Accepted Manuscript
Effect of Alirocumab, a Monoclonal Proprotein Convertase Subtilisin/Kexin 9Antibody, on Lipoprotein(a) Concentrations (a Pooled Analysis of 150 mg Every 2Weeks Dosing from Phase 2 Trials)
Daniel Gaudet, MD, PhD Dean Kereiakes, MD James McKenney, PharmD Eli Roth,MD Corinne Hanotin, MD Dan Gipe, MD Yunling Du, PhD Anne-Catherine Ferrand,MSc Henry Ginsberg, MD Evan Stein, MD, PhD
PII: S0002-9149(14)01299-5
DOI: 10.1016/j.amjcard.2014.05.060
Reference: AJC 20520
To appear in: The American Journal of Cardiology
Received Date: 24 March 2014
Revised Date: 15 May 2014
Accepted Date: 28 May 2014
Please cite this article as: Gaudet D, Kereiakes D, McKenney J, Roth E, Hanotin C, Gipe D, DuY, Ferrand A-C, Ginsberg H, Stein E, Effect of Alirocumab, a Monoclonal Proprotein ConvertaseSubtilisin/Kexin 9 Antibody, on Lipoprotein(a) Concentrations (a Pooled Analysis of 150 mg Every2 Weeks Dosing from Phase 2 Trials), The American Journal of Cardiology (2014), doi: 10.1016/j.amjcard.2014.05.060.
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Effect of Alirocumab, a Monoclonal Proprotein Convertase
Subtilisin/Kexin 9 Antibody, on Lipoprotein(a)
Concentrations (a Pooled Analysis of 150 mg Every 2
Weeks Dosing from Phase 2 Trials)
Daniel Gaudet, MD, PhDa,*, Dean Kereiakes, MDb, James McKenney, PharmDc, Eli
Roth, MDd, Corinne Hanotin, MDe, Dan Gipe, MDf, Yunling Du, PhDf, Anne-
Catherine Ferrand, MSce, Henry Ginsberg, MDg, Evan Stein, MD, PhDh
aThe ECOGENE-21 Clinical Research Center and Lipid Clinic, Department of
Medicine, Université de Montreal, Chicoutimi, Quebec, Canada; bThe Christ Hospital
Heart and Vascular Center/The Lindner Research Center, Cincinnati, OH, USA;
cVirginia Commonwealth University, Richmond, VA, USA; dSterling Research Group,
Cincinnati, OH, USA; eSanofi, Paris, France; fRegeneron Pharmaceuticals, Inc.,
Tarrytown, NY, USA; gColumbia University, New York, NY, USA; hMetabolic and
Atherosclerotic Research Center, Cincinnati, OH, USA
Running title: Alirocumab Reduces Plasma Lipoprotein(a) Levels
Sources of funding: This analysis was funded by Sanofi and Regeneron.
*Corresponding author: Dr. Daniel Gaudet, PhD, Department of Medicine,
Université de Montréal, ECOGENE 21 Clinical Research Center, Chicoutimi
Hospital, Chicoutimi, G7H 5H6, Canada, Tel: 418-541-1077; Fax: 418-541-1116;
E-mail address: [email protected]
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Abstract
Lipoprotein(a) [Lp(a)] is an independent risk factor for cardiovascular disease, with
limited treatment options. This analysis evaluated the effect of a monoclonal
antibody to proprotein convertase subtilisin/kexin 9 (PCSK9), alirocumab 150 mg
every 2 weeks (Q2W), on Lp(a) levels in pooled data from 3 double-blind,
randomized, placebo-controlled phase 2 studies of 8 or 12 weeks duration
conducted in patients with hypercholesterolemia on background lipid-lowering
therapy (NCT01266876, NCT01288469, NCT01288443). Data were available for
102/108 patients who received alirocumab 150 mg Q2W and 74/77 patients who
received placebo. Alirocumab resulted in a significant reduction in Lp(a) from
baseline compared with placebo (–30.3% versus –0.3%, p <0.0001). Median
percentage Lp(a) reductions in the alirocumab group were of a similar magnitude
across a range of baseline Lp(a) levels, resulting in greater absolute reductions in
Lp(a) in patients with higher baseline levels. Regression analysis indicated that less
than 5% of the variance in the reduction of Lp(a) was explained by the effect of
alirocumab on low-density lipoprotein cholesterol (LDL-C). In conclusion, pooled data
from 3 phase 2 trials demonstrate substantive reduction in Lp(a) with alirocumab 150
mg Q2W, including patients with baseline Lp(a) >50 mg/dl. Reductions in Lp(a) only
weakly correlated with the magnitude of LDL-C lowering.
