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The PCSK9 Inhibitors: A Novel Therapeutic Target Enters Clinical Practice

December 2015 Vol 8, No 9 - Clinical

There is a critical need for alternative, potent agents that can reduce low-density lipoprotein cholesterol (LDL-C) levels in patients with heterozygous familial hyperlipidemia and statin intolerance and those not reaching lipid-lowering treatment goals who are at high risk for cardiovascular (CV) events. The first proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor was approved in July 2015 by the US Food and Drug Administration as an adjunct to diet and maximally tolerated statin therapy for treatment of adults with heterozygous familial hyperlipidemia or clinical atherosclerotic CV disease, who require additional lowering of LDL-C levels. In clinical trials, PCSK9 inhibitors have been shown to reduce LDL-C levels by as much as 60% to 70% when administered as monotherapy or as an add-on treatment to statins and other lipid-lowering therapies. In studies of PCSK9 genetic mutations, loss of function in the PCSK9 allele was associated with a relative decrease of 88% in the risk for atherosclerotic CV events during 15 years of patient follow-up. The use of PCSK9 inhibitors may eventually support the LDL-C hypothesis that the lower the LDL-C level, the lower the CV risk. Although some recent clinical practice guidelines have deemphasized the importance of numeric LDL-C targets, many clinicians are reluctant to discard them, and this position is supported by recent clinical evidence. We eagerly await the results of the ODYSSEY, FOURIER, and SPIRE clinical outcome trials, which we anticipate will provide further validation that “lower is better” with respect to reducing LDL-C levels and improving clinical outcomes.

Key Words: familial hypercholesterolemia, low-density lipoprotein cholesterol, statin treatment, unmet needs, PCSK9 inhibitors, alirocumab, evolocumab, bococizumab, clinical guidelines, clinical studies, LDL-C hypothesis

Am Health Drug Benefits. 2015;8(9):483-488
Disclosures are at end of text

Many believe that proprotein convertase subtil­isin/kexin type 9 (PCSK9) inhibitors are the pharmacotherapeutic innovation of the decade for prevention of cardiovascular (CV) events. In clinical trials, PCSK9 inhibitors have reduced low-density lipoprotein cholesterol (LDL-C) levels by as much as 60% to 70% when administered as monotherapy or as an add-on treatment to statins and other lipid-lowering therapies.1

The PCSK9 protein was first discovered to be integral to lipid metabolism in 2003.2 This protein, produced by the hepatocyte, binds to the LDL-C and LDL receptor (LDLR) complex on the surface of the hepatocyte and is internalized into the liver cell. LDL-C binding to LDLR on the hepatocyte is the mechanism for elimination of LDL-C and other atherogenic non–high-density lipoproteins (HDL-C). However, when the PCSK9 is bound to the LDLR LDL-C complex, it leads to lysosomal catabolism of LDLR within the hepatocyte, and prevents the normal process of LDLR recycling, which can occur 150 times and further LDL-C elimination.

By sequestering PCSK9, the PCSK9 inhibitors block the binding of PCSK9 protein to the LDLR. This prevents LDLR catabolism, which, in turn, preserves LDLR recycling and increased receptor density on the hepatocyte surface. Increased LDLR density increases LDL-C binding and clearance from the blood. The PCSK9 inhibitors prolong the functional life span of, and amplify the effect of, each LDLR, resulting in the reduction of circulating LDL-C.

Atherosclerosis is caused primarily by dyslipidemia and other factors that promote deposition of cholesterol in the arterial wall. Once deposited, cholesterol plays an important role in arterial plaque development and progression, and in the pathogenesis of CV events, such as sudden cardiac death, acute coronary syndrome, stroke, and peripheral vascular disease. The Framingham Heart Study was first to show a direct correlation between total cholesterol levels, LDL-C levels, and the incidence of adverse CV events.3 Clinical trials of primary and secondary prevention with many statin and nonstatin LDL-C–lowering agents have consistently demonstrated that lowering LDL-C levels results in the reduction of CV events (Figure 1).4 The use of statins to reduce lipid levels remains the treatment of first choice for primary and secondary prevention of atherosclerotic CV events.

Figure 1

Filling Unmet Needs in Hyperlipidemia

There is great need for alternative, potent LDL-C–lowering agents for patients with heterozygous familial hyperlipidemia and statin intolerance who have a high risk for CV events. Furthermore, in patients with symptomatic atherosclerotic disease or those at high risk for it (ie, diabetes plus additional risk factors) who are unable to attain their LDL-C reduction goals despite maximally tolerated lipid-lowering therapy, additional safe and effective add-on therapies are desperately needed.

