Abstract
Proprotein convertase subtilisin/kexin type 9 inhibitors serve as a valuable addition to the armamentarium of lipid-lowering agents and have promising potential. By inhibiting the proprotein convertase subtilisin/kexin type 9 enzyme, this novel molecule leads to increased low-density lipoprotein receptor density and decreased circulation of low-density lipoprotein. 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.
Keywords
Proprotein convertase subtilisin/kexin type 9 was first discovered in 2003.
1
After 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 important, proprotein convertase subtilisin/kexin type 9 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 proprotein convertase subtilisin/kexin type 9 inhibitor was approved by the Food and Drug Administration (FDA).4
Although statins remain a mainstay treatment for hypercholesterolemia and secondary prevention of cardiovascular events, proprotein convertase subtilisin/kexin type 9 inhibitors serve as a valuable addition to the armamentarium of lipid-lowering agents and have promising potential.FDA approves Praluent to treat certain patients with high cholesterol first in a new class of injectable cholesterol-lowering drugs. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm455883.htm. Accessed August 16, 2016.
Mechanism of Action
Proprotein convertase subtilisin/kexin type 9, a serine protease produced predominantly within hepatocytes, serves to regulate low-density lipoprotein receptor (LDL-R) density on hepatocytes.
5
When LDL-C comes into contact with LDL-R on the surface of hepatocytes, the low-density lipoprotein (LDL)/LDL-R complex that is formed subsequently undergoes endocytosis. After endocytosis, the LDL particle undergoes degradation in the lysosome, and in the absence of proprotein convertase subtilisin/kexin type 9, the LDL-R is recycled and taken back to the cell surface. On the contrary, in the presence of proprotein convertase subtilisin/kexin type 9, the LDL-R is flagged for destruction within the lysosome along with the LDL particle, effectively reducing the LDL-R density on hepatocytes. Thus, proprotein convertase subtilisin/kexin type 9 concentrations are indirectly proportional to LDL-R density and directly proportional to serum LDL-C concentrations. Therefore, by directing inhibiting proprotein convertase subtilisin/kexin type 9, LDL-R density is increased and circulating LDL-C is reduced.Indications
Currently, there are 2 FDA-approved proprotein convertase subtilisin/kexin type 9 inhibitors, each of which is human monoclonal antibodies available in prefilled pens for subcutaneous administration 1 to 2 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 who require additional LDL-C lowering. Evolocumab is approved for the treatment of both heterozygous familial hypercholesterolemia and homozygous familial hypercholesterolemia, whereas alirocumab is approved only for the treatment of heterozygous familial hypercholesterolemia.Table 1Pharmacology of Currently Available Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors
| Alirocumab (Praluent; Sanofi-Aventis LLC, Bridgewater, NJ) | Evolocumab (Repatha; Amgen Inc, Thousand Oaks, Calif) | |
|---|---|---|
| Elimination route | Saturable binding to PCSK9; nonsaturable proteolytic pathway | Saturable binding to PCSK9; nonsaturable proteolytic pathway |
| Dose adjustments | None | None |
| Half-life | 17-20 d | 11-17 d |
| Drug interactions | None | None |
| Dosing | 75-150 mg every 2 wk | 140 mg every 2 wk or 420 mg ever 4 wk |
| Monitoring | Lipid panel 4-8 wk after initiation | Lipid panel 4-8 wk after initiation |
PCSK9 = proprotein convertase subtilisin/kexin type 9.
∗ Starting dose 75 mg every 2 weeks. If response inadequate, dose may be increased to 150 mg every 2 wk.
Ongoing studies are being conducted to evaluate the use of proprotein convertase subtilisin/kexin type 9 inhibitors in patients after acute coronary syndrome, patients with human immunodeficiency virus, and patients with diabetes, among others.
8
In addition, a third proprotein convertase subtilisin/kexin type 9 inhibitor, bococizumab, is in phase III clinical trials and being evaluated in similar populations as alirocumab and evolocumab, as well as in a separate clinical trial in human immunodeficiency virus–infected subjects.Ongoing Clinical Trials with PCSK9 Inhihbitors. Available at: www.clinicaltrials.gov. Accessed August 19, 2016.