Keywords: Lipoprotein(a); low-density lipoprotein cholesterol; alirocumab;
monoclonal antibodies; PCSK9
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Introduction
Elevated lipoprotein(a) [Lp(a)] levels are considered to be an independent risk
factor for cardiovascular disease, with risk continuing to increase as levels rise.1,2
The 2011 European Atherosclerosis Society (EAS)/European Society of Cardiology
dyslipidemia management guidelines recommend measurement of Lp(a) in high-risk
patients or in those with a family history of premature cardiovascular disease,3 and
the EAS define high-risk Lp(a) levels as >50 mg/dl, approximately the 80th percentile
in the Caucasian population.2 Of the widely prescribed lipid-modifying therapies, only
nicotinic acid consistently reduces Lp(a).2 Despite the potent effect of statins on LDL-
C levels, in general they show little to no effect on Lp(a) in clinical trials.4 Alirocumab
(formerly SAR236553/REGN727), a highly specific, fully human monoclonal antibody
to proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly (p <0.001)
reduced LDL cholesterol (LDL-C) by up to 72.4% when combined with statin or other
lipid-lowering therapy in phase 2 trials, and showed a trend to reduce Lp(a), a
secondary parameter, across all dosing regimens tested.5–7 The objective of the
present pooled analysis of alirocumab 150 mg Q2W, a common dose in all phase 2
trials, was to provide, post-hoc, a more robust assessment of its effects on Lp(a),
and examine the relationship with baseline levels and LDL-C reductions.
Methods
Data were pooled from 3 double-blind, randomized, placebo-controlled phase 2
studies with alirocumab of 8- or 12-weeks’ duration (NCT01288443; NCT01266876;
NCT01288469). The study designs (Supplementary Figure 1) have been previously
described.5–7 Briefly, in these studies a total of 352 patients with heterozygous
familial hypercholesterolemia or non-familial forms of hypercholesterolemia and LDL-
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C ≥100 mg/dl under background statin or statin plus ezetimibe 10 mg treatment were
randomized to alirocumab 50–300 mg Q2W or every 4 weeks (n = 275) or placebo
(n = 77). One of the studies included up-titration of background atorvastatin from 10
mg to 80 mg in the placebo arm and 1 of 2 alirocumab arms; in the other alirocumab
arm patients remained at a background atorvastatin dose of 10 mg.7 This study was
included in the pooled analysis since impact of statin uptitration on Lp(a) was
expected to be low based on previous studies.4 This analysis focuses on the dose
regimen alirocumab 150 mg Q2W, which was common to all 3 phase 2 studies and
was considered to provide consistent, robust effects on LDL-C;5,6 this is also one of
the doses being evaluated in the alirocumab phase 3 clinical trials.
In all phase 2 studies, Lp(a) levels were measured at the same laboratory Lp(a)
using rate immunonephelometry (Dade Behring BNII nephelometer, Siemens
Healthcare Diagnostics, Deerfield, Illinois).5,6 Data on Lp(a) levels at baseline and
end of treatment (week 8/12 on-treatment value or the last available on-treatment
value carried forward) from the modified intention-to-treat populations of the
3 studies were pooled, and percentage changes from baseline for alirocumab
150 mg Q2W and placebo were compared using analysis of covariance with
treatment group and study as fixed effects and baseline Lp(a) as covariate. P-values
associated with these exploratory analyses are provided for descriptive purposes
only and were not adjusted for multiplicity. The relationship between the percentage
changes from baseline in Lp(a) and LDL-C was assessed using linear regression,
and the Spearman’s correlation coefficient was calculated.
