- Email: [email protected]
Kexin Type 9 Inhibitors: A Brief Overview
Accepted Manuscript Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors: A Brief Overview Zachary R. Noel, PharmD, BCPS, Craig J. Beavers, PharmD, FAHA, AACC, BCPSAQ Cardiology, CACP PII:
S0002-9343(16)31028-2
DOI:
10.1016/j.amjmed.2016.09.021
Reference:
AJM 13738
To appear in:
The American Journal of Medicine
Received Date: 9 September 2016 Accepted Date: 9 September 2016
Please cite this article as: Noel ZR, Beavers CJ, Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors: A Brief Overview, The American Journal of Medicine (2016), doi: 10.1016/ j.amjmed.2016.09.021. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors: A Brief Overview
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Zachary R. Noel, PharmD, BCPS1 and Craig J. Beavers, PharmD, FAHA, AACC, BCPSAQ Cardiology, CACP2
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1. University of Maryland College of Pharmacy, PPS Department, Pharmacy Hall, Room S428, Baltimore, Maryland 21201. [email protected] 2. Department of Pharmacy Services, UK Healthcare and University of Kentucky College of Pharmacy, 800 Rose Street, Lexington, Kentucky, 40536. [email protected]
Corresponding Author:
Craig J. Beavers, PharmD, FAHA, AACC, BCPS-AQ Cardiology, CACP Cardiovascular Clinical Pharmacy Coordinator
Department of Pharmacy Services, UK Healthcare
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Adjunct Assistant Professor, University of Kentucky College of Pharmacy 800 Rose Street, Lexington Kentucky 40536 Phone: 859-218-4267 Fax: 859-323-2077
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E-mail: [email protected]
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Keywords: Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors, PCSK9, hyperlipidemia, LDL Conflict of Interest: Neither author has a conflict of interest and have nothing to disclose. All authors have provided content, developed, read, and reviewed the whole manuscript through all stages of the process. Finally, there is no conflict of interest with any of the authors.
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Abstract:
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Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors serve as a valuable addition to the armamentarium of lipid lowering agents and have promising potential. By inhibiting the PCSK9 enzyme, this novel molecule leads to increase low density lipoprotiein (LDL) receptor density and decreased circulation of LDL. The fact the agent is a monoclonal antibody has led to limited drug interactions and minimized adverse drug events. It is critical for all providers to have a basic understanding of these novel therapies with their introduction and use for treatment.
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Introduction
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Proprotein convertase subtilisin-kexin type 9 (PCSK9) was first discovered in 2003.1 Following its discovery, individuals with gain- and loss-of-function genes were identified and found to have substantially elevated and reduced low-density lipoprotein cholesterol (LDL-C), respectively. More importantly, PCSK9 function was found to have a strong correlation with cardiovascular disease.2,3 In 2015, just 12 years from the target discovery date, the first PCSK9 inhibitor was approved by the FDA.4 Although statins remain a mainstay treatment for hypercholesterolemia and secondary prevention of cardiovascular events, PCSK9 inhibitors serve as a valuable addition to the armamentarium of lipid lowering agents and have promising potential. Mechanism of action
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Indications
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PCSK9, a serine protease produced predominantly within hepatocytes, serves to regulate LDL receptor (LDL-R) density on hepatocytes.5 When LDL-C comes in contact with LDL-receptors on the surface of hepatocytes, the LDL/LDL-R complex that is formed subsequently undergoes endocytosis. Following endocytosis, the LDL particle undergoes degradation in the lysosome and, in the absence of PCSK9, the LDL-R is recycled and taken back to the cell surface. On the contrary, in the presence of PCSK9, the LDL-R is flagged for destruction within the lysosome along with the LDL particle, effectively reducing the LDL-R density on hepatocytes. Thus, PCSK9 concentrations are indirectly proportional to LDL-R density and directly proportional to serum LDL cholesterol concentrations. Therefore, by directing inhibiting PCSK9, LDL-R density is increased and circulating LDL-C is reduced.
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Currently, there are two FDA-approved PCSK9 inhibitors, each of which are human monoclonal antibodies available in prefilled pens for subcutaneous administration one to two times monthly (Table 1).6,7 Alirocumab and evolocumab are both approved for the treatment of primary hypercholesterolemia in combination with diet and maximally tolerated statin therapy in patients with atherosclerotic cardiovascular disease (ASCVD) who require additional LDL-C lowering. Evolocumab is approved for the treatment of both heterozygous familial hypercholesterolemia (HeFH) and homozygous familial hypercholesterolemia whereas alirocumab is approved for the treatment of HeFH only. Ongoing studies are being conducted to evaluate the use of PCSK9 inhibitors in patients who are post-acute coronary syndrome, patients with human immunodeficiency virus (HIV), and patients with diabetes, among others.8 In addition, a third PCSK9 inhibitor, bococizumab, is in phase III clinical trials and being evaluated in similar populations as alirocumab and evolocumab, as well a separate clinical trial in HIV infected subjects.9
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Efficacy
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Available studies to date of alirocumab and evolocumab show these agents to be remarkably effective at lowering LDL-C (Table 2).10,11 Average LDL-C reduction with a PCSK9 inhibitor compared to placebo in a meta-analysis of available trials is 58%.12 In the ODYSSEY LONG TERM and OSLER trials, ~80% of patients receiving a PCSK9 inhibitor achieved a goal LDL-C less than 70mg/dl, compared to <10% in the placebo groups. Total cholesterol, apolipoprotein B, and triglycerides are also reduced considerably with alirocumab or evolocumab therapy, while HDL cholesterol increases only slightly.12,13
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Although PCSK9 inhibitors have a profound impact on atherogenic lipid fractions, it is important to note that long term outcomes data on mortality and cardiovascular events are ongoing and not expected to result until 2017-18. Systematic reviews and meta-analyses of current prospective PCSK9 inhibitors trials suggest an all-cause mortality benefit, but a reduction in cardiovascular mortality or major adverse cardiovascular events has not been detected.12,13
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Adverse events
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Although PCSK9 has a role in many others tissues, such as the intestines, brain, and pancreas, its exact purpose beyond the liver has not been well elucidated.14 Observations of individuals with loss-of-function genes of PCSK9 have not been found to have a heightened risk of untoward effects.15-17 Consistent with these observations, data from randomized-controlled trials has shown PCSK9 inhibitors to be very well tolerated with no difference in serious adverse effects compared to placebo.12,13 The most common adverse events experienced in clinical trials were injection site reactions. In addition, PCSK9 inhibitors appear to invoke fewer muscle-related adverse effects as compared to statins.18,19 Disturbances in liver function tests and creatinine kinase have not been observed in available studies.
Cost
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Early evidence shows a potential correlation with PCSK9 inhibitors and neurocognitive impairment. The overall incidence of this is low (<1%) and long term safety studies are being conducted to establish whether causation exists.20
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The annual cost of alirocumab and evolocumab are ~$14,000.21 Estimations predict that if all eligible individuals between age 35-75 years old were to use an approved PCSK9 inhibitor annual prescription spending would increase by 38% (~$125 billion) and United States health care expenditures would increase by 4% (~$120 billion).21 At the current expense, PCSK9 inhibitors are not believed to be cost effective medications for patients with HeFH or ASCVD. Cost analyses suggest a price reduction approximately 60-85% of the current price would be necessary for the agents to be considered cost-effective.21,22 Advice to clinicians (how and when to use) PCSK9 inhibitors have the potential to change the landscape of how we treat hypercholesterolemia; however, such enthusiasm should be approached cautiously to ensure
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judicious resource utilization until outcomes data are available and they are made more cost effective. Although PCSK9 inhibitors and other non-statin therapies can be considered in highrisk patients who are intolerant to statins, unable to tolerate goal doses, or who have suboptimal response to statins, it is important to remember that statins remain the backbone for treatment of hypercholesterolemia and in individuals with cardiovascular disease.23 Given the wealth of data showing mortality and cardiovascular benefit of statins, it would be negligent to curtail their use in the absence of a contraindication or intolerable adverse effect. Also note that, although not in the FDA labeling of alirocumab and evolocumab, a minimum LDL-C of 70-100mg/dl was used in clinical trials as a cutoff for treatment inclusion with either agent. Most insurance companies will only have one of these agents on formulary and will require strict pre-certification before paying for them, including documentation of a high intensity statin and, in some instances, use of ezetimibe first. Due to their cost, specialty pharmacies will often be required by third party payers.
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1. Farnier M. PCSK9: From discovery to therapeutic applications. Archives of Cardiovascular Diseases. 2014;107(1):58-66. doi: http://dx.doi.org/10.1016/j.acvd.2013.10.007.
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2. Seidah NG, Awan Z, Chretien M, Mbikay M. PCSK9: A key modulator of cardiovascular health. Circ Res. 2014;114(6):1022-1036. doi: 10.1161/CIRCRESAHA.114.301621 [doi].
3. Cohen JC, Boerwinkle E, Mosley TH, Hobbs HH. Sequence variations in PCSK9, low LDL,
SC
and protection against coronary heart disease. N Engl J Med. 2006;354(12):1264-1272.
http://survey.hshsl.umaryland.edu/?url=http://search.ebscohost.com/login.aspx?direct=true&db=
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a9h&AN=24929791&site=eds-live. doi: 10.1056/NEJMoa054013.
4. FDA approves praluent to treat certain patients with high cholesterol first in a new class of injectable cholesterol-lowering drugs.
08/16, 2016.
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http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm455883.htm. Accessed
5. Bergeron N, Phan BAP, Ding Y, Fong A, Krauss RM. Proprotein convertase subtilisin/kexin
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type 9 inhibition: A new therapeutic mechanism for reducing cardiovascular disease risk. Circulation. 2015;132(17):1648-1666.
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http://survey.hshsl.umaryland.edu/?url=http://search.ebscohost.com/login.aspx?direct=true&db= cmedm&AN=26503748&site=eds-live. doi: 10.1161/CIRCULATIONAHA.115.016080.
6. Praluent (alirocumab) package insert. bridgewater, NJ: Sanofi-aventis LLC.; 2015 jul. .
7. Repatha (evolocumab) injection. thousand oaks, CA: Amgen inc.; 2016 jul. .
8. www.clinicaltrials.gov. Accessed 08/19, 2016.
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9. Two additional phase 3 lipid-lowering studies of bococizumab deliver positive topline results http://www.pfizer.com/news/press-release/press-release-
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detail/two_additional_phase_3_lipid_lowering_studies_of_bococizumab_deliver_positive_toplin e_results. Accessed 08/19, 2016.
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10. Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372(16):1489-1499. doi:
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10.1056/NEJMoa1501031 [doi].
11. Sabatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372(16):1500-1509. doi: 10.1056/NEJMoa1500858 [doi].
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12. Navarese EP, Kolodziejczak M, Schulze V, et al. Effects of proprotein convertase subtilisin/kexin type 9 antibodies in adults with hypercholesterolemia: A systematic review and
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meta-analysis. Ann Intern Med. 2015;163(1):40-51. doi: 10.7326/M14-2957 [doi].
13. Lipinski MJ, Benedetto U, Escarcega RO, et al. The impact of proprotein convertase
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subtilisin-kexin type 9 serine protease inhibitors on lipid levels and outcomes in patients with primary hypercholesterolaemia: A network meta-analysis. Eur Heart J. 2016;37(6):536-545. doi: 10.1093/eurheartj/ehv563 [doi].
14. Cariou B, Si-Tayeb K, Le May C. Role of PCSK9 beyond liver involvement. Curr Opin Lipidol. 2015;26(3):155-161.
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http://survey.hshsl.umaryland.edu/?url=http://search.ebscohost.com/login.aspx?direct=true&db= cmedm&AN=25887680&site=eds-live. doi: 10.1097/MOL.0000000000000180.
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15. Bonnefond A, Yengo L, Le May C, et al. The loss-of-function PCSK9 p.R46L genetic variant does not alter glucose homeostasis. Diabetologia. 2015;58(9):2051-2055.
http://survey.hshsl.umaryland.edu/?url=http://search.ebscohost.com/login.aspx?direct=true&db=
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cmedm&AN=26049403&site=eds-live. doi: 10.1007/s00125-015-3659-8.
16. Zhao Z, Tuakli-Wosornu Y, Lagace TA, et al. Molecular characterization of loss-of-function
2006;79(3):514-523.