9
Two additional phase 3 lipid-lowering studies of bococizumab deliver positive topline results. Available at: http://www.pfizer.com/news/press-release/press-release-detail/two_additional_phase_3_lipid_lowering_studies_of_bococizumab_deliver_positive_topline_results. Accessed August 19, 2016.
Efficacy
Available studies to date of alirocumab and evolocumab show these agents to be remarkably effective at lowering LDL-C (Table 2).
10
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Average LDL-C reduction with a proprotein convertase subtilisin/kexin type 9 inhibitor compared with placebo in a meta-analysis of available trials is 58%.12
In the ODYSSEY LONG TERM and OSLER trials, approximately 80% of patients receiving a proprotein convertase subtilisin/kexin type 9 inhibitor achieved a goal LDL-C less than 70 mg/dL, compared with <10% in the placebo groups. Total cholesterol, apolipoprotein B, and triglycerides also are reduced considerably with alirocumab or evolocumab therapy, whereas high-density lipoprotein cholesterol increases only slightly.12
, 13
Table 2Results of the Long-Term LDL Lowering Trials for the Currently Approved PCSK9 Inhibitors
| ODYSSEY LONG TERM Results - Alirocumab | OSLER Results - Evolocumab | |
|---|---|---|
| Inclusion Criteria | HeFH, established ASCVD, or CHD risk equivalent; Maximum tolerated statin | Variable |
| Percent receiving statin (%) | 99 | 70 |
| LDL-C cutoff for inclusion | 70 mg/dL | 85-100 mg/dL |
| Average follow-up period | 80 wk | 50 wk |
| LDL-C reduction (%) | 61 | 58 |
ASCVD = atherosclerotic cardiovascular disease; CHD = coronary heart disease; HeFH = heterozygous familial hypercholesterolemia; LDL-C = low-density lipoprotein cholesterol.
∗ 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.
Although proprotein convertase subtilisin/kexin type 9 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 or 2018. Systematic reviews and meta-analyses of current prospective proprotein convertase subtilisin/kexin type 9 inhibitors trials suggest an all-cause mortality benefit, but a reduction in cardiovascular mortality or major adverse cardiovascular events has not been detected.
12
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Adverse Events
Although proprotein convertase subtilisin/kexin type 9 has a role in many other 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 proprotein convertase subtilisin/kexin type 9 have not shown a heightened risk of untoward effects.15
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Consistent with these observations, data from randomized controlled trials have shown proprotein convertase subtilisin/kexin type 9 inhibitors to be well tolerated with no difference in serious adverse effects compared with placebo.12
, 13
The most common adverse events experienced in clinical trials were injection site reactions. In addition, proprotein convertase subtilisin/kexin type 9 inhibitors seem to invoke fewer muscle-related adverse effects compared with statins.18
, 19
Disturbances in liver function test results and creatinine kinase have not been observed in available studies.Early evidence shows a potential correlation with proprotein convertase subtilisin/kexin type 9 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
Cost
The annual cost of alirocumab and evolocumab is approximately $14,000.
21
Estimations predict that if all eligible individuals aged 35 to 75 years were to use an approved proprotein convertase subtilisin/kexin type 9 inhibitor, annual prescription spending would increase by 38% (∼$125 billion) and US health care expenditures would increase by 4% (∼$120 billion).21
At the current expense, proprotein convertase subtilisin/kexin type 9 inhibitors are not believed to be cost-effective medications for patients with heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease. Cost analyses suggest a price reduction of approximately 60% to 85% of the current price would be necessary for the agents to be considered cost-effective.21
, 22
Institute for Clinical and Economic Review. PCSK9 inhibitors for treatment of high cholesterol: effectiveness, value, and ValueBased price benchmarks. Available at: https://icer-review.org/wp-content/uploads/2016/01/Final-Report-for-Posting-11-24-15-1.pdf. Accessed August 16, 2016.
Advice to Clinicians (How and When to Use)
Proprotein convertase subtilisin/kexin type 9 inhibitors have the potential to change the landscape of how we treat hypercholesterolemia; however, such enthusiasm should be approached cautiously to ensure judicious resource use until outcomes data are available and they are made more cost-effective. Although proprotein convertase subtilisin/kexin type 9 inhibitors and other nonstatin therapies can be considered in high-risk patients who are intolerant to statins, are unable to tolerate goal doses, or have suboptimal response to statins, it is important to remember that statins remain the backbone for the 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 to 100 mg/dL was used in clinical trials as a cutoff for treatment inclusion with either agent. Most insurance companies will have only 1 of these agents on formulary and will require strict precertification before paying for them, including documentation of a high-intensity statin and, in some instances, use of ezetimibe first. Because of the cost of these agents, specialty pharmacies often will be required by third-party payers.- Lloyd-Jones D.M.