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Results
Baseline characteristics (Table 1) were well-balanced. All patients were
receiving background statin therapy and 11/108 patients (10%) in the alirocumab
group and 11/77 patients (14%) in the placebo group also received ezetimibe 10 mg.
Baseline and on-treatment Lp(a) data were available for 102 of the 108 patients who
received alirocumab and 74 of the 77 patients who received placebo (Table 2).
Thirty-six (34%) patients treated with alirocumab and 25 (33%) patients treated with
placebo had baseline Lp(a) >50 mg/dl, the high-risk cut-point by the EAS guidelines.2
Absolute and percentage median reductions from baseline in Lp(a) are shown
in Figure 1A and 1B, respectively. The median absolute reductions in Lp(a) from
baseline were substantially greater in patients with the higher baseline Lp(a) (Figure
1A). Reductions in Lp(a) were only weakly correlated with the magnitude of LDL-C
lowering (Spearman’s correlation coefficient: 0.2236; Supplementary Figure 2A).
Similar results were observed using a regression analysis comparing actual
achieved LDL-C levels and percentage reduction in Lp(a) (Supplementary
Figure 2B). The percentage reductions in Lp(a) from baseline with alirocumab were
consistent between a pool of the 2 12-week studies and a pool of the two arms
receiving alirocumab in the 8-week study (–28.3% and –32.1%, respectively).
The most common treatment-emergent adverse event in the alirocumab phase
2 trials was injection site reaction, typically episodic and of mild intensity and short
duration; five serious adverse events occurred in 4 patients (1.5%) who received
alirocumab.5–7
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Discussion
This analysis of pooled data from the phase 2 studies with alirocumab 150 mg
Q2W compared with placebo demonstrated robust and statistically significant
(p <0.0001) reductions in Lp(a) of ~30%. This compares favorably with those
reported with extended-release nicotinic acid 2 g/day (~20–35%),8,9 and is consistent
with those reported with the PCSK9 monoclonal antibody evolocumab (18–32%
versus placebo).10,11 As reported for evolocumab, the absolute (mg/dl) reductions in
Lp(a) with alirocumab showed a greater reduction in the patients considered by
treatment guidelines to have elevated Lp(a) levels.2,10,11
The effect of statins on Lp(a) has been extensively evaluated over the past
3 decades and in all large well-controlled studies there has been no or only minimal
effects.4,12 Of the widely prescribed lipid-lowering therapies, only nicotinic acid 1–3 g
per day has been shown to consistently reduce Lp(a) levels.2 Recently, reductions in
Lp(a) of 21–33% have been reported with apo B synthesis inhibition using
mipomersen,13,14 and of 15–17% with microsomal triglyceride transfer protein
inhibition using lomitapide.15 However, these drugs are approved only for rare
patients with homozygous familial hypercholesterolemia. Inhibition of cholesteryl
ester transfer protein (CETP) with anacetrapib was reported to reduce Lp(a) by 17–
24%,16 however this drug is still in development and other CETP-inihibitors
(torcetrapib, dalcetrapib) have so far failed to demonstrate a positive effect on
cardiovascular events and be approved for use. In addition to drug therapy,
apheresis reduces high Lp(a) levels, but its use in routine practice is also limited.2
The mechanisms by which Lp(a) is synthesized, metabolized and cleared from
the circulation are poorly understood (Figure 2), and the mechanism by which
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PCSK9 monoclonal antibodies reduce Lp(a) is also unclear. Both statins and
alirocumab are thought to reduce LDL-C and most other apo B-containing
lipoproteins by increasing the number of LDL receptors on hepatocytes: statins via
HMG-CoA inhibition,17 alirocumab via PCSK9 blockade.18 It is generally considered