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mutations in PCSK9 and identification of a compound heterozygote. Am J Hum Genet.
http://survey.hshsl.umaryland.edu/?url=http://search.ebscohost.com/login.aspx?direct=true&db= a9h&AN=21887958&site=eds-live.
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17. Marais AD, Kim JB, Wasserman SM, Lambert G. PCSK9 inhibition in LDL cholesterol reduction: Genetics and therapeutic implications of very low plasma lipoprotein levels.
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Pharmacol Ther. 2015;145:58-66. doi: http://dx.doi.org/10.1016/j.pharmthera.2014.07.004.
18. Cho L, Rocco M, Colquhoun D, et al. Clinical profile of statin intolerance in the phase 3
[doi].
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GAUSS-2 study. Cardiovasc Drugs Ther. 2016;30(3):297-304. doi: 10.1007/s10557-016-6655-4
19. Nissen SE, Stroes E, Dent-Acosta RE, et al. Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: The GAUSS-3 randomized clinical trial. JAMA. 2016;315(15):1580-1590. doi: 10.1001/jama.2016.3608 [doi].
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20. Swiger KJ, Martin SS. PCSK9 inhibitors and neurocognitive adverse events: Exploring the FDA directive and a proposal for N-of-1 trials. Drug Saf. 2015;38(6):519-526. doi:
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10.1007/s40264-015-0296-6 [doi].
21. Tice JA, Kazi DS, Pearson SD. Proprotein convertase subtilisin/kexin type 9 (PCSK9)
inhibitors for treatment of high cholesterol levels: Effectiveness and value. JAMA INTERN MED.
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2016;176(1):107-108.
http://survey.hshsl.umaryland.edu/?url=http://search.ebscohost.com/login.aspx?direct=true&db=
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c8h&AN=112147980&site=eds-live. doi: 10.1001/jamainternmed.2015.7248.
22. Institute for Clinical and Economic Review. PCSK9 inhibitors for treatment of high cholesterol: Effectiveness, value, and ValueBased price benchmarks. https://icer-review.org/wpcontent/uploads/2016/01/Final-Report-for-Posting-11-24-15-1.pdf. Accessed 08/16, 2016.
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23. Writing Committee, Lloyd-Jones DM, Morris PB, et al. 2016 ACC expert consensus decision pathway on the role of non-statin therapies for LDL-cholesterol lowering in the management of
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atherosclerotic cardiovascular disease risk: A report of the american college of cardiology task force on clinical expert consensus documents. J Am Coll Cardiol. 2016;68(1):92-125. doi:
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10.1016/j.jacc.2016.03.519 [doi].
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11-17 days None
140mg every 2 weeks or 420mg ever 4 weeks Lipid panel 4-8 weeks Lipid panel 4-8 Monitoring following initiation weeks following initiation *Starting dose 75mg every 2 weeks. If response inadequate dose may be increased to 150mg every 2 weeks
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Dosing
75-150mg every 2 weeks*
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17-20 days None
Half-life Drug Interactions
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TABLE 1 Pharmacology of Currently Available PCSK9 Inhibitors Evolocumab Alirocumab (PRALUENT®) (REPATHA®) Saturable binding to Saturable binding to Elimination route PCSK9; non-saturable PCSK9; nonproteolytic pathway saturable proteolytic pathway None None Dose Adjustments
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TABLE 2
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ODYSSEY LONG TERM OSLER Results Results - Alirocumab Evolocumab HeFH, established ASCVD, Variable* Inclusion Criteria or CHD risk equivalent; Max tolerated statin 99 70 Percent receiving statin (%) 70mg/dl 85-100mg/dl LDL-C Cutoff for Inclusion 80 weeks 50 weeks Average Follow-up Period 61 58 LDL-C Reduction (%) HeFH= heterozygous familial hypercholesterolemia; ASCVD=atherosclerotic cardiovascular disease; CHD=coronary heart disease; LDL=low-density lipoprotein *Results of the OSLER 1 and OSLER 2 trials were combined and reported. OSLER 1 and 2 consisted of patients who enrolled in 1 or 12 parent studies and opted to continue treatment into a long-term extension.