- Morris P.B.
- et al.
Writing Committee
2016 ACC expert consensus decision pathway on the role of non-statin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: a report of the American College of Cardiology task force on clinical expert consensus documents.
2016 ACC expert consensus decision pathway on the role of non-statin therapies for LDL-cholesterol lowering in the management of 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: 92-125
References
- PCSK9: from discovery to therapeutic applications.Arch Cardiovasc Dis. 2014; 107: 58-66
- PCSK9: a key modulator of cardiovascular health.Circ Res. 2014; 114: 1022-1036
- Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.N Engl J Med. 2006; 354: 1264-1272
FDA approves Praluent to treat certain patients with high cholesterol first in a new class of injectable cholesterol-lowering drugs. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm455883.htm. Accessed August 16, 2016.
- Proprotein convertase subtilisin/kexin type 9 inhibition: a new therapeutic mechanism for reducing cardiovascular disease risk.Circulation. 2015; 132: 1648-1666
- Praluent (Alirocumab) Package Insert. Sanofi-Aventis LLC, Bridgewater, NJ2015
- Repatha (Evolocumab) Injection. Amgen Inc, Thousand Oaks, CA2016
Ongoing Clinical Trials with PCSK9 Inhihbitors. Available at: www.clinicaltrials.gov. Accessed August 19, 2016.
Two additional phase 3 lipid-lowering studies of bococizumab deliver positive topline results. Available at: http://www.pfizer.com/news/press-release/press-release-detail/two_additional_phase_3_lipid_lowering_studies_of_bococizumab_deliver_positive_topline_results. Accessed August 19, 2016.
- Efficacy and safety of alirocumab in reducing lipids and cardiovascular events.N Engl J Med. 2015; 372: 1489-1499
- Efficacy and safety of evolocumab in reducing lipids and cardiovascular events.N Engl J Med. 2015; 372: 1500-1509
- Effects of proprotein convertase subtilisin/kexin type 9 antibodies in adults with hypercholesterolemia: a systematic review and meta-analysis.Ann Intern Med. 2015; 163: 40-51
- The impact of proprotein convertase 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: 536-545
- Role of PCSK9 beyond liver involvement.Curr Opin Lipidol. 2015; 26: 155-161
- The loss-of-function PCSK9 p.R46L genetic variant does not alter glucose homeostasis.Diabetologia. 2015; 58: 2051-2055
- Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote.Am J Hum Genet. 2006; 79: 514-523
- PCSK9 inhibition in LDL cholesterol reduction: genetics and therapeutic implications of very low plasma lipoprotein levels.Pharmacol Ther. 2015; 145: 58-66
- Clinical profile of statin intolerance in the phase 3 GAUSS-2 study.Cardiovasc Drugs Ther. 2016; 30: 297-304
- Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: the GAUSS-3 randomized clinical trial.JAMA. 2016; 315: 1580-1590
- PCSK9 inhibitors and neurocognitive adverse events: exploring the FDA directive and a proposal for N-of-1 trials.Drug Saf. 2015; 38: 519-526
- Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors for treatment of high cholesterol levels: effectiveness and value.JAMA Intern Med. 2016; 176: 107-108
Institute for Clinical and Economic Review. PCSK9 inhibitors for treatment of high cholesterol: effectiveness, value, and ValueBased price benchmarks. Available at: https://icer-review.org/wp-content/uploads/2016/01/Final-Report-for-Posting-11-24-15-1.pdf. Accessed August 16, 2016.
- 2016 ACC expert consensus decision pathway on the role of non-statin therapies for LDL-cholesterol lowering in the management of 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: 92-125
Article info
Publication history
Published online: October 14, 2016
Footnotes
Funding: None.
Conflict of Interest: None.
Authorship: Both authors had access to the data and played a role in writing this manuscript.
Identification
Copyright
© 2016 Elsevier Inc. All rights reserved.
