Author + information
- Received October 3, 2013
- Revision received December 29, 2013
- Accepted January 6, 2014
- Published online April 8, 2014.
- Frederick J. Raal, MB BCh, MMed, PhD∗,
- Robert P. Giugliano, MD, SM†,
- Marc S. Sabatine, MD, MPH†,
- Michael J. Koren, MD‡,
- Gisle Langslet, MD§,
- Harold Bays, MD‖,
- Dirk Blom, PhD, MD¶,
- Mats Eriksson, MD#,
- Ricardo Dent, MD∗∗,
- Scott M. Wasserman, MD∗∗,
- Fannie Huang, MS∗∗,
- Allen Xue, PhD∗∗,
- Moetaz Albizem, MD∗∗,
- Rob Scott, MD∗∗ and
- Evan A. Stein, MD, PhD††∗ ()
- ∗Carbohydrate and Lipid Metabolism Research Unit, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa
- †TIMI Study Group, Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
- ‡Jacksonville Center For Clinical Research, Jacksonville, Florida
- §Lipid Clinic, Oslo University Hospital, Oslo, Norway
- ‖Louisville Metabolic and Atherosclerosis Research Center, Louisville, Kentucky
- ¶Department of Medicine, University of Cape Town, Cape Town, South Africa
- #Karolinska University Hospital, Stockholm, Sweden
- ∗∗Amgen Inc., Thousand Oaks, California
- ††EVLIN Consultants, Chicago, Illinois
- ↵∗Reprint requests and correspondence:
Dr. Evan A. Stein, Metabolic and Atherosclerosis Research Center, 5355 Medspace Way, Cincinnati, Ohio 452227.
Objectives The purpose of this study was assess the effect of evolocumab (AMG 145) on lipoprotein (Lp)(a) from a pooled analysis of 4 phase II trials.
Background Lp(a), a low-density lipoprotein (LDL) particle linked to the plasminogen-like glycoprotein apolipoprotein(a), shows a consistent and independent positive association with cardiovascular disease risk in epidemiological studies. Current therapeutic options to reduce Lp(a) are limited.
Methods A pooled analysis of data from 1,359 patients in 4 phase II trials assessed the effects of evolocumab, a fully human monoclonal antibody to PCSK9, on Lp(a), the relationship between Lp(a) and lowering of low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B, and the influence of background statin therapy. Lp(a) was measured using a standardized isoform-independent method.
Results Evolocumab treatment for 12 weeks resulted in significant (p < 0.001) mean (95% confidence interval) dose-related reductions in Lp(a) compared to control: 29.5% (23.3% to 35.7%) and 24.5% (20.4% to 28.7%) with 140 mg and 420 mg, dosed every 2 and 4 weeks, respectively, with no plateau of effect. Lp(a) reductions were significantly correlated with percentages of reductions in LDL-C (Spearman correlation coefficient, 0.5134; p < 0.001) and apolipoprotein B (Spearman correlation coefficient, 0.5203; p < 0. 001). Mean percentage reductions did not differ based on age or sex but the trend was greater in those patients taking statins.
Conclusions Inhibition of PCSK9 with evolocumab resulted in significant dose-related reductions in Lp(a). While the mean percentage of reduction was significantly greater in those patients with baseline Lp(a) of ≤125 nmol/l, the absolute reduction was substantially larger in those with levels >125 nmol/l.
Lipoprotein(Lp)(a) is a low-density lipoprotein (LDL)-like particle consisting of hepatically synthesized apolipoprotein B100 that is noncovalently bound to the plasminogen-like glycoprotein apolipoprotein(a) (1). The biological role of Lp(a) is uncertain, but it is present only in humans, hedgehogs, primates, and old-world monkeys (2). Lp(a) is recognized as an independent risk factor for myocardial infarction, stroke, and peripheral arterial disease and is believed to increase the risk for cardiovascular disease (CVD) via its atherogenic LDL moiety and its prothrombotic, proinflammatory apolipoprotein(a) moiety (3,4). Levels of Lp(a) >125 nmol/l (approximately 50 mg/dl), the 80th percentile for most populations, have shown a consistent and independent positive association with CVD risk in epidemiological studies (5,6). Recently, a large Mendelian randomization study demonstrated that a genetically determined doubling of Lp(a) was associated with a 22% increase in CVD risk, suggesting a causal link (7). In addition, elevated Lp(a) is an independent CVD risk factor in patients with familial hypercholesterolemia (8).
