Background

It has been a decade since the initial reported association between loss of function genetic variants impairing the gene encoding anti-proprotein convertase subtilisin/kexin type 9 (PCSK9), a lifelong reduction in LDL cholesterol (LDL-C) levels, and protection from cardiovascular disease.¹ In this short span of time, anti-PCSK9 monoclonal antibodies were developed and recently shown to have favorable safety and efficacy profiles in phase III lipid-lowering trials. These antibodies target PCSK9, a protease that binds and promotes degradation of the LDL receptor, leading more LDL receptors on the surface of hepatocytes, and a lower level of serum LDL-C.

A synergistic benefit of using PCSK9 inhibitors with statins is also proposed since statin therapy causes upregulation of PCSK9 levels in hepatocytes. PCSK9 inhibitors demonstrated an unprecedented 60% reduction in LDL-C on the background of statin therapy with evolocumab in the OSLER (Open Label Study of Long Term Evaluation Against LDL-C) clinical trials and with alirocumab in the ODYSSEY LONG TERM (Long-term Safety and Tolerability of Alirocumab [SAR236553/REGN727] Versus Placebo on Top of Lipid-Modifying Therapy in High Cardiovascular Risk Patients With Hypercholesterolemia) clinical trial.^2,3 Furthermore, addition of PCSK9 inhibitors reduced cardiovascular events by approximately 50%, although these phase III lipid-lowering trials were not designed as outcome trials, and the event rates were low.

Current Indications

In light of the promising findings from the phase II and III lipid-lowering trials, during the summer of 2015 the US Food and Drug Administration fast-track approved the use of anti-PCSK9 monoclonal antibodies, namely evolocumab and alirocumab, as adjuncts to diet and maximally tolerated statin therapy for patients with familial hypercholesterolemia (FH), and those with clinical atherosclerotic cardiovascular disease (ASCVD), requiring a greater reduction in LDL-C levels. These indications were selected since these subgroups confer the highest risk of future cardiovascular events, and were previously studied in phase II and III lipid-lowering trials. Although several trials studied the use of PCSK9 inhibitors in other patient subgroups, such as statin-intolerant patients in the GAUSS-3 (Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-3) trial, these agents are not currently approved for other indications.⁴ Nevertheless, a meta-analysis by Navarese and colleagues incorporating 24 phase II and III trials revealed no heterogeneity among the included trial results, proposing that the benefits of PCSK9 inhibitors can be extended to other subgroups of patients studied.⁵ Table 1 shows indications for evolocumab and alirocumab from their US prescribing labels.

Table 1: FDA Approved Indications for Anti-PCSK9 Monoclonal Antibodies in Addition to Diet and Maximally Tolerated Statin Therapy for Additional LDL-C Lowering

	Clinical ASCVD*	Heterozygous FH	Homozygous FH
Evolocumab (Repatha)	+	+	+
Alirocumab (Praluent)	+	+	-

Costs

Alirocumab and evolocumab are estimated to cost approximately $14,350 per patient for a one-year supply in the United States, or approximately $1200 per month.⁶ The cost of these monoclonal antibodies is comparable to other biologic agents currently in use. For example, the average cost for etanercept and adalimumab, tumor necrosis factor blocking agents used for rheumatoid arthritis, ranges from approximately $1,000 to $2,500 per month, respectively. A report by the Institute for Clinical and Economic Review (ICER) showed that PCSK9 inhibitors produced ICER values of $290,000, $302,000, and $170,000 per quality-adjusted life-year (QALY) free of major adverse cardiac event in patients with FH, in secondary-prevention patients with LDL-C ≥70mg/dL on statin therapy, and in patients following a first myocardial infarction (MI), respectively. Thus, it is estimated based on these calculations that the cost of these drugs would need to be reduced substantially to reach a willingness-to-pay threshold of $50,000 per QALY gained. Using a more generous willingness-to-pay threshold of $150,000 per QALY gained, these agents would be cost-effective at half the current price for the first two scenarios, and with a price reduction of approximately 12% in patients with first MI. However, it is important to note that this ICER analysis based cardiovascular event rate assumptions on the meta-analysis by Navarese and colleagues from studies with very low event rates.⁵ Therefore, the cost-effectiveness should be more favorable in higher risk patients currently being studied in the ongoing phase III outcomes studies.^7-10

