Proprotein convertase subtilisin/kexin type 9 (PCSK9) is the ninth and final member of a class of pro-proteins. Mapped to the short arm of chromosome 1 in 2003 by Abifadel, this pro-protein is unique among its class. Though like others from this group it is released from the hepatocyte as a zymogen and requires auto cleavage to endow it with activity, it differs insofar as its prosegment subsequently binds to the molecule's enzymatic site. Thus, in its active form PCSK9 is strictly a binding protein. It plays no role in catalysis. And it is in its binding that PCSK9 plays a dominant part in LDL metabolism.

PCSK9 binds almost exclusively to the LDL receptors (LDLR) residing in clatharin coated pits on hepatocytes. Its role in LDL metabolism is fascinating and consequential. When bound to an LDLR, PCSK9 leads to the intracellular destruction of the LDLR along with the receptor's intended cargo, an LDL particle. As the LDLR is intended to make approximately 150 trips in and out of the hepatocyte, bringing 150 LDL particles to their demise, cutting short the lifespan of the LDLr leads to a dramatic rise in circulating LDL-C levels.

Our growing understanding of LDL-C has created a shift from the 'LDL Hypothesis' to the 'LDL Truth.' Higher LDL-C levels do cause more heart attacks, strokes, and death while lower LDL-C levels cause the opposite effect. Numerous lines of evidence, such as multiple confirmatory Randomized Controlled Trials (RCT) and Mendelian Randomization Studies (MR), have proved this to be true. Consequently, Abifadel's discovery catalyzed a surge of research to create a therapeutic solution which would lower PCSK9 levels, lower LDL-C, and concomitantly presumably lower cardiovascular events.

In 2007, scientists from Pfizer and Amgen independently published PCSK9's crystal structure; in 2010, Regeneron/Sanofi and Amgen began human clinical trials with fully human monoclonal antibodies (mAb) to PCSK9, and in 2015 alirocumab and evolocumab were approved by the FDA. These drugs rapidly bind all circulating PCSK9, essentially removing PCSK9 from involvement in LDL metabolism and thereby intensively and predictably lowering LDL-C levels in the blood. Disturbingly, their approval was not met with the celebratory response one might have anticipated. Instead, battles have ruled the day.

Even before their FDA approval, organizations such as the Institute for Clinical and Economic Review (ICER) and papers in powerful journals such as the Journal of the American Medical Association projected that these novel and costly fully human monoclonal antibodies would bankrupt our healthcare system.^1,2 They projected a 1.2-billion-dollar cost in the first year following their release. Insurance companies were proactive. They armed themselves with complex prior authorization (PA) requirements, burdensome step therapy demands, and approval processes that have been shown to be capricious. As a result, the PCSK9 mAb cost to our nation was a mere 83 million dollars in year one, about 1.2% of predicted. Translation: far fewer people received these FDA approved medications than had been predicted, and, accordingly, far fewer people were better protected against cardiovascular events. The last two years represent an unfortunate time in modern medicine. Doctors possess a long-awaited superb, novel therapeutic; yet, they are unable to appropriately provide it to their patients.

Some of the evidence demonstrating illogical payer processes stem from two posters and one paper.^3-5 These data reveal that regardless of statin therapy, the use of ezetimibe, or even dual anti-platelet therapy--prescriptions that are pathognomonic for clinical ASCVD--approval rates are unaffected. Additionally, final approval rates are abysmally low, 30.5% in commercial insurance and 58% in Medicare recipients. Higher approval rates and shorter times to approval in Medicare beneficiaries implies an impact from Federal oversight, and a high level of reversals from 'denied' to 'approved' implies improper adjudication. Knowles et al. demonstrated similar findings of frequent PCSK9i denials in high risk, 'appropriate' patients. One of the most egregious discoveries was in those with familial hypercholesterolemia (FH) and extremely high LDL-C. Of the 237 presumptive FH patients who had an LDL-C value >190 mg/dL despite evidence of statin-based LLT, 63% of prescriptions for PCSK9 inhibitors were rejected. In comparison, 9% of prescriptions for ezetimibe were rejected in a similar patient population.

Looking closer at who bears the brunt of insurance restrictions, one need search no further than the drugs' package inserts (PI). These medications have been FDA approved for patients with FH (a common high-ASCVD-risk monogenic LDL disorder occurring in 1/250 individuals worldwide) or clinical ASCVD on maximally tolerated statin therapy yet requiring greater LDL reduction. Parsing the PI, five definitions require clarification: FH (both heterozygous and homozygous), clinical ASCVD, maximally tolerated statin therapy, and requiring greater reduction in LDL-C.

To elucidate these definitions and ease the burden on patients, clinicians, and yes, even payers, the American Society for Preventive Cardiology (ASPC) convened a group of experts from various organizations – the FH Foundation, American Association of Clinical Endocrinologists, the National Lipid Association, and the American College of Cardiology. Multiple Town Halls provided an opportunity to understand the nuances of PCSK9 mAb access issues and find solutions to these problems. Ultimately the group's findings and recommendations were published in Clinical Cardiology, the official journal of the ASPC.⁶

An example of one such definition is: "Maximally tolerated statin therapy is defined as the highest tolerated intensity and frequency of a statin, even if the dose is zero..." The document also contains single page PA and Appeal letters. The letters and their five consensus definitions have been constructed to simplify and thereby improve access to these drugs. I highly recommend utilizing the paper and its two attachments as a resource when prescribing this class of medication. To date, they have helped numerous clinicians obtain these medications for suitable patients.

Finally, FOURIER (Further Cardiovascular Outcomes Research With PCSK0 Inhibition in Subjects With Elevated Risk) recently shed light on the efficacy of evolocumab, and by extension the potential impact of inappropriate PCSK9i denials.⁷ FOURIER evaluated 27,564 individuals with prior ASCVD, comparing evolocumab to placebo. A 59% LDL-C reduction with evolocumab resulted in a 20% decrease in MI, CVA, or CV death in the 2-year trial. Through a landmark analysis, a 25% reduction in these endpoints was found in year two. Such results are comparable to what was anticipated from the findings in the Cholesterol Treatment Trialists' Collaboration (CTTC). Thus, FOURIER demonstrated what many lipidologists had anticipated, a proportionate reduction in cardiovascular events in line with a given reduction in LDL-C.

In sum, three points should be emphasized. First, LDL-C is causally related to ASCVD. Higher LDL-C levels cause more events, and diminishing LDL-C reduces such events. Second, FOURIER proved that evolocumab, a PCSK9i, on top of maximally tolerated statin therapy statistically significantly lowers the combined risk of heart attack, stroke and CV death. And finally, clinicians must often advocate on behalf of their patients to gain access to the PCSK9 mAb. Using the Clinical Cardiology paper previously cited can help us accomplish this, and in so doing, help us to help our patients.

PCSK9 Inhibitors: A Revolution in Lipid Lowering Therapy: Breaking Down Barriers to Access PCSK9, an integral aspect of LDL-C metabolism. PCSK9 inhibitors: intensive and predictable therapies to lower LDL-C. PCSK9 inhibitors: fully human monoclonal antibodies to PCSK9. PCSK9 inhibitors are costly and extreme barriers have been erected to limit their use. FDA indications for PCSK9 inhibitors are clear and can be understood by reading http://onlinelibrary.wiley.com/doi/10.1002/clc.22713/pdf. Download the prior authorization and appeals letters from above-cited paper to gain access for appropriate patients.

References

1. ICER draft report on effectiveness, value, and pricing benchmarks for PCSK9 inhibitors for high cholesterol posted for public comment. Institute for Clinical and Economic Review website. https://icerreview.org/announcements/pcsk9-draft-report-release. Accessed 15 March 2017.
2. Kazi DS, Moran AE, Coxson PG, et al. Cost-effectiveness of PCSK9 inhibitor therapy in patients with heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease. JAMA 2016;316:743-53.
3. Baum SJ, Chen C, Rane PB. Time to approval in patients requesting access to PCSK9i therapy by payer type. Presented at AMCP 2017.
4. Baum S, Chen C, Rane PB. Characteristics of patients approved and denied access to PCSK9i Therapy by Payers. Presented at American College of Cardiology Scientific Sessions 2017.
5. Knowles JW, Howard WB, Karayan L, et al. Access to non-statin lipid lowering therapies in patients at high-risk of atherosclerotic cardiovascular disease. Circulation 2017;135:2204-6.
6. Baum SJ, Toth PP, Underberg JA, Jellinger P, Ross J, Wilemon K. PCSK9 inhibitor access barriers-issues and recommendations: improving the access process for patients, clinicians and payers. Clin Cardiol 2017;40:243-54.
7. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713-22.

Keywords: Hyperlipoproteinemia Type II, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Blood Platelets, Chromosomes, Human, Pair 1, Antibodies, Monoclonal, Receptors, LDL, Nerve Tissue Proteins, Transcription Factors, Drosophila Proteins, Cholesterol, Stroke, Proprotein Convertases, Myocardial Infarction, Enzyme Precursors, Hepatocytes, Lipids, Catalysis, Subtilisins, Dyslipidemias

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