Lp(a) levels are primarily genetically determined and are dependent mainly on the rate of hepatic synthesis. Formation of Lp(a) appears to take place at the hepatic cell surface, where an apolipoprotein(a) kringle moiety is noncovalently linked to LDL apolipoprotein B (9). The lower the number of kringle IV type 2 repeats in the apolipoprotein(a) gene, the higher the plasma level of Lp(a) (10). Clearance of circulating Lp(a) is not well understood but is thought to occur primarily by hepatic and renal pathways, although these metabolic routes do not appear to govern plasma Lp(a) levels. The LDL receptor does not appear to participate in Lp(a) clearance, reinforced by the fact that statins, which act mainly by upregulating LDL receptor activity, do not lower Lp(a) (11,12).
Lp(a) is relatively refractory to both lifestyle and drug intervention, with current therapeutic options limited to nicotinic acid, which shows consistent reductions of 15% to 25% (13,14). Studies using monoclonal antibody inhibition of the proprotein convertase subtilisin/kexin type 9 (PCSK9) have demonstrated reductions in Lp(a) levels, but the studies have been of short duration with small numbers of subjects; and relationships to dose, sex, and background lipid therapy have not been fully established (15–17). PROFICIO (Program to Reduce LDL-C and Cardiovascular Outcomes Following Inhibition of PCSK9 In Different Populations), a pooled analysis of 1,359 patients from 4 phase II trials, provided the ability to robustly assess the effects of evolocumab (AMG 145), a fully human monoclonal antibody to PCSK9, on Lp(a), the relationship between Lp(a) and the lowering of LDL-C and apolipoprotein B, and the influence of factors such as sex, baseline Lp(a), and background statin therapy. In addition, the open-label extension of these trials allowed for evaluation of the maintenance or discontinuation of evolocumab therapy on Lp(a) levels.
Study design and participants
This analysis included patients who participated in 4 randomized, double-blind, controlled phase II studies of evolocumab (15,18–20). The patient populations, background lipid therapy, and treatment arms in these studies were described previously and are summarized in Table 1. All studies were of 12-week durations and examined a range of evolocumab doses and dose frequencies administered subcutaneously (SC): 70 mg, 105 mg, or 140 mg every 2 weeks (Q2W) or 280 mg, 350 mg, or 420 mg every 4 weeks (Q4W) and were compared with placebo (Q2W or Q4W, respectively); in 2 trials, ezetimibe was administered, either alone or concomitantly with evolocumab or placebo (Fig. 1). The primary endpoint for all 4 trials was the percentage change from baseline in LDL-C at week 12, measured by ultracentrifugation (UC LDL-C); pooled results for this endpoint and other lipid analyses, as well as pooled safety data, were reported separately (21). This analysis focuses on Lp(a), including the percentage of change from baseline at week 12 in Lp(a) by dose group and for the patient subgroup considered to be at highest risk as indicated by baseline Lp(a) values that exceeded 125 nmol/l (approximately 50 mg/dl). Additional analyses included the relationship between Lp(a) lowering and lowering of UC LDL-C and apolipoprotein B and the effects of sex, age, baseline LDL-C and statin therapy on Lp(a) lowering. In addition, the phase II open-label extension study (NCT01439880) allowed for evaluation of evolocumab maintenance or discontinuation on Lp(a) levels during the first 12 weeks of follow-up for patients re-randomized to receive either evolocumab, 420 mg Q4W, or to continue with background lipid-lowering standard of care (SOC) therapy.
Lp(a) was measured using an isoform-independent immunoturbidometric assay (Denka Seiken Co. Ltd., Lp(a) assay, Polymedco, Cortlandt Manor, New York) with a AU5400 analyzer (Olympus, Beckman Coulter Instruments, Brea, California) (22).