The cost-effectiveness of these agents may be even more favorable if PCSK9 inhibitors cause plaque regression, similar to statins, resulting in a "legacy effect" after discontinuation. Plaque regression and stabilization is another benefit of lipid-lowering therapy (particularly of statins), follows a linear relation to the achieved LDL-C, and is thought to play a significant role in persistent relative cardiovascular event reduction in post-trial follow-up.¹¹ Such a legacy effect was reported in the WOSCOPS (West of Scotland Coronary Prevention Study) trial in which patients receiving 5 years of statin therapy continued to have significantly reduced mortality even 15 years after the trial was completed.¹² PCSK9 inhibitors, offering a more robust and persistent LDL-C lowering, could provide a more profound legacy effect, such that uninterrupted life-long therapy with PCSK9 inhibitors may not be required. Thus, it is interesting to speculate whether patients could be treated for several years with a PCSK9 inhibitor and then have an interval break to reduce drug cost. Such a strategy should be prospectively tested in a follow-up study if the ongoing phase III outcome studies are positive.

Clinical Use

There are a four ongoing and highly anticipated phase III cardiovascular outcome trials of PCSK9 inhibitors. Table 2 summarizes the main characteristics of these trials including the populations studied. The populations studied in these phase III outcome trials will establish the future indications for PCSK9 inhibitors. For example, positive results in these trials could extend the indications of these agents to patients with high risk of cardiovascular events with LDL-C levels ≥70 mg/dL.

Table 2: Phase III Cardiovascular Outcome Trials of PCSK9 inhibitors

	Alirocumab	Evolocumab	Bococizumab
Sponsor	Sanofi/Regeneron	Amgen	Pfizer
Trial	ODYSSEY Outcomes	FOURIER	SPIRE I	SPIRE II
Sample size	18,000	27,500	17,000	11,000
Patients	4-52 wks post-ACS	MI, stroke or PAD	High risk of CV event
Statin	Evidence-based med Rx	Atorvastatin ≥20 mg or equivalent	Lipid-lowering therapy
LDL-C (mg/dL)	≥ 70	≥ 70	70-99	≥ 100
PCSK9 inhibitor dosing	Q2W	Q2W or Q4W	Q2W
Endpoint	CHD death, MI, ischemic stroke, or hospitalization for UA	CV death, MI, stroke, hospitalization for UA, or revascularization	CV death, MI, stroke, or urgent revascularization
Completion	2017	Before end of 2016	2017

Although outcome trial data are pending, we can project potential cardiovascular outcome results with PCSK9 inhibitors based on the statin trials. The landmark Cholesterol Treatment Trialists' (CTT) meta-analysis projected a 21% reduction in major vascular events per 1 mmol/L reduction in LDL-C with statins over a median of approximately 5 years of follow up.¹³ In the aforementioned trials,^2,3 PCSK9 inhibitors achieved an LDL-C reduction of 1.83 mmol/L and 1.89 mmol/L for alirocumab and evolocumab, respectively. When the CTT meta-analysis projections are applied to the LDL-C level reductions observed with PCSK9 inhibitors (assuming a 10% early stoppage rate), we estimate approximately35% reduction in major vascular events, ~42% reduction in major coronary events, ~25% reduction in stroke and ~15% reduction in all-cause mortality.

These estimations are based on cardiovascular event reductions observed from trials with statin therapy, and statins also have been associated with several pleiotropic benefits beyond LDL-C reduction that may contribute to a reduction in cardiovascular events.¹⁴ If pleotropic effects are important, then we may see a lesser clinical benefit of PCSK9 inhibitors than predicted on LDL-C reduction alone. On the other hand, recently, the non-statin ezetimibe reduced LDL-C and cardiovascular events to the degree predicted by the CTT meta-analysis based on LDL-C reduction alone in the IMPROVE-IT (Examining Outcomes in Subjects With Acute Coronary Syndrome: Vytorin [Ezetimibe/Simvastatin] vs Simvastatin [P04103]) trial.¹⁵ The same pleotropic effects reported with statins are not believed to be present with ezetimibe to the same degree; thus the data from IMPROVE-IT support the hypothesis that it is the LDL-C lowering effect alone that is the key to the reduction in cardiovascular events.

The safety profile of anti-PCSK9 monoclonal antibodies are also important to consider. Side effects thus far have been attributed to injection site reactions including erythema, pruritis, swelling and tenderness. The most common non-injection side effect reported has been nasopharyngitis. The ongoing studies are evaluating neurocognitive function in patients since there was a numeric imbalance in neurocognitive adverse events in individuals receiving PCSK9 inhibitors in OSLER and ODYSSEY LONG-TERM trials.¹⁶ While these events, including confusion and memory impairment, are uncommon and have not be consistently associated with on-treatment LDL-C levels,¹⁶ given the very low LDL-C that will be achieved with PSCK9 inhibitors (most patients will achieve <50 mg/dl, and a substantial proportion will achieve <25 mg/dL) this deserves careful evaluation. Of note, long term exposure (average 6 years) to ezetimibe plus simvastatin in a cohort of 970 patients in the IMPROVE-IT trial that achieved an LDL-C below 30 mg/dL at 1 month was not associated with an increase in adverse events.¹⁷