The heterozygous phenotype, which accounts for 60% to 80% of cases of familial hyperlipidemia, is often directly attributable to a heterozygous pathogenic variant in 1 of 3 genes—LDLR, APOB, PCSK9.5 Heterozygous familial hyperlipidemia occurs in 1 of 200 to 500 persons in the general population.5 Among people with untreated heterozygous familial hyperlipidemia, the risk for coronary heart disease is approximately 20-fold higher than in the general population. Patients with homozygous or heterozygous familial hyperlipidemia, and those with statin intolerance and clinical atherosclerotic cardiovascular disease (CVD), are in greatest need of PCSK9 inhibitor therapy, particularly because no adequate alternative therapies are available.

Although the gold standard for diagnosing heterozygous familial hyperlipidemia is genetic testing for the LDLR, APOB, and PCSK9 genes, clinical criteria, such as those derived from the UK Simon Broome Familial Hypercholesterolemia Registry,6 are frequently used to diagnose heterozygous familial hyperlipidemia. No widely accepted definition is available for statin intolerance. In clinical trials of PCSK9 inhibitors, the criteria for statin intolerance included muscle-related side effects with the use of at least 2 statins, of which at least 1 was administered at or below the lowest commercially available dose; the symptoms resolved after statin discontinuation.7

Sequencing of the PCSK9 gene in patients with low LDL-C demonstrated that LDL-C levels of individuals with loss-of-function PCSK9 mutations were 28% lower than those without this mutation.8 More important, and key to appreciating the potential clinical implications of PCSK9 inhibition, was the 88% relative decrease in risk for atherosclerotic CV events during 15 years of follow­up among individuals with the PCSK9 loss-of-function mutation. Conversely, gain-of-function mutations for PCSK9 led to increased levels of LDL-C.

Clinical Evidence for the Development of PCSK9 Inhibitors

In what has been a blistering pace of drug development, and only 12 years from the discovery of the relationship between the PCSK9 protein and lipid metabolism, the first PCSK9 inhibitor, alirocumab (Praluent), was approved by the US Food and Drug Administration (FDA) in July 2015. Alirocumab is indicated as an adjunct to diet and maximally tolerated statin therapy for treatment of adults with heterozygous familial hyperlipidemia or with clinical atherosclerotic CVD, who require additional lowering of LDL-C levels. Soon after, in August 2015, the FDA approved the second PCSK9 inhibitor, evolocumab (Repatha), for patients with heterozygous or homozygous familial hyperlipidemia who were unable to reach their LDL-C goals with other treatments.

A third PCSK9 inhibitor, bococizumab, is currently in development. Alirocumab, evolocumab, and bococizu­mab continue to be evaluated in clinical trials. These agents have a similar mechanism of action for reducing LDL-C values. The binding of the PCSK9 inhibitor to the PCSK9 protein prevents LDLR degradation and increases LDLR density as well as LDL-C clearance from the circulation (Figure 2).

Figure 2

To date, the clinical trial programs for these 3 PCSK9 inhibitors have evaluated a variety of clinical scenarios, including patients with heterozygous or homozygous familial hyperlipidemia, statin intolerance, and moderate to very high CV risk in patients receiving maximally tolerated statin doses and other lipid-lowering therapies whose LDL-C goals have not been achieved. In these trials, PCSK9 inhibitors have been administered as add-on to statin and/or other lipid-lowering therapies or as monotherapy in statin-intolerant patients.

In the ODYSSEY clinical trial program involving patients with heterozygous familial hyperlipidemia I and II, alirocumab therapy was associated with an LDL-C reduction of 48%, whereas placebo was associated with an increase in LDL-C.9-11 In the MONO study of patients with moderate CV risk and LDL levels ≥100 mg/dL, alirocumab decreased LDL-C concentrations by 47% at week 24 versus 16% reduction with ezetimibe.10,12 In the ODYSSEY COMBO II study of patients with high CV risk using maximally tolerated statin therapy, LDL-C levels were reduced by 51% with alirocumab and by 21% with ezetimibe at 24 weeks.13

To date, the ODYSSEY Long Term study is the largest clinical trial of a PCSK9 inhibitor.14 In this randomized study, alirocumab was compared with placebo in patients with heterozygous familial hyperlipidemia and high CV risk who were receiving maximally tolerated statins, regardless of other lipid-lowering therapies. By 24 weeks, alirocumab reduced baseline LDL-C by 61% versus 1% with placebo. Alirocumab also reduced non–HDL-C by 52% and lipoprotein(a) by 29%.14