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PCSK9 Inhibitors are novel entities that are becoming more commonly used. It is critical for providers to have a basic understanding of the pharmacology, indications, efficacy, safety, and proper use of these agents.
S0002-9343(16)31028-2
DOI:
10.1016/j.amjmed.2016.09.021
Reference:
AJM 13738
To appear in:
The American Journal of Medicine
Received Date: 9 September 2016 Accepted Date: 9 September 2016
Please cite this article as: Noel ZR, Beavers CJ, Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors: A Brief Overview, The American Journal of Medicine (2016), doi: 10.1016/ j.amjmed.2016.09.021. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors: A Brief Overview
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Zachary R. Noel, PharmD, BCPS1 and Craig J. Beavers, PharmD, FAHA, AACC, BCPSAQ Cardiology, CACP2
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1. University of Maryland College of Pharmacy, PPS Department, Pharmacy Hall, Room S428, Baltimore, Maryland 21201. [email protected] 2. Department of Pharmacy Services, UK Healthcare and University of Kentucky College of Pharmacy, 800 Rose Street, Lexington, Kentucky, 40536. [email protected]
Corresponding Author:
Craig J. Beavers, PharmD, FAHA, AACC, BCPS-AQ Cardiology, CACP Cardiovascular Clinical Pharmacy Coordinator
Department of Pharmacy Services, UK Healthcare
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Adjunct Assistant Professor, University of Kentucky College of Pharmacy 800 Rose Street, Lexington Kentucky 40536 Phone: 859-218-4267 Fax: 859-323-2077
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E-mail: [email protected]
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Keywords: Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors, PCSK9, hyperlipidemia, LDL Conflict of Interest: Neither author has a conflict of interest and have nothing to disclose. All authors have provided content, developed, read, and reviewed the whole manuscript through all stages of the process. Finally, there is no conflict of interest with any of the authors.
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Abstract:
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Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors serve as a valuable addition to the armamentarium of lipid lowering agents and have promising potential. By inhibiting the PCSK9 enzyme, this novel molecule leads to increase low density lipoprotiein (LDL) receptor density and decreased circulation of LDL. The fact the agent is a monoclonal antibody has led to limited drug interactions and minimized adverse drug events. It is critical for all providers to have a basic understanding of these novel therapies with their introduction and use for treatment.
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Introduction
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Proprotein convertase subtilisin-kexin type 9 (PCSK9) was first discovered in 2003.1 Following its discovery, individuals with gain- and loss-of-function genes were identified and found to have substantially elevated and reduced low-density lipoprotein cholesterol (LDL-C), respectively. More importantly, PCSK9 function was found to have a strong correlation with cardiovascular disease.2,3 In 2015, just 12 years from the target discovery date, the first PCSK9 inhibitor was approved by the FDA.4 Although statins remain a mainstay treatment for hypercholesterolemia and secondary prevention of cardiovascular events, PCSK9 inhibitors serve as a valuable addition to the armamentarium of lipid lowering agents and have promising potential. Mechanism of action
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Indications
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PCSK9, a serine protease produced predominantly within hepatocytes, serves to regulate LDL receptor (LDL-R) density on hepatocytes.5 When LDL-C comes in contact with LDL-receptors on the surface of hepatocytes, the LDL/LDL-R complex that is formed subsequently undergoes endocytosis. Following endocytosis, the LDL particle undergoes degradation in the lysosome and, in the absence of PCSK9, the LDL-R is recycled and taken back to the cell surface. On the contrary, in the presence of PCSK9, the LDL-R is flagged for destruction within the lysosome along with the LDL particle, effectively reducing the LDL-R density on hepatocytes. Thus, PCSK9 concentrations are indirectly proportional to LDL-R density and directly proportional to serum LDL cholesterol concentrations. Therefore, by directing inhibiting PCSK9, LDL-R density is increased and circulating LDL-C is reduced.
