Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein that regulates low-density lipoprotein cholesterol (LDL-C) levels in the blood by regulating LDL receptor metabolism. Missense mutations in PCSK9, leading to increased LDL receptor degradation, have been associated with hypercholesterolemia since being identified in humans in 2003.¹ Subsequent studies determined that PCSK9 activity correlates with plasma LDL-C levels, thus making PCSK9 inhibitors a potential target for therapy to lower LDL-C.² Another potent therapy to lower LDL-C raises the continuing question: is the pharmacologic ability to lower LDL-C a surrogate for improvement in cardiovascular outcomes? This brief commentary will examine the current evidence related to PCSK9 inhibition and CVD events.

The first suggestion that impaired PCSK9 activity might lower CVD events stems from a study in 2006 looking at mutations in the gene. Even in high-risk populations, mutations resulting in loss of function of PCSK9 resulted in not only LDL-C reductions but also even greater reductions in CVD events.³

Currently, three PCSK9 antibodies have been used in clinical trials: alirocumab, evolocumab, and bococuzumab. Each is an injectable medication administered subcutaneously. The first two have completed phase 3 clinical trials, while the third is recruiting for phase 3.⁴ Two recent trials that were presented at ACC.15 and published concurrently in The New England Journal of Medicine present data regarding these first two drugs.

Monoclonal Antibody	Route of Administration	Phase of Development	Pivotal Trial
Alirocumab	Subcutaneous	III - completed	ODYSSEY
Evolucumab	Subcutaneous	III - completed	OSLER
Bococuzumab	Subcutaneous	III - enrolling	SPIRE

The Open-Label Study of Long-Term Evaluation Against LDL Cholesterol (OSLER) trial examined the long-term effects of evolocumab as an extension of the open-label, randomized controlled OSLER 1 and 2 trials and included 4,465 patients. Eligible patients had completed either of the trials without suffering any adverse events that required discontinuation of study drug. Participating patients were re-randomized to the PCSK9 inhibitor plus standard therapy versus standard therapy alone without placebo control. Approximately 70% of patients were receiving background statin therapy. The majority of patients were Caucasian with approximately 80% having other cardiovascular risk factors including hypertension, diabetes, metabolic syndrome, current cigarette use, or family history of premature coronary artery disease or familial hypercholesterolemia. Throughout the 48-56-week trial period, study patients had regular visits while the standard care group was contacted only by telephone.

The incidence of adverse events, the primary endpoint, was more common in the evolocumab group (69.2% vs. 64.8%). However, serious adverse events were similar (7.5% in each group). Percent reduction in LDL-C was a secondary endpoint. Baseline LDL-C was 120 mg/dL before the initial randomization into the parent studies and was reduced by 61% to a mean of 48 mg/dL, which is consistent with previous findings regarding the percent reduction. An important point is that although the levels of LDL-C were driven very low, adverse neurocognitive events did not correlate with the level of LDL-C despite occurring more frequently in the evolocumab group (0.9% vs. 0.3% in the standard-therapy group). A key endpoint of clinical significance to address the above questions was the adjudicated incidence of cardiovascular events, including death, myocardial infarction, unstable angina requiring hospitalization, coronary revascularization, stroke, transient ischemic attack, and heart failure requiring hospitalization. These cardiovascular events occurred in a 1% of the evolocumab group versus 2% of the standard therapy group (HR 0.47, p = 0.0003).⁵ The Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) study is ongoing to confirm this finding and to determine if adding a PCSK9 inhibitor to standard, proven therapy with statins will further decrease cardiovascular events over long-term follow-up.

The ODYSSEY LONG TERM trial enrolled 2,341 high-risk patients with heterozygous familial hypercholesterolemia, known coronary artery disease, or coronary artery disease risk equivalent in a randomized, double-blind, placebo-controlled trial. Eligible patients had LDL-C levels above 70 mg/dL and were currently taking either high-dose statins or maximum tolerated dosages. Other lipid lowering therapies were also allowed, and all patients were instructed on the Therapeutic Lifestyle Changes or equivalent diet. The majority (93%) of patients were Caucasian with nearly 18% having heterozygous familial hypercholesterolemia. Mean LDL-C at baseline was 122.7 mg/dL in the alirocumab group versus 121.9 in the placebo group.

The primary endpoint, change in LDL-C levels from baseline to 24 weeks, was positive. LDL-C levels were reduced by 61% in the alirocumab group to a mean of 48 mg/dL compared to an increase of 0.8% in the placebo group. This degree of change is consistent with previous studies. Importantly, as was seen in the OSLER trial, no effect was seen in levels of fat-soluble vitamins or cortisol as a result of the significantly decreased LDL-C levels. The safety endpoints included adverse events as well as adjudicated cardiovascular events and were not significantly different between the two groups.

Adjudicated cardiovascular events occurred in 4.6% of the alirocumab group versus 5.1% of the control group (p = 0.02). A post-hoc analysis of cardiovascular events that included a composite of death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization showed lower rates with alirocumab than with placebo (1.7% vs. 3.3%, HR 0.52, p = 0.02).⁶ However, unlike the OSLER trial, heart failure requiring hospitalization and ischemia-driven revascularization were not included as cardiovascular events in this post hoc analysis. When these events were included, the difference between groups was no longer significant.

The ODYSSEY OUTCOMES trial, which is currently ongoing, will focus on cardiovascular events as a primary endpoint following an acute coronary syndrome.⁷

Most recently, a systematic review and meta-analysis was conducted looking at PCSK9 inhibition and mortality as primary clinical endpoints using 24 randomized controlled trials encompassing 10,159 patients. All-cause mortality was significantly lower in the PCSK9 group compared to placebo (0.31% vs. 0.53% respectively, OR 0.45, p = 0.015). However, cardiovascular mortality did not show a statistically significant reduction (0.19% vs. 0.33%, OR = 0.50, p = 0.08), although this was most likely due to insufficient power as there was a strong trend towards a reduction with PCSK9 inhibitors.⁴

Taken together, current studies show promise for the future clinical application of PCSK9 inhibitors. Certainly the role of PCSK9 in cardiovascular disease has come a long way since the gene was discovered in 2003. The issue remains that LDL-C lowering is not always a surrogate for reduction of clinically meaningful events. Clearly PCSK9 inhibition is a potent effector of LDL-C – but we still do not know if those reductions are associated with CV benefit in long-term use, or if those benefits are countered by harm (e.g., neurocognitive defects) that counterbalance the benefit.

References

1. Abifadel M, Varret M, Rabes J-P, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 2003;34:154-6.
2. Kotowski IK, Pertsemlidis A, Luke A, et al. A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol. Am J Hum Genet 2006;78:410-22.
3. Cohen JC, Boerwinkle E, Mosley TH, et al. Sequence Variation in PCSK9, Low LDL, and Protection against Coronary Heart Disease. N Engl J Med 2006;354:1264-72.
4. 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 meta-analysis. Ann Intern Med 2015 Apr 28. [Epub ahead of print]
5. Sabatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1500-9.
6. Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1489-99.
7. U.S. National Institutes of Health. NCT01663402: ODYSSEY outcomes: evaluation of cardiovascular outcomes after an acute coronary syndrome during treatment with alirocumab SAR236553 (REGN727) (ClinicalTrials.gov website). 2015. Available at: http://ClinicalTrials.gov/show/NCT01663402. Accessed 5/23/15.

Keywords: Acute Coronary Syndrome, Angina, Unstable, Cardiovascular Diseases, Cholesterol, Cholesterol, LDL, Control Groups, Coronary Artery Disease, Diabetes Mellitus, Diet, Double-Blind Method, Follow-Up Studies, Heart Failure, Hospitalization, Hydrocortisone, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypercholesterolemia, Hyperlipoproteinemia Type II, Hypertension, Incidence, Ischemic Attack, Transient, Life Style, Lipoproteins, LDL, Metabolic Syndrome, Mutation, Missense, Myocardial Infarction, Outcome Assessment, Health Care, Parents, Pharmaceutical Preparations, Proprotein Convertases, Random Allocation, Receptors, LDL, Risk Factors, Stroke, Subtilisins, Vitamins

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