In a hypothesis­generating retrospective post hoc analysis of the Long Term study, a 52% reduction in adjudicated major CV events was observed (Figure 3).14 Furthermore, the incidence of treatment-emergent adverse events was similar for alirocumab and for placebo (81% vs 83%, respectively), as was the incidence of treatment­emergent serious adverse events (19% vs 20%, respectively).14 Treatment-emergent local injection-site reactions were 6% in patients receiving aliroc­umab and 4% with placebo; neurologic events occurred in approximately 4% of each group.14

Figure 3

The ODYSSEY Alternative trial, which involved statin-intolerant patients, demonstrated efficacy and safety similar to those of the other trials.15 The ODYSSEY Outcomes trial is under way. In this large, long-term assessment, alirocumab is being compared with placebo in patients with acute coronary syndrome who are receiving concomitant high-potency or maximally tolerated statin therapy.16 This study should provide the data required to associate the LDL-C reduction with aliroc­umab and a clinical benefit.

The Proficio phase 3 clinical trial program involves 14 clinical trials evaluating the safety and efficacy of evoloc­umab in multiple patient populations. In the GAUSS-2 clinical trial, patients were randomized in a 2:2:1:1 manner to receive subcutaneous evolocumab 140 mg every 2 weeks or 420 mg monthly, both regimens with daily oral placebo or with subcutaneous placebo every 2 weeks or once monthly, and with daily oral ezetimibe (10 mg).17 After 12 weeks, LDL-C concentrations were reduced 53% to 56% with evolocumab versus 37% to 39% with ezetimibe.17 In the RUTHERFORD-2 clinical trial, investigators used a similar dosing regimen of evolocumab 140 mg every 2 weeks or 420 mg monthly in patients with heterozygous familial hyperlipidemia, and showed a 60% reduction of LDL-C levels at 12 weeks.18 The TESLA trial is the only study of a PCSK9 inhibitor in patients with homozygous familial hyperlipidemia who were taking statin therapy; it showed a 31% reduction of LDL-C levels.19

Bococizumab is being investigated in the SPIRE 1 and SPIRE 2 clinical trials to assess its efficacy and safety in patients at high risk for CV events.20,21 All patients had baseline LDL-C of 70 mg/dL to 100 mg/dL (SPIRE 1) or >100 mg/dL (SPIRE 2) with lipid-lowering therapy. Reduction of CV events is the primary end point of this trial.20,21

The results observed with PCSK9 inhibitors confirm their safety and LDL-C–lowering efficacy when administered as monotherapy or an add-on therapy in patients with homozygous or heterozygous familial hyperlipidemia and/or statin intolerance, and as an add-on treatment for those at high risk for CV events whose LDL-C goals have not been achieved with other lipid-lowering therapies. To date, no sign of neurocognitive impairment or diabetes has been observed with these agents. The ongoing long-term outcome trials will shed additional light on efficacy in terms of CV-event risk reduction as well as safety with longer-term administration.

Indications, Clinical Guidelines, and Practice

The FDA has approved a broad indication for aliroc­umab as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hyperlipidemia or with clinical atherosclerotic CVD who require additional LDL-C reductions. This leaves considerable discretion to the prescribing physician.

Defining the patients with clinical atherosclerotic CVD or with high risk for CV events who have not met LDL-C goals is complicated; multiple guidelines with different approaches to lipid treatment goals have created confusion among clinicians. Although the emphasis of the most current lipid guidelines of the American College of Cardiology and American Heart Association (ACC/AHA) Task Force has shifted from targeted LDL-C goals to the use of statin therapy of “medium” or “high” potency in patients with moderate and high or very high risk for CV events, respectively,22 many clinicians are reluctant to discard numeric targets.23

This position in favor of targeted goals is supported by the recently reported IMPROVE-IT trial, which enrolled high-risk patients with acute coronary syndrome who were randomly assigned to treatment with simvastatin alone (40-80 mg) or with simvastatin plus ezetimibe, a nonstatin LDL-C–reducing agent.24 Combination therapy reduced LDL-C concentrations further than simvastat­in monotherapy (median on-treatment LDL-C levels of 54 mg/dL and 70 mg/dL, respectively) and was associated with a highly significant reduction in the composite primary end point of adverse CV events. Death, myocardial infarction, and ischemic stroke (which were secondary end points) also were reduced significantly by the more aggressive lipid-lowering therapy. The median levels of LDL-C achieved in both treatment groups might have been considered well-controlled previously, and certainly consistent or better than might be achievable by the more empiric prescription of high-dose statin therapy advocated by the 2013 AHA/ACC lipid guidelines.24

A post hoc meta-analysis including IMPROVE-IT coincides with the linear relationship demonstrated between the LDL-C achieved on therapy and the percentage of reduction in adverse CV events observed from all clinical trials of lipid-lowering agents.19,25 Thus, IMPROVE­IT adds considerable weight to the premise that “lower LDL-C is better” and supports a more targeted approach to therapy. Further supporting this premise are other lipid guidelines, such as those published by the National Lipid Association and the European Society of Cardiology, which have maintained numeric LDL-C treatment goals.25

Practical Considerations

For now, the decision to prescribe PCSK9 inhibitors will likely be influenced more by economics than by clinicians’ judgment of which treatment is in the best interest of their patients. It is likely that payers will require clinicians to document their patients’ statin intolerance or to justify the need to lower LDL-C targets in patients already receiving maximum doses, or maximally tolerated doses, of statins and/or other lipid-lowering therapies. Based on the extensive experience gleaned from clinical trials to date, patients tolerate subcutaneous self-administration once or twice monthly very well, and few patients discontinue treatment because of local injection-site reactions (0.2% taking alirocumab vs 0.4% taking placebo).

Furthermore, results of clinical trials indicate that the majority of patients who receive alirocumab will reach targeted LDL-C levels of <70 mg/dL or <100 mg/dL with the lowest approved dose (75 mg) of this drug.11 The algorithm for initiating alirocumab therapy is to start by administering the 75-mg dose subcutaneously every 2 weeks and then obtain a lipid profile 8 to 10 weeks later. If the LDL-C concentration remains above the desired level, the alirocumab dose can be titrated up to 150 mg, and lipid levels should be reevaluated 8 to 12 weeks later. Uptitration to achieve LDL-C goal was required in only 17% to 42% of patients enrolled in clinical trials, and was dependent on the underlying clinical syndrome, baseline LDL-C level, and intensity of concomitant therapy.11

PCSK9 inhibition is an intuitively attractive option to allow for lower (and better tolerated) doses of statins to be administered in combination. Although statins upregulate LDLR, they also upregulate PCSK9, by 25% to 35% (on average), depending on gender, and thus counteract their own beneficial effect to a variable degree. A PCSK9 inhibitor can block the intrinsic counterbalancing effect of statins, further increase LDLR density on the surface of hepatocytes, and enhance LDL-C clearance. It is hoped that ongoing clinical trials will confirm and validate the direct relationship between the on-treatment LDL-C level and the incidence of meaningful adverse CV events. In a pooled analysis of clinical trials, although 796 patients treated with aliroc­umab had ≥2 consecutive LDL-C measurements of ≤25 mg/dL, there have been no specific neurologic or neurocognitive serious adverse events associated with such low LDL-C levels.26 Although this is promising, longer-term follow-up in larger treated populations will be necessary to provide definitive evidence of safety with the very low LDL-C levels now achievable with these effective and well-tolerated novel therapeutic options.


We eagerly await the results of the ODYSSEY, FOURIER, and SPIRE clinical outcome trials to provide further validation that “lower is better” with respect to LDL-C reduction and improvement of clinical outcomes. A recent meta-analysis of placebo-controlled randomized clinical trials of alirocumab or of evolocu­mab demonstrated significant reductions, favoring PCSK9 therapy, in all-cause mortality and myocardial infarction.27 Furthermore, we await the results of the long-term outcome trials to confirm the LDL-C hypothesis for improving CV outcomes and to overcome third-party payer reluctance to provide coverage for these novel and potentially lifesaving cholesterol-reducing therapies.

Author Disclosure Statement
Dr Lepor has received research support from Amgen, Regeneron, Pfizer, and Sanofi; is an advisor to Regeneron and Sanofi; and is a speaker for Amgen, Regeneron, and Sanofi. Dr Kereiakes has received research support from Amgen and Pfizer, and is a consultant to, and on the Speaker’s Bureau of, Sanofi.

Dr Lepor is Clinical Professor of Medicine, Geffen School of Medicine, University of California, and Faculty Member, Cedars-Sinai Heart Institute, Los Angeles, CA. Dr Kereiakes is Medical Director, the Christ Hospital Heart and Vascular Center, and the Carl and Edyth Lindner Center for Research and Education at the Christ Hospital, Cincinnati, OH, and Professor of Clinical Medicine, Ohio State University, Columbus.


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