Findings from the ongoing PCSK9 inhibitor outcome trials undoubtedly will result in changes to existing guidelines on cholesterol treatment. The most recent 2013 ACC/AHA cholesterol guidelines de-emphasized LDL-C targets, recommended statins as the primary evidence-based agent to reduce cardiovascular events, and thereby the use of non-statin lipid lowering agents were discouraged. Following the publication of the positive results of the IMPROVE-IT trial, as well as encouraging data with PCSK9 inhibitors in the phase III lipid-lowering trials, the 2016 ACC expert consensus document expanded the role of non-statin therapies for LDL-C lowering in the management of ASCVD.¹⁸ In this expert consensus document, addition of non-statin therapies, namely ezetimibe as the first line and PCSK9 inhibitors as the second line of choice, is encouraged for patients at high ASCVD risk who continue to have high LDL-C despite maximally tolerated statin therapy. New more comprehensive Cholesterol Treatment guidelines are expected after completion of the phase III cardiovascular outcome trials with PCSK9 inhibitors.

References

1. 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;354:1264-72.
2. 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.
3. 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.
4. 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;315:1580-90.
5. Navarese EP, Koloedziejczak M, Schulze V, et al. Effects of proprotein convertase subtilisin/kexin type 9 antibodies in adults withhypercholesterolemia: a systematic review and meta-analysis. Ann Intern Med 2015;163:40.
6. Institute for Clinical and Economic Review. PCSK9 Inhibitors for Treatment of High Cholesterol: Effectiveness, Value, and Value-Based Price Benchmarks Final Report. Published November 24, 2015.
7. Sabatine MS, Giugliano RP, Keech A, et al. Rationale and design of the Further cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk trial. Am Heart J 2016;173:94-101.
8. Schwartz GG, Bessac L, Berdan LG, et al. Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY outcomes trial. Am Heart J 2014;168:682-9.
9. ClinicalTrials.gov. The Evaluation of Bococizumab (PF-04950615;RN316) in Reducing the Occurrence of Major Cardiovascular Events in High Risk Subjects (SPIRE-1).http://clinicaltrials.gov/ct2/show/NCT01975376?term=SPIRE-1&rank=1. Accessed April 28, 2016.
10. ClinicalTrials.gov. The Evaluation of Bococizumab (PF-04950615; RN316) in Reducing the Occurrence of Major Cardiovascular Events in High Risk Subjects (SPIRE-2).http://clinicaltrials.gov/ct2/show/NCT01975389?term=SPIRE-2&rank=1. Accessed April 28, 2016.
11. Robinson JG, Helstad DD, Fox KA. Atherosclerosis stabilization with PCSK9 inhibition: an evolving concept for cardiovascular prevention. Atherosclerosis. 2015;243:593-7.
12. Packard C, Ford I, Murray HM, McCowan C. Lifetime clinical and economic benefits of statin-based LDL lowering in the 20-year follow up of the West of Scotland Coronary Prevention Study. Circulation 2014;130:2105-26.
13. Cholesterol Treatment Trialists' (CTT) Collaboration, Fulcher J, O'Connell R, et al. Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials. Lancet 2015;385:1397-405.
14. Bonetti PO, Lerman LO, Napoli C, Lerman A. Statin effects beyond lipid lowering--are they clinically relevant? Eur Heart J 2003;24:225-48.
15. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015;372:2387-97.
16. 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;38:519-26.
17. Giugliano RP, Wiviott SD, Blazing MA, et al. Safety and efficacy of long-term very low achieved LDL-C in the IMPROVE IT trial. Eur Heart J 2015;36:1-161.
18. Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. 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. [Epub ahead of print]

Keywords: Acute Coronary Syndrome, Angina, Unstable, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Arthritis, Rheumatoid, Biological Factors, Cholesterol, LDL, Confusion, Diet, Drug Costs, Erythema, Hepatocytes, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypercholesterolemia, Hyperlipoproteinemia Type II, Ischemic Attack, Transient, Myocardial Infarction, Nasopharyngitis, Peptide Hydrolases, Peripheral Arterial Disease, Pharmaceutical Preparations, Proprotein Convertases, Pruritus, Quality-Adjusted Life Years, Receptors, LDL, Risk Factors, Stroke, Simvastatin, Subtilisins, Tumor Necrosis Factors, Up-Regulation, United States Food and Drug Administration

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