Data extraction and statistical analysis
A total of 1,359 patients were enrolled, and the pooled analyses included all randomly assigned patients who received at least 1 dose of investigational product or placebo in the 4 phase II studies (Fig. 1). In the Lp(a) analyses, patients randomized to receive either ezetimibe or placebo therapy were included in the control groups. Analyses for Lp(a), UC LDL-C, and apolipoprotein B were performed using the analysis of covariance model in each dosing regimen (Q2W or Q4W), with the last observation carried forward imputation for missing data, to compare the efficacy of evolocumab doses to those of the control. Analyses were not controlled for multiplicity. The correlations between Lp(a) and UC LDL-C or apolipoprotein B for patients randomized to evolocumab and placebo combined were assessed using the Spearman correlation coefficient for patients with Lp(a) ≥5 nmol/l (the lower limit of detection) at week 12. All analyses were done with SAS/STAT version 9.2 software (SAS Institute, Cary, North Carolina).
In a population with an age of 56.4 ± 11.7 years, 56.2% women, and 60.3% patients taking statin therapy, the median baseline Lp(a) concentration was 40.0 nmol/l (interquartile range [IQR]: 13.0 to 144.0 nmol/l), and the mean baseline UC LDL-C concentration was 140.6 ± 38.9 mg/dl Table 2. Evolocumab treatment resulted in significant (p < 0.001) dose-related mean reductions in Lp(a) for all treatment groups compared with control (Fig. 2, Table 3). Lp(a) reductions were accompanied by significant reductions from baseline in UC LDL-C and apolipoprotein B (Table 3). Significant correlations were observed between percentages of reductions in Lp(a) and UC LDL-C (Spearman correlation coefficient, 0.5134; p < 0.001) (Fig. 3A) and between reductions in Lp(a) and apolipoprotein B (Spearman correlation coefficient, 0.5203; p < 0.001) (Fig. 3B).
Results were also analyzed according to consensus-based “high-risk” Lp(a) levels >125 nmol/l (approximately 50 mg/dl, or the 80th percentile of the population) (6) (Table 4). There were significantly more patients in the high-risk Lp(a) group with coronary artery disease and hypertension and who were taking statins or ezetimibe at baseline and who were black (Table 4). Baseline UC LDL-C was 141.6 ± 39.1 mg/dl and 138.2 ± 38.8 mg/dl in the low- and high-risk groups, respectively, and apolipoprotein B was 110.8 ± 25.2 mg/dl and 110.7 ± 25.9 mg/dl in the 2 groups.
Statistically significant reductions (p < 0.001) in Lp(a), UC LDL-C, and apolipoprotein B were observed with evolocumab, regardless of patients’ baseline Lp(a) levels (Table 5). Patients with baseline Lp(a) levels ≤125 nmol/L had greater percentage reductions than controls in Lp(a) compared to those in the high-risk group (for 140 mg Q2W: –33.2% vs. –20.0%, respectively; for 420 mg Q4W: –28.7% vs. –16.1%, respectively), whereas the absolute reductions compared to those of control were substantially greater in the high-risk Lp(a) group (for 140 mg Q2W: 34.1 nmol/l vs. 8.9 nmol/l, respectively; for 420 mg Q4W: 38.6 nmol/l vs. 9.7 nmol/l, respectively). Baseline Lp(a) also appeared to have an impact on both the percentages and absolute reductions versus placebo in LDL-C and apolipoprotein B, with those with baseline Lp(a) >125 nmol/l experiencing a lower percent reduction of approximately 6% to 8% and a modestly smaller absolute reduction (Table 5).
There were no differences in Lp(a) responses based on sex, age (below and at or above 65 years), or LDL-C (below and at or above median baseline levels) (Online Fig. S1). Reductions in Lp(a) were numerically greater in patients on background statin therapy than in those not on statin therapy and were statistically significant compared to controls at all doses except 70 mg Q2W. The treatment differences between those taking statins and those not taking statins within evolocumab doses were numerically greater, but the interaction effects were not statistically significant except in the 105-mg-Q2W group (interaction, p = 0.0112) (Online Fig. S2).
For patients who were randomized to receive SOC and stopped evolocumab therapy in the open-label extension study, Lp(a) values returned to their pre-treatment levels. Patients who were taking evolocumab, 420 mg Q4W, and continued with this dosage during the open-label extension maintained the reduction in Lp(a) as shown in Figure 4.
Overall, adverse events were reported in 56.8% and 49.2% of patients in the combined evolocumab and combined placebo groups, respectively, with no relationship to dose or frequency. Serious adverse events were reported in 2.0% and 1.2% of patients in the evolocumab and placebo groups, respectively; none of these adverse events were considered by the investigators to be treatment related. Anti-evolocumab binding antibodies were observed in 1 patient taking evolocumab and in 1 patient in the placebo group; no neutralizing antibodies were detected.
PROFICIO analysis confirms some observations and shows contrasts with other observations in a smaller individual trial with a PCSK9 monoclonal antibody (17) and provides additional insights into responses by sex, age, baseline Lp(a), and background lipid therapy. In this pooled analysis of more than 1,300 patients, evolocumab treatment resulted in highly significant dose-related reductions in Lp(a). Unlike the analysis from the trial of evolocumab in patients with dyslipidemia treated with statins included in this pooled analysis (17), we demonstrate that, overall, within each dosing regimen, either 2- or 4-week dosing, there were continued reductions in Lp(a) as the dose increased, with no plateau effect. Furthermore, PROFICIO was differentiated in that it included a large number of patients not taking background statin treatment, and, although numerical reductions in treatment differences for Lp(a) appeared to be greater with statin therapy in all dose groups, these reductions were only statistically significant (p < 0.02) for the 105-mg-Q2W dosage. Significant reductions in Lp(a) compared to control were observed with all evolocumab doses (except the lowest dosage of 70 mg Q2W), regardless of background therapy). In addition, we show for the first time that the reductions in Lp(a) were both related to treatment with evolocumab and reversible upon discontinuation of evolocumab or maintained with continued therapy. The PROFICIO data pool was also large enough to provide meaningful analysis based on the consensus high-risk cut point above 125 mmol/l (approximately 50 mg/dl) and that for subjects with Lp(a) above this level, evolocumab produced absolute reductions of 35 to 40 nmol/l at the highest doses administered, either every 2 or 4 weeks. PROFICIO also demonstrated that baseline Lp(a) appears to have an impact on LDL-C and apolipoprotein B response in patients with levels >125 nmol/l experiencing approximately 6% to 8% less LDL-C and apolipoprotein B reduction.
The statistically significant (p < 0.001) associations between reductions in Lp(a) and those in LDL-C and apolipoprotein B may provide some insight into the potential mechanism(s) by which PCSK9 inhibition results in Lp(a) reduction. Lp(a) reduction could result from decreased production or assembly, increased clearance, or a combination of both mechanisms.
As shown by Tsimikas et al. (23), Koschinsky et al. (24), and Koschinsky and Marcovina (25), there is a strong inverse relationship between triglyceride and Lp(a) levels, consistent with the requirement for delipidation of triglyceride-rich forms of apolipoprotein B in the circulation as a prerequisite for Lp(a) assembly, which likely occurs at the cell surface and not intracellularly. Patients with defects in very low-density lipoprotein clearance or, alternatively, those with abetalipoproteinemia who have mutations in the microsomal triglyceride transfer protein (MTP) gene required for lipoprotein assembly, have very low plasma levels of all apolipoprotein B containing lipoproteins, including Lp(a), supporting this hypothesis (26). Further evidence of the critical role of apolipoprotein B availability and LDL in the formation of Lp(a) comes from reductions in Lp(a) seen when apolipoprotein B synthesis is downregulated with an antisense drug (27). While a direct effect on reducing apolipoprotein B synthesis by inhibition of PCSK9 has not been established, the converse has been shown in animal models where excess circulating PCSK9 increases apolipoprotein B synthesis independently of the decreased uptake of LDL/apolipoprotein B by the LDL receptor. These findings may lend support to the notion that either reduced apolipoprotein B synthesis or decreased LDL-apolipoprotein B availability, or both, could lead to reduced Lp(a) formation (28–30).