that the Lp(a) particle has poor affinity for the LDL receptor.19 One hypothesis is that
the further upregulation of the LDL receptor combined with the very low LDL and apo
B levels achieved with alirocumab treatment allows for uptake of Lp(a) by LDL
receptors. For example, the mean achieved LDL-C level for the 150 mg Q2W arms
in these 3 studies ranged from 34.2 mg/dl to 50.3 mg/dl, mean levels that are lower
than those typically achieved in randomized trials of statins alone (~60–100
mg/dl).20,21
Regression analysis conducted in this study (Supplementary Figure 2) showed
that a portion of the observed reduction in Lp(a) was not dependent on the
magnitude of LDL-C lowering or LDL-C level achieved. In addition the JUPITER trial
achieved LDL-C levels <50 mg/dl in 7,746 patients with no reductions seen in
Lp(a).22 These data suggest an effect of alirocumab on Lp(a) production or fractional
clearance that may be independent of, or in addition to, the mechanism of LDL-C
lowering. The LDL receptor independent reduction is supported by the recent report
of a 15–20% decrease in Lp(a) in 2 LDL receptor-negative homozygous familial
hypercholesterolemia patients treated with evolocumab, who had no associated
reduction in LDL-C.23 However, two reports on the effects of evolocumab on
Lp(a)10,11 indicated a stronger correlation between Lp(a) and LDL-C reductions than
what was observed in the present analysis; this discrepancy may be due to the
larger patient numbers increasing the statistical power of the evolocumab studies.
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In terms of synthesis, apo(a), one of the principal components of Lp(a), is
expressed by hepatocytes and released into the circulation where the assembly of
apo(a) and LDL apo B-containing particles bind to form Lp(a) particles at the outer
hepatocyte surface.24 The ability to reduce Lp(a) by either inhibition of LDL-apo B or
apo(a) synthesis indicates the requirement of both for its formation.14,25 The liver
contributes to Lp(a) removal from the circulation26 although, as mentioned above, the
mechanism is unclear.19 The kidney as well as peripheral tissues may also play an
important role in Lp(a) clearance.27 New, emerging receptors have also been
proposed, although their respective contributions to Lp(a) clearance remain to be
determined. Such receptors include, among others, sorting receptors (such as
sortilin28), endocytic receptors (such as the syndecan-1 heparan sulfate
proteoglycan29) or docking receptors. The effect of PCSK9 inhibition on the
regulation of receptors other than the LDL receptor is still under investigation.
The present analysis did not take into consideration variations in the number of
kringle IV repeats in the LPA gene encoding apo(a), which account for ~25–30% of
the variation in Lp(a) plasma concentrations.2,30 However, we did not observe a
relationship between Lp(a) concentration and the response to alirocumab in terms of
LDL-C lowering. Approximately 30% of patients in this analysis had Lp(a) >50 mg/dl
at baseline. High Lp(a) levels are known to affect LDL-C levels calculated using the
Friedewald method, with ~8% of the cholesterol measured as LDL-C estimated to be
due to Lp(a) in patients with baseline Lp(a) 30–60 mg/dl, and a corresponding figure
of ~20% with Lp(a) >60 mg/dl.4 This was not taken into account for the regression
analysis; to correct for the cholesterol in LDL-C which was due to Lp(a), previous
studies have subtracted the Lp(a) mass, multiplied by 0.3, from the LDL-C values.4
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Acknowledgments
Medical writing support was provided by Rob Campbell of Prime Medica Ltd,
Knutsford, Cheshire, UK, supported by Sanofi and Regeneron.
Disclosures
D. Gaudet has worked as a consultant and on advisory boards for Sanofi,
Regeneron, Novartis, Isis, Catabasis, Aegerion, and Amgen (all modest).
D. Kereiakes has no relevant financial disclosures. J.M. McKenney and E. Roth are
employed by companies that have received research funds and have received
consulting fees from Regeneron and/or Sanofi (significant). D. Gipe and Y. Du are
employees of Regeneron (both significant). C. Hanotin and A.-C. Ferrand are
employees of Sanofi (both significant). H. Ginsberg has received research funding
from Sanofi (significant) and has worked as a consultant and on advisory boards for
Sanofi and Regeneron (modest). E. Stein has received consultant fees from Sanofi,
Regeneron, Amgen, BMS/Adnexus, and Roche/Genentech (all modest).
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Figure 1. Effect of alirocumab 150 mg Q2W on Lp(a) (pooled modified intention-to-
treat population). Shown are absolute changes from baseline (A) or percentage
changes from baseline (B) in Lp(a), with patients subdivided by baseline Lp(a)
levels.
*p <0.0001 versus placebo.
P-values were derived from analysis of covariance with treatment group and study as fixed effects and
baseline Lp(a) as covariate and are provided for descriptive purposes only, and were not adjusted for multiplicity.
IQR = inter-quartile range; LOCF = last observation carried forward; Lp(a) = lipoprotein(a); Q2W = every
2 weeks; SD = standard deviation.
Figure 2. Biology of Lp(a).
(1) Lp(a) consists in an apo(a) covalently bound to the apo B-100 component of a LDL-like particle. The
Lp(a) proteic backbone [apo(a) and apoB-100] is synthesized in the liver, whereas the Lp(a) assembly is
suspected to take place at the outer hepatocyte surface. Apo(a) proteins vary in size due to a variable number of
kringle IV repeats in the LPA gene. (2) The half-life of Lp(a) in circulation is >3 days. Although the mechanisms
through which Lp(a) promotes atherosclerosis and atherothrombosis are not clearly understood, proposed
mechanisms include inflammatory cell recruitment, increased Lp(a)-cholesterol entrapment in the intima,
transport of proatherogenic oxidized phospholipids and platelet activation, impairing fibrinolysis by inhibition of
plasminogen activation, and enhancing coagulation by inhibition of the tissue factor pathway inhibitor. (3) Lp(a)
has been recently associated with valvular calcification and aortic stenosis. (4) The pathways of Lp(a) clearance
are unclear. The liver seems to be importantly involved, although the contribution of the LDL-receptor in this
process appears to be less important than expected. Several clearance receptors have been identified, although
their respective contributions to Lp(a) removal remain to be determined. (5) The kidney appears to contribute to
Lp(a) clearance. Peripheral tissues also may contribute to Lp(a) removal from the plasma.
Apo = apolipoprotein; LDL, low-density lipoprotein; Lp(a), lipoprotein(a); LPA = apolipoprotein(a) gene;
PAI-1 = plasminogen activator inhibitor-1; TFPI = tissue factor pathway inhibitor; SMC = smooth muscle cells.
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Table 1 Patient baseline characteristics (pooled randomized population)
Mean ± standard deviation unless otherwise stated
Placebo (n = 77)
Alirocumab 150 mg every 2 weeks (n = 108)
Age (years) 54 ± 9 58 ± 10
Males 38 (49%) 47 (44%)
White or European American 65 (84%) 96 (89%)
Black or African American 10 (13%) 12 (11%)
Other race 2 (3%) 0
Body mass index (kilograms per meter2)
29 ± 5 29 ± 5
Low-density lipoprotein cholesterol (milligrams per deciliter)
131 ± 28 127 ±25
Total cholesterol (milligrams per deciliter)
211 ± 32 208 ± 31
High-density lipoprotein cholesterol (milligrams per deciliter)
52 ± 14 54 ± 15
Non-high-density lipoprotein cholesterol (milligrams per deciliter)
159 ± 31 154 ± 31
Triglycerides, median (interquartile range) (milligrams per deciliter)
123 (92–174) 124 (88–169)
Apolipoprotein B* (milligrams per deciliter)
109 ± 23 108 ± 24
*n = 76 and n = 107 patients randomized to placebo and alