binding protein 2 (SREBP2) regulates LDL-C receptor expression and increases PCSK9 synthesis. PCSK9 binds to an epidermal growth factor (EGF)–like repeat located at the extracellular domain of the LDL-C receptor and is subsequently internalized and prevents the recycling of LDL-C receptors to the cell surface. As displayed in Figure 1, the resultant decrease in the number of LDL-C receptors by means of lysosomal degradation leads to an increase of LDL-C particles in circulation which contributes to the generation of atherosclerotic plaque. Sequence variations that cause decreased activity of the PCSK9 gene leading to decreased serum LDL-C is associated with coronary heart disease risk reduction [9].
2214-6245/Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). http://dx.doi.org/10.1016/j.jecr.2016.07.001
24
F. Meah et al. / Journal of Clinical and Translational Endocrinology: Case Reports 2 (2016) 23–26
Figure 1. PCSK9 plays an important role in regulating the number of LDL-C receptors located at the hepatocyte cell surface. In the absence of PCSK9, the LDL particle binds to the LDL receptor followed by internalization. The LDL particle is targeted for degradation by the lysosome and the LDL receptor is recycled to the cell surface. In the presence of PCSK9, PCSK9 binds to the LDL particle-LDL receptor complex. The LDL receptor bound to PCSK9 is unable to recycle to the cell surface and is subject to degradation. A decrease in LDL receptors results in an increase of serum LDL particles.
Therapies that lower circulating PCSK9 levels significantly lower LDL-C levels. This category of lipid lowering therapy offers an important option not previously available and has demonstrated significant efficacy in lowering LDL-C and a large meta-analysis has suggested that this lowering might decrease adverse CV outcomes. Monoclonal antibodies that inhibit PCSK9 (anti-PCSK9 abs) reduce LDL-C by as much as 70% in a dose dependent manner. They have been shown to lower LDL-C by as much as 60% in statin treated patients [10]. A comprehensive meta-analysis of 24 randomized trials (n = 10,159) encompassing a large cohort of clinical situations including familial hypercholesterolemia,
statin-intolerant patients, and those not on any statin therapy found that anti-PCSK9 abs lowered all-cause mortality (odds ratio [OR] 0.45, 95% CI 0.23–0.86), CV mortality (OR 0.50, CI 0.23–1.10), and MI (OR 0.49, CI 0.26–0.93) [11]. The benefits of anti-PCSK9 abs appear to be similar across a wide range of clinical situations and CV risks similar to what has been noted with statin therapy. Therapy with anti-PCSK9 abs appears to result in additional reductions in CV risk even in patients already on intensive or maximal statin therapy. Table 1 displays similarities and differences between the current FDA approved PCSK9 inhibitors in select placebo controlled trials.
Table 1 Comparison of the FDA-approved PCSK9 Inhibitors
Monoclonal Ab Characteristics
Indications for Use LDL-C Reduction Trial Duration Biweekly Therapy Percentage (%) Dosage and Administration
Cost Adverse Effects
Alirocumab
Evolocumab
100% Human 4th generation IgG1 HeFH
100% Human 4th gen IgG2 HoFH, HeFH
Odyssey Long-Term Mendel-2 24 weeks 12 weeks Alirocumab Placebo Evolocumab Placebo −61.0 0.8 −57.0 0.1 1. Injection: Single-dose pre-filled pen/syringe 1. Injection: 140 mg/mL solution in a single-use prefilled syringe 75 mg/mL 2. Injection: 140 mg/mL solution in a single-use prefilled SureClick® autoinjector 150 mg/mL To administer the 420 mg dose, give three 140 mg/dL injections consecutively within 30 minutes ~ $15,000/year ~$14,500/year Nasopharyngitis, Bronchitis, Sinusitis, Influenza, Cough, Myalgia, Urinary tract infections, Diarrhea, Muscle spasms, Musculoskeletal pain, Injection site reactions, Neurocognitive effects
HeFH = Heterozygous Familial Hypercholesterolemia; HoFH = Homozygous Familial Hypercholesterolemia.
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Alirocumab trials Alirocumab (Praluent) is a human monoclonal antibody against PCSK9. In the Efficacy and Safety of Alirocumab SAR236553 (REGN727) Versus Ezetimibe in Patients with Hypercholesterolemia (ODYSSEY MONO) study, alirocumab was evaluated in 103 patients with hypercholesterolemia who were not on lipid-lowering therapy but who had a 1–5% 10-year risk of CV death as assessed by the European Systematic Coronary Risk Estimation. The patients were randomized to ezetimibe 10 mg daily or alirocumab 75 mg every 2 weeks. The alirocumab dose was titrated up to 150 mg if week 8 LDL-C was ≥70 mg/dL. After 24 weeks, alirocumab reduced LDL-C by 47% compared with 16% with ezetimibe. With alirocumab, levels of apo B and non–HDL-C were reduced by 37% and 41%, respectively. There were no differences in treatment-related adverse events between alirocumab and ezetimibe [12]. In the Study of Alirocumab (REGN727/SAR236553) in Patients with Primary Hypercholesterolemia and Moderate, High, or Very High Cardiovascular Risk who are Intolerant to Statins (ODYSSEY ALTERNATIVE) trial, alirocumab was evaluated in patients with statin intolerance who did not have muscle-related adverse events on screening with subcutaneous or oral placebo. Patients (n = 314) were randomized to alirocumab 75 mg every 2 weeks, ezetimibe 10 mg daily, or atorvastatin 20 mg daily. At 24 weeks of treatment, alirocumab reduced LDL-C by 45% compared with 15% with ezetimibe. Treatment-emergent adverse events were similar in the 2 groups, with rates of skeletal muscle-related events being lower in the alirocumab than in the atorvastatin group [13,14]. The Efficacy and Safety of Alirocumab (SAR236553/REGN727) Versus Ezetimibe on Top of Statin in High Cardiovascular Risk Patients with Hypercholesterolemia (ODYSSEY COMBO) I and II trials tested alirocumab as add-on therapy to maximally tolerated statin in high-CV disease-risk patients with suboptimal cholesterol control. In ODYSSEY COMBO I, patients (n = 316) were randomized to 75 mg every 2 weeks or placebo. After 24 weeks, alirocumab reduced LDL-C by 48% compared with 2% with placebo [15]. In Efficacy and Safety of Alirocumab (SAR236553/REGN727) Versus Ezetimibe on Top of Statin in High Cardiovascular Risk Patients with Hypercholesterolemia (ODYSSEY COMBO II), patients (n = 720) were randomized to 75 mg every 2 weeks or ezetimibe 10 mg daily. After 24 weeks, alirocumab reduced LDL-C by 51% compared with 21% with ezetimibe [16]. The Long-term Safety and Tolerability of Alirocumab (SAR236553/ REGN727) Versus Placebo on Top of Lipid-Modifying Therapy in High Cardiovascular Risk Patients With Hypercholesterolemia (ODYSSEY LONG-TERM) trial evaluated the efficacy and safety of treatment with alirocumab for 78 weeks in patients with heterozygous familial hypercholesterolemia with established CHD or CHD equivalent with LDL-C ≥70 mg/dL on maximal tolerated statin dose (47% of patients were on high-dose statin) or other lipid-lowering therapy. Patients (n = 2341) were randomized to alirocumab 150 mg or placebo every 2 weeks. Alirocumab decreased LDL-C by 61% from baseline at 24 weeks and by 52% at 78 weeks. Reductions in non– HDL-C of 52%, apo B of 54%, and Lp (a) of 26% were observed with alirocumab therapy. In addition to evaluating safety and efficacy, the trial collected data on prespecified adjudicated CV disease outcomes. Notably, a post hoc analysis showed that treatment with alirocumab was associated with a lower rate of major adverse cardiovascular outcomes [17]. In addition to the already completed safety and efficacy trials, there is a large ongoing outcome trial evaluating the impact of PCSK9 inhibition with alirocumab on CVD end points. The ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment with Alirocumab SAR236553 (REGN727; ODYSSEY OUTCOMES) trial will randomize 18,000