It is known that apolipoprotein(a), once cleaved from LDL-apolipoprotein B, is degraded by elastases and proteases, and the resultant fragments are excreted in urine, where they can be measured (9). As patients with advanced renal failure have increased Lp(a) levels, usually made up of large isoforms, there does appear to be a significant role for the kidney in Lp(a) clearance (9). Thus, if there were a reduction in Lp(a) formation due to decreased LDL-apolipoprotein B availability subsequent to the marked fall in LDL associated with PCSK9 inhibition with evolocumab, an increase in “free” apolipoprotein(a) would occur if apolipoprotein(a) synthesis rates remained constant, resulting in increased urinary excretion of intact apolipoprotein(a) or its fragments. Future studies with PCSK9 inhibitors should assess this by measurements in pre- and post-treated patients.
Mechanisms for clearance of Lp(a) are not well established, and no known specific receptors or pathways have been validated. Studies assessing clearance of radiolabeled Lp(a) in both rodents and humans with LDL receptor defects do not support a significant role for the LDL receptor (12). Clinical evidence for the role of the LDL receptor is, however, conflicting as patients with heterozygous and especially homozygous familial hypercholesterolemia (FH) have higher levels of Lp(a) than non-FH populations and their relatives with similar Lp(a) isoforms (31). Numerous trials with drugs that upregulate LDL receptor activity, especially statins, have shown no or minimal reduction in Lp(a) (13). Approximately 10% to 15% of Lp(a) is converted to LDL when apolipoprotein(a) is cleaved, and this LDL could then be cleared more rapidly with PCSK9 inhibition as LDLR activity is markedly enhanced (13). This may contribute to the reduction in Lp(a) when LDL levels are very low.
There are currently no approved pharmacological agents to specifically lower plasma Lp(a) levels without affecting other lipoproteins. Of the lipid-altering drugs approved for LDL-C reduction in the general population, only nicotinic acid has been shown to consistently reduce Lp(a) (14,32). Reductions in Lp(a) were reported with therapeutic agents recently approved under very strict prescribing guidelines for the sole indication of treating homozygous familial hypercholesterolemia (33,34), such as antisense oligonucleotides to apolipoprotein B (mipomersen), and MTP inhibitors (lomitapide). However, the effect with lomitapide appeared to be lost after 78 weeks. Drugs that inhibit cholesteryl ester transfer protein (CETP), either in development or terminated due to toxicity or lack of efficacy on cardiovascular endpoints, such as torcetrapib, dalcetrapib, anacetrapib and evacetrapib (35), have also been shown to reduce Lp(a). The hepatic thyroid analog eprotirome also reduced Lp(a), but development was recently terminated due to toxicity (36). For both drug classes, the mechanism for Lp(a) reduction remains unclear (37).
It remains unknown whether lowering Lp(a) will yield clinical benefit and reduce cardiovascular mortality. Nevertheless, the strong epidemiologic and genetic evidence suggesting that Lp(a) is an independent causal risk factor for CVD makes it a valid interventional target for therapy when attempting to further reduce CVD risk. Definitive outcome trials are likely to be very difficult as all current drug strategies do not reduce Lp(a) selectively but affect multiple other lipoprotein classes. In addition to the marked reduction in LDL-C, the reduction in Lp(a) seen with evolocumab may be of greater benefit to patients with increased levels of this risk factor. However the apparent 6% to 8% less LDL-C and apolipoprotein B reduction seen in patients with elevated Lp(a) will make it very difficult to isolate the impact on CVD risk of Lp(a) reduction by PCSK9 inhibitors in any clinical trial.
Inhibition of PCSK9 with evolocumab yielded significant dose-related reductions in Lp(a) with both 2- and 4-week dosing. The reductions were both reversible upon discontinuation of evolocumab and sustained during longer-term therapy. The reductions were independent of age, sex and baseline LDL-C and tended to be greater in those on statin background therapy than those on diet alone. Although percentage reductions from baseline were greater in those with lower starting Lp(a) levels, the absolute reductions were substantially greater in those considered at higher risk, with baseline Lp(a) >125 nmol/l. Those with higher baseline Lp(a) levels had 6% to 8% less LDL-C and apolipoprotein B reduction than those with Lp(a) in the normal range. The reductions in Lp(a) demonstrated strong correlation with reductions in LDL-C and apolipoprotein B, but the mechanism by which PCSK9 reduces Lp(a) remains to be elucidated.