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Currently, there are two FDA-approved PCSK9 inhibitors, each of which are human monoclonal antibodies available in prefilled pens for subcutaneous administration one to two times monthly (Table 1).6,7 Alirocumab and evolocumab are both approved for the treatment of primary hypercholesterolemia in combination with diet and maximally tolerated statin therapy in patients with atherosclerotic cardiovascular disease (ASCVD) who require additional LDL-C lowering. Evolocumab is approved for the treatment of both heterozygous familial hypercholesterolemia (HeFH) and homozygous familial hypercholesterolemia whereas alirocumab is approved for the treatment of HeFH only. Ongoing studies are being conducted to evaluate the use of PCSK9 inhibitors in patients who are post-acute coronary syndrome, patients with human immunodeficiency virus (HIV), and patients with diabetes, among others.8 In addition, a third PCSK9 inhibitor, bococizumab, is in phase III clinical trials and being evaluated in similar populations as alirocumab and evolocumab, as well a separate clinical trial in HIV infected subjects.9
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Efficacy
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Available studies to date of alirocumab and evolocumab show these agents to be remarkably effective at lowering LDL-C (Table 2).10,11 Average LDL-C reduction with a PCSK9 inhibitor compared to placebo in a meta-analysis of available trials is 58%.12 In the ODYSSEY LONG TERM and OSLER trials, ~80% of patients receiving a PCSK9 inhibitor achieved a goal LDL-C less than 70mg/dl, compared to <10% in the placebo groups. Total cholesterol, apolipoprotein B, and triglycerides are also reduced considerably with alirocumab or evolocumab therapy, while HDL cholesterol increases only slightly.12,13
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Although PCSK9 inhibitors have a profound impact on atherogenic lipid fractions, it is important to note that long term outcomes data on mortality and cardiovascular events are ongoing and not expected to result until 2017-18. Systematic reviews and meta-analyses of current prospective PCSK9 inhibitors trials suggest an all-cause mortality benefit, but a reduction in cardiovascular mortality or major adverse cardiovascular events has not been detected.12,13
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Adverse events
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Although PCSK9 has a role in many others tissues, such as the intestines, brain, and pancreas, its exact purpose beyond the liver has not been well elucidated.14 Observations of individuals with loss-of-function genes of PCSK9 have not been found to have a heightened risk of untoward effects.15-17 Consistent with these observations, data from randomized-controlled trials has shown PCSK9 inhibitors to be very well tolerated with no difference in serious adverse effects compared to placebo.12,13 The most common adverse events experienced in clinical trials were injection site reactions. In addition, PCSK9 inhibitors appear to invoke fewer muscle-related adverse effects as compared to statins.18,19 Disturbances in liver function tests and creatinine kinase have not been observed in available studies.
Cost
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Early evidence shows a potential correlation with PCSK9 inhibitors and neurocognitive impairment. The overall incidence of this is low (<1%) and long term safety studies are being conducted to establish whether causation exists.20
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The annual cost of alirocumab and evolocumab are ~$14,000.21 Estimations predict that if all eligible individuals between age 35-75 years old were to use an approved PCSK9 inhibitor annual prescription spending would increase by 38% (~$125 billion) and United States health care expenditures would increase by 4% (~$120 billion).21 At the current expense, PCSK9 inhibitors are not believed to be cost effective medications for patients with HeFH or ASCVD. Cost analyses suggest a price reduction approximately 60-85% of the current price would be necessary for the agents to be considered cost-effective.21,22 Advice to clinicians (how and when to use) PCSK9 inhibitors have the potential to change the landscape of how we treat hypercholesterolemia; however, such enthusiasm should be approached cautiously to ensure
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judicious resource utilization until outcomes data are available and they are made more cost effective. Although PCSK9 inhibitors and other non-statin therapies can be considered in highrisk patients who are intolerant to statins, unable to tolerate goal doses, or who have suboptimal response to statins, it is important to remember that statins remain the backbone for treatment of hypercholesterolemia and in individuals with cardiovascular disease.23 Given the wealth of data showing mortality and cardiovascular benefit of statins, it would be negligent to curtail their use in the absence of a contraindication or intolerable adverse effect. Also note that, although not in the FDA labeling of alirocumab and evolocumab, a minimum LDL-C of 70-100mg/dl was used in clinical trials as a cutoff for treatment inclusion with either agent. Most insurance companies will only have one of these agents on formulary and will require strict pre-certification before paying for them, including documentation of a high intensity statin and, in some instances, use of ezetimibe first. Due to their cost, specialty pharmacies will often be required by third party payers.