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patients to alirocumab every 2 weeks or placebo who have had recent hospitalization for acute myocardial infarction or unstable angina and are on a background of statin therapy. The primary outcome is time to first occurrence of CHD death, acute myocardial infarction, hospitalization for unstable angina, or ischemic stroke. The estimated study completion date is January 2018 [18]. Evolucumab trials Evolucumab (Repatha) is another human monoclonal antibody against PCSK9. The MENDEL studies in 2012 and 2014 proved the significant reduction in LDL-C by 55–57% from baseline compared to placebo and 38–40% more than ezetimibe with both biweekly and monthly doses of Evolucumab [19,20]. Significant increase in HDL-C and decrease in triglycerides and VLDL-C levels was also observed. Three hundred seven patients intolerant to at least 2 statins were randomized in the GAUSS-2 placebo and ezetimibe controlled study [21]. Similar reduction in LDL-C was noted (55–56%). More than 75% achieved LDL-C less than 100 mg/dL in 12 weeks. The drug was well tolerated with very low incidence of myalgia, 7% and 9% in the weekly and monthly doses respectively. Patients with primary hypercholesterolemia and mixed dyslipidemia on moderate or high intensity statins, when given a trial of evolocumab either biweekly or monthly, showed equal reductions in LDL-C by 65–75% over a 12-week trial, compared to placebo (LAPLACE-2) [22]. The reduction in LDL-C observed was significantly greater (66%) with evolocumab when compared to ezetimibe (24%). About 86–94% of patients achieved LDL-C <70 mg/dL in 12 weeks with evolocumab and background statin therapy, in contrast to 17–62% achieving the same goal in the ezetimibe group. Subsequent to 12 weeks, analysis of effects on other lipids demonstrated 12% and 6–16% reduction in the triglycerides with the biweekly and monthly doses respectively. HDL-C levels were modestly elevated by 5–10% in both dose groups. Evolocumab was well tolerated, with an uncommon incidence of neurocognitive events ≤1% in this study. In January 2015, Lancet published the TESLA Part B (a randomized, double-blinded, placebo controlled, phase 3 trial) [23] conducted at 17 sites in 10 countries (North America, Europe, the Middle East, and South Africa) on 50 patients with homozygous familial hypercholesterolemia (HoFH) ≥12 years of age. After 4 weeks of a stable lipid lowering agent (statin with or without ezetimibe) without receiving apheresis, patients randomized to the evolocumab group (420 mg subcutaneous monthly) significantly reduced the LDL-C at 12 weeks by 30.9% compared to placebo. Upper respiratory tract infections and influenza were the most common adverse events noted in the evolocumab group with no serious adverse events noted. The RUTHERFORD-2, a multicenter randomized 12 week study of 331 participants with heterozygous familial hypercholesterolemia (HeFH) age 18–80 years showed a robust 60% reduction in LDL-C compared to placebo [24]. Nasopharyngitis and musclerelated adverse events were the most commonly reported side effects. The year 2015 also introduced the OSLER studies: OSLER 1 (comprising of patients completing phase 2 trials in 190 centers) and OSLER 2 (comprising of patients completing phase 3 trials in 305 centers); 2 open labeled randomized trials with more than 4000 patients, studied the efficacy and safety of evolocumab in reducing lipids and cardiovascular events [25]. Evolocumab reduced cholesterol levels by 61% in 12 weeks compared to the standard therapy alone, by reducing the pretreatment median of 120 mg/ dL to 48 mg/dL and, sustaining the reduction through 48 weeks. Evolocumab was reported to have nonspecific adverse events (arthralgia, headache, limb pain, and fatigue) and some neurocognitive adverse events like dementia, delirium, confusion, amnesia, attention
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deficits, disturbance in mental thinking and perception, more frequently than the standard therapy group. The cardiovascular benefits are yet to be established. Though the analysis was exploratory, the modest reduction in LDL-C showed consistency with the one-year reduction in cardiovascular events in the OSLER trials. However, larger randomized placebo controlled trials are underway with the intention of providing a more conclusive assessment of the cardiovascular benefit of evolocumab [Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) study] [26]. Evolocumab is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with HeFH or clinical atherosclerotic CV disease and HoFH in conjunction with diet and other lipid-lowering therapies (e.g. statins, ezetimibe, LDL-C apheresis), who require additional lowering of LDL-C. Two dose formulations are available, 140 mg subcutaneous every 2 weeks or 420 mg monthly. Nasopharyngitis, upper respiratory tract infections, injection site reactions, myalgias, headaches and, rarely, neurocognitive effects were among the noted adverse effects. The role of PCSK9 and statin in lowering LDL-C is additive, 70% when combined as compared to 50% when used alone, with maximum lowering effect seen within 2 weeks of therapy [27]. Summary PCSK9 inhibition is an exciting and promising new therapy for protection against macrovascular events. However, for now, use should be restricted to those with familial hypercholesterolemia or patients with clinical atherosclerotic cardiovascular disease, who require additional lowering of LDL-C. Prospective trials examining CV outcomes are underway and the results are eagerly awaited. Conflict of interest The authors declare they have no conflicts of interest. References [1] Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;129(25 Suppl. 2):S1–45. [2] Reiner Z, Catapano AL, De Backer G, Graham I, Taskinen MR, Wiklund O, 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(14):1769– 818. [3] Jellinger PS, Smith DA, Mehta AE, Ganda O, Handelsman Y, Rodbard HW, et al. American Association of Clinical Endocrinologists’ guidelines for management of dyslipidemia and prevention of atherosclerosis. Endocr Pract 2012;18(Suppl. 1):1–78. [4] Standards of medical care in diabetes – 2016: summary of revisions. Diabetes Care 2016;39(Suppl. 1):S4–5. [5] Tabas I, Garcia-Cardena G, Owens GK. Recent insights into the cellular biology of atherosclerosis. J Cell Biol 2015;209(1):13–22. [6] Libby P, Tabas I, Fredman G, Fisher EA. Inflammation and its resolution as determinants of acute coronary syndromes. Circ Res 2014;114(12):1867–79. [7] Goldstein JL, Brown MS. A century of cholesterol and coronaries: from plaques to genes to statins. Cell 2015;161(1):161–72.
[8] Latimer J, Batty JA, Neely DD, Kunadian V. PCSK9 inhibitors in the prevention of cardiovascular disease. J Thromb Thrombolysis 2016;doi:10.1007/s11239016-1364-1. [9] Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006;354(12):1264–72. [10] Roth EM, McKenney JM, Hanotin C, Asset G, Stein EA. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N Engl J Med 2012;367(20):1891–900. [11] Navarese EP, Kolodziejczak M, Schulze V, Gurbel PA, Tantry U, Lin Y, et al. Effects of proprotein convertase Subtilisin/Kexin type 9 antibodies in adults with hypercholesterolemia: a systematic review and meta-analysis. Ann Intern Med 2015;163(1):40–51. [12] Roth EM, Taskinen MR, Ginsberg HN, Kastelein JJ, Colhoun HM, Robinson JG, et al. Monotherapy with the PCSK9 inhibitor alirocumab versus ezetimibe in patients with hypercholesterolemia: results of a 24 week, double-blind, randomized Phase 3 trial. Int J Cardiol 2014;176(1):55–61. [13] Moriarty PM, Jacobson TA, Bruckert E, Thompson PD, Guyton JR, Baccara-Dinet MT, et al. Efficacy and safety of alirocumab, a monoclonal antibody to PCSK9, in statin-intolerant patients: design and rationale of ODYSSEY ALTERNATIVE, a randomized phase 3 trial. J Clin Lipidol 2014;8(6):554–61. [14] Moriarty PMTP, Cannon CP, Guyton JR, Bergeron J, Zieve FJ, Bruckert E, et al. Late-Breaking Clinical Trial Abstracts: ODYSSEY ALTERNATIVE: efficacy and safety of the proprotein convertase subtilisin/kexin type 9 monoclonal antibody, alirocumab, versus ezetimibe, in patients with statin intolerance as defined by a placebo run-in and statin rechallenge arm. Circulation 2014;2105–26. [15] Kereiakes DJ, Robinson JG, Cannon CP, Lorenzato C, Pordy R, Chaudhari U, et al. Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: The ODYSSEY COMBO I study. Am Heart J 2015;169(6): 906–15, e13. [16] Cannon CP, Cariou B, Blom D, McKenney JM, Lorenzato C, Pordy R, et al. Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial. Eur Heart J 2015;36(19):1186– 94. [17] Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372(16):1489–99. [18] ODYSSEY outcomes: evaluation of cardiovascular outcomes after an acute coronary syndrome during treatment with alirocumab.