The authors thank the patients who participated in the study and the research professionals at the clinical centers. They also thank Sam Tsimikas, MD, for critical review of the manuscript. We also thank Wei Cui, MS, for programming support and Sue Hudson, BA, on behalf of Amgen, Inc., and Meera Kodukulla, PhD, of Amgen, for editorial support.
This study was funded by Amgen, Inc. Dr. Raal has received consulting fees from Amgen, Inc., and Sanofi related to PCSK9 inhibitors; and his institution has received research funding related to PCSK9 inhibitor clinical trials from Amgen, Inc., and Sanofi. Dr. Giugliano has received honoraria for consulting and CME lectures from Amgen, Daiichi Sankyo, Bristol-Myers Squibb, Merck, Regeneron, and Sanofi; and participates in lipid research as a member of the TIMI Study Group, which has received research grant support for clinical trials from Amgen, Daiichi-Sankyo, and Merck. Dr. Sabatine has received grant support through Brigham and Women’s Hospital from Amgen, AstraZeneca, AstraZeneca/Bristol-Myers Squibb Alliance, Bristol-Myers Squibb/Sanofi Joint Venture, Daiichi Sankyo, Eisai, Genzyme, GlaxoSmithKline, Merck, Sanofi, Takeda, Abbott Laboratories, Accumetrics, Critical Diagnostics, Nanosphere, and Roche Diagnostics; and has consulted for Aegerion, Amgen, Diasorin, GlaxoSmithKline, Merck, Pfizer, Sanofi, AstraZeneca, and Vertex. Dr. Koren is an employee of Jacksonville Center for Clinical Research, which has received grants from Amgen Inc. Dr. Langslet is a consultant for and advisory board member of Janssen Pharmaceutical. Dr. Bays has consulted for and received speaker fees from Amarin, Amgen, AstraZeneca, Bristol-Myers Squibb, Catabasis, Daiichi Sankyo, Eisai Merck, VIVUS, and WBL Biotech Co.; and his research site has received grants from Alere, Amarin, Amgen, Ardea, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, California Raisin Board, Catabasis, Eisai, Elcelyx, Eli Lilly, Esperion, Essentialis, Forest, Gilead, Given, GlaxoSmithKline, High Point Pharmaceuticals LLC, Hoffman LaRoche, Home Access, Janssen, Merck, Micropharma Limited, Necktar, Novartis, Novo Nordisk, Omthera, Orexigen, Pfizer, Pronova, Regeneron, Stratum Nutrition, Takeda, TIMI, Transtech Pharma, Trygg, VIVUS, WBL Biotech Co., and Xoma. Dr. Blom has received consulting fees from Amgen Inc. and Sanofi related to PCSK9 inhibitors; has served on advisory boards of Amgen, Sanofi, Aegerion, and Merck, Sharpe, Dohme; has received speaker honoraria from Amgen, Aegerion, Merck, Sharpe, Dohme, Unilever, Pfizer, AstraZeneca, Ranbaxy, PharmaDynamics, and Sanofi; and his institution has received research funding related to PCSK9 inhibitor clinical trials from Amgen, Inc., and Sanofi. Dr. Eriksson has received lecture fees from Merck, Sharpe, Dohme and AstraZeneca and consulting fees from Amgen, Sanofi, and Novo Nordisk. Drs. Dent, Wasserman, Huang, Xue, Albizem, and Scott are employees of Amgen, Inc., and have received Amgen stock/stock options. Dr. Stein has received consulting fees from Amgen Inc., Adnexus Therapeutics/Bristol-Myers Squibb, Genentech/Roche, and Regeneron/Sanofi related to PCSK9 inhibitors.
- Abbreviations and Acronyms
- cardiovascular disease
- low-density lipoprotein
- proprotein convertase subtilisin/kexin type 9
- every 2 weeks
- every 4 weeks
- UC LDL-C
- low-density lipoprotein cholesterol measured by ultracentrifugation
- Received October 3, 2013.
- Revision received December 29, 2013.
- Accepted January 6, 2014.
- 2014 American College of Cardiology Foundation
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