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1. Farnier M. PCSK9: From discovery to therapeutic applications. Archives of Cardiovascular Diseases. 2014;107(1):58-66. doi: http://dx.doi.org/10.1016/j.acvd.2013.10.007.
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2. Seidah NG, Awan Z, Chretien M, Mbikay M. PCSK9: A key modulator of cardiovascular health. Circ Res. 2014;114(6):1022-1036. doi: 10.1161/CIRCRESAHA.114.301621 [doi].
3. Cohen JC, Boerwinkle E, Mosley TH, Hobbs HH. Sequence variations in PCSK9, low LDL,
SC
and protection against coronary heart disease. N Engl J Med. 2006;354(12):1264-1272.
http://survey.hshsl.umaryland.edu/?url=http://search.ebscohost.com/login.aspx?direct=true&db=
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a9h&AN=24929791&site=eds-live. doi: 10.1056/NEJMoa054013.
4. FDA approves praluent to treat certain patients with high cholesterol first in a new class of injectable cholesterol-lowering drugs.
08/16, 2016.
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http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm455883.htm. Accessed
5. Bergeron N, Phan BAP, Ding Y, Fong A, Krauss RM. Proprotein convertase subtilisin/kexin
EP
type 9 inhibition: A new therapeutic mechanism for reducing cardiovascular disease risk. Circulation. 2015;132(17):1648-1666.
AC C
http://survey.hshsl.umaryland.edu/?url=http://search.ebscohost.com/login.aspx?direct=true&db= cmedm&AN=26503748&site=eds-live. doi: 10.1161/CIRCULATIONAHA.115.016080.
6. Praluent (alirocumab) package insert. bridgewater, NJ: Sanofi-aventis LLC.; 2015 jul. .
7. Repatha (evolocumab) injection. thousand oaks, CA: Amgen inc.; 2016 jul. .
8. www.clinicaltrials.gov. Accessed 08/19, 2016.
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9. Two additional phase 3 lipid-lowering studies of bococizumab deliver positive topline results http://www.pfizer.com/news/press-release/press-release-
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detail/two_additional_phase_3_lipid_lowering_studies_of_bococizumab_deliver_positive_toplin e_results. Accessed 08/19, 2016.
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10. Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372(16):1489-1499. doi:
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10.1056/NEJMoa1501031 [doi].
11. Sabatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372(16):1500-1509. doi: 10.1056/NEJMoa1500858 [doi].
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12. Navarese EP, Kolodziejczak M, Schulze V, et al. Effects of proprotein convertase subtilisin/kexin type 9 antibodies in adults with hypercholesterolemia: A systematic review and
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meta-analysis. Ann Intern Med. 2015;163(1):40-51. doi: 10.7326/M14-2957 [doi].
13. Lipinski MJ, Benedetto U, Escarcega RO, et al. The impact of proprotein convertase
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subtilisin-kexin type 9 serine protease inhibitors on lipid levels and outcomes in patients with primary hypercholesterolaemia: A network meta-analysis. Eur Heart J. 2016;37(6):536-545. doi: 10.1093/eurheartj/ehv563 [doi].
14. Cariou B, Si-Tayeb K, Le May C. Role of PCSK9 beyond liver involvement. Curr Opin Lipidol. 2015;26(3):155-161.
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http://survey.hshsl.umaryland.edu/?url=http://search.ebscohost.com/login.aspx?direct=true&db= cmedm&AN=25887680&site=eds-live. doi: 10.1097/MOL.0000000000000180.
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15. Bonnefond A, Yengo L, Le May C, et al. The loss-of-function PCSK9 p.R46L genetic variant does not alter glucose homeostasis. Diabetologia. 2015;58(9):2051-2055.
http://survey.hshsl.umaryland.edu/?url=http://search.ebscohost.com/login.aspx?direct=true&db=
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cmedm&AN=26049403&site=eds-live. doi: 10.1007/s00125-015-3659-8.
16. Zhao Z, Tuakli-Wosornu Y, Lagace TA, et al. Molecular characterization of loss-of-function
2006;79(3):514-523.
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mutations in PCSK9 and identification of a compound heterozygote. Am J Hum Genet.
http://survey.hshsl.umaryland.edu/?url=http://search.ebscohost.com/login.aspx?direct=true&db= a9h&AN=21887958&site=eds-live.
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17. Marais AD, Kim JB, Wasserman SM, Lambert G. PCSK9 inhibition in LDL cholesterol reduction: Genetics and therapeutic implications of very low plasma lipoprotein levels.
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Pharmacol Ther. 2015;145:58-66. doi: http://dx.doi.org/10.1016/j.pharmthera.2014.07.004.
18. Cho L, Rocco M, Colquhoun D, et al. Clinical profile of statin intolerance in the phase 3
[doi].
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GAUSS-2 study. Cardiovasc Drugs Ther. 2016;30(3):297-304. doi: 10.1007/s10557-016-6655-4
19. Nissen SE, Stroes E, Dent-Acosta RE, et al. Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: The GAUSS-3 randomized clinical trial. JAMA. 2016;315(15):1580-1590. doi: 10.1001/jama.2016.3608 [doi].
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20. Swiger KJ, Martin SS. PCSK9 inhibitors and neurocognitive adverse events: Exploring the FDA directive and a proposal for N-of-1 trials. Drug Saf. 2015;38(6):519-526. doi:
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10.1007/s40264-015-0296-6 [doi].
21. Tice JA, Kazi DS, Pearson SD. Proprotein convertase subtilisin/kexin type 9 (PCSK9)
inhibitors for treatment of high cholesterol levels: Effectiveness and value. JAMA INTERN MED.
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2016;176(1):107-108.
http://survey.hshsl.umaryland.edu/?url=http://search.ebscohost.com/login.aspx?direct=true&db=
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c8h&AN=112147980&site=eds-live. doi: 10.1001/jamainternmed.2015.7248.
22. Institute for Clinical and Economic Review. PCSK9 inhibitors for treatment of high cholesterol: Effectiveness, value, and ValueBased price benchmarks. https://icer-review.org/wpcontent/uploads/2016/01/Final-Report-for-Posting-11-24-15-1.pdf. Accessed 08/16, 2016.
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23. Writing Committee, Lloyd-Jones DM, Morris PB, et al. 2016 ACC expert consensus decision pathway on the role of non-statin therapies for LDL-cholesterol lowering in the management of
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atherosclerotic cardiovascular disease risk: A report of the american college of cardiology task force on clinical expert consensus documents. J Am Coll Cardiol. 2016;68(1):92-125. doi:
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10.1016/j.jacc.2016.03.519 [doi].
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11-17 days None
140mg every 2 weeks or 420mg ever 4 weeks Lipid panel 4-8 weeks Lipid panel 4-8 Monitoring following initiation weeks following initiation *Starting dose 75mg every 2 weeks. If response inadequate dose may be increased to 150mg every 2 weeks
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Dosing
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Half-life Drug Interactions
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TABLE 1 Pharmacology of Currently Available PCSK9 Inhibitors Evolocumab Alirocumab (PRALUENT®) (REPATHA®) Saturable binding to Saturable binding to Elimination route PCSK9; non-saturable PCSK9; nonproteolytic pathway saturable proteolytic pathway None None Dose Adjustments
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TABLE 2
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ODYSSEY LONG TERM OSLER Results Results - Alirocumab Evolocumab HeFH, established ASCVD, Variable* Inclusion Criteria or CHD risk equivalent; Max tolerated statin 99 70 Percent receiving statin (%) 70mg/dl 85-100mg/dl LDL-C Cutoff for Inclusion 80 weeks 50 weeks Average Follow-up Period 61 58 LDL-C Reduction (%) HeFH= heterozygous familial hypercholesterolemia; ASCVD=atherosclerotic cardiovascular disease; CHD=coronary heart disease; LDL=low-density lipoprotein *Results of the OSLER 1 and OSLER 2 trials were combined and reported. OSLER 1 and 2 consisted of patients who enrolled in 1 or 12 parent studies and opted to continue treatment into a long-term extension.
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PCSK9 Inhibitors are novel entities that are becoming more commonly used. It is critical for providers to have a basic understanding of the pharmacology, indications, efficacy, safety, and proper use of these agents.