CLINICAL
SPECIAL FEATURE
The PCSK9 Inhibitors: A Novel Therapeutic Target Enters Clinical Practice Norman E. Lepor, MD, and Dean J. Kereiakes, MD 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 Am Health Drug Benefits. improving clinical outcomes. 2015;8(9):483-488 www.AHDBonline.com KEY WORDS: familial hypercholesterolemia, low-density lipoprotein cholesterol, statin treatment, unmet needs, PCSK9 inhibitors, alirocumab, evolocumab, bococizumab, clinical guidelines, clinical studies, Disclosures are at end of text LDL-C hypothesis
M
any believe that proprotein convertase subtil isin/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 lipo protein 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 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.
Vol 8, No 9
l
December 2015
on the hepatocyte is the mechanism for elimination of LDL-C and other atherogenic non–high-density lipopro teins (HDL-C). However, when the PCSK9 is bound to the LDLR LDL-C complex, it leads to lysosomal catabo lism 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 pre vents LDLR catabolism, which, in turn, preserves LDLR recycling and increased receptor density on the hepato cyte surface. Increased LDLR density increases LDL-C binding and clearance from the blood. The PCSK9 in hibitors 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 pro gression, and in the pathogenesis of CV events, such as sudden cardiac death, acute coronary syndrome, stroke,
www.AHDBonline.com
l
American Health & Drug Benefits
l
483
CLINICAL
The FDA approved the first PCSK9 inhibitors in 2015, and clinicians must understand how best to incorporate these agents into clinical practice. ➤ Patients with familial hyperlipidemia and those with clinical atherosclerotic cardiovascular (CV) disease (CVD) not reaching lipid-reducing goals, including those with statin intolerance, are at greatest need of PCSK9 inhibitors, because no adequate alternative therapies exist. ➤ No widely accepted definition for statin intolerance is available. ➤ Multiple national and societal guidelines with different approaches to lipid treatment have created confusion among clinicians; thus, defining the patients with clinical atherosclerotic CVD or with high CV risk who have not met LDL-C treatment goals is complicated. ➤ Although the PCSK9 inhibitors may support the LDL-C hypothesis (the lower the LDL-C level, the lower the CV risk), the results of ongoing long-term outcome studies may not be available for some time. ➤ Prescribing PCSK9 inhibitors will likely be limited by economics rather than by clinicians’ judgment about the best interest of their patients. ➤
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 sec ondary 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.
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 symp tomatic 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 ef fective add-on therapies are desperately needed. The heterozygous phenotype, which accounts for 60% to 80% of cases of familial hyperlipidemia, is often direct ly attributable to a heterozygous pathogenic variant in 1
484
l
American Health & Drug Benefits
l
oronary Heart Disease Event Rates in Figure 1 C Secondary Prevention Trialsa 30 y = 0.1629x – 4.6776 R2=0.9029 P 100 mg/dL (SPIRE 2) with lipid-lowering thera py. 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 adminis tered as monotherapy or an add-on therapy in patients with homozygous or heterozygous familial hyperlipid emia and/or statin intolerance, and as an add-on treat ment 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.
www.AHDBonline.com
December 2015
l
Vol 8, No 9
The PCSK9 Inhibitors: A Novel Therapeutic Target
Indications, Clinical Guidelines, and Practice The FDA has approved a broad indication for aliroc umab as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous famil ial 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 creat ed 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 clini cians 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 thera py reduced LDL-C concentrations further than simvastat in 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 pri mary 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 co incides 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 IT trials of lipid-lowering agents.19,25 Thus, IMPROVE- 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 clini
Vol 8, No 9
l
December 2015
cians’ judgment of which treatment is in the best interest of their patients. It is likely that payers will require clini cians 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 discon tinue 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
SPECIAL FEATURE
The PCSK9 Inhibitors: A Novel Therapeutic Target Enters Clinical Practice Norman E. Lepor, MD, and Dean J. Kereiakes, MD 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 Am Health Drug Benefits. improving clinical outcomes. 2015;8(9):483-488 www.AHDBonline.com KEY WORDS: familial hypercholesterolemia, low-density lipoprotein cholesterol, statin treatment, unmet needs, PCSK9 inhibitors, alirocumab, evolocumab, bococizumab, clinical guidelines, clinical studies, Disclosures are at end of text LDL-C hypothesis
M
any believe that proprotein convertase subtil isin/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 lipo protein 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 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.
Vol 8, No 9
l
December 2015
on the hepatocyte is the mechanism for elimination of LDL-C and other atherogenic non–high-density lipopro teins (HDL-C). However, when the PCSK9 is bound to the LDLR LDL-C complex, it leads to lysosomal catabo lism 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 pre vents LDLR catabolism, which, in turn, preserves LDLR recycling and increased receptor density on the hepato cyte surface. Increased LDLR density increases LDL-C binding and clearance from the blood. The PCSK9 in hibitors 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 pro gression, and in the pathogenesis of CV events, such as sudden cardiac death, acute coronary syndrome, stroke,
www.AHDBonline.com
l
American Health & Drug Benefits
l
483
CLINICAL
The FDA approved the first PCSK9 inhibitors in 2015, and clinicians must understand how best to incorporate these agents into clinical practice. ➤ Patients with familial hyperlipidemia and those with clinical atherosclerotic cardiovascular (CV) disease (CVD) not reaching lipid-reducing goals, including those with statin intolerance, are at greatest need of PCSK9 inhibitors, because no adequate alternative therapies exist. ➤ No widely accepted definition for statin intolerance is available. ➤ Multiple national and societal guidelines with different approaches to lipid treatment have created confusion among clinicians; thus, defining the patients with clinical atherosclerotic CVD or with high CV risk who have not met LDL-C treatment goals is complicated. ➤ Although the PCSK9 inhibitors may support the LDL-C hypothesis (the lower the LDL-C level, the lower the CV risk), the results of ongoing long-term outcome studies may not be available for some time. ➤ Prescribing PCSK9 inhibitors will likely be limited by economics rather than by clinicians’ judgment about the best interest of their patients. ➤
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 sec ondary 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.
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 symp tomatic 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 ef fective add-on therapies are desperately needed. The heterozygous phenotype, which accounts for 60% to 80% of cases of familial hyperlipidemia, is often direct ly attributable to a heterozygous pathogenic variant in 1
484
l
American Health & Drug Benefits
l
oronary Heart Disease Event Rates in Figure 1 C Secondary Prevention Trialsa 30 y = 0.1629x – 4.6776 R2=0.9029 P 100 mg/dL (SPIRE 2) with lipid-lowering thera py. 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 adminis tered as monotherapy or an add-on therapy in patients with homozygous or heterozygous familial hyperlipid emia and/or statin intolerance, and as an add-on treat ment 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.
www.AHDBonline.com
December 2015
l
Vol 8, No 9
The PCSK9 Inhibitors: A Novel Therapeutic Target
Indications, Clinical Guidelines, and Practice The FDA has approved a broad indication for aliroc umab as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous famil ial 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 creat ed 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 clini cians 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 thera py reduced LDL-C concentrations further than simvastat in 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 pri mary 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 co incides 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 IT trials of lipid-lowering agents.19,25 Thus, IMPROVE- 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 clini
Vol 8, No 9
l
December 2015
cians’ judgment of which treatment is in the best interest of their patients. It is likely that payers will require clini cians 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 discon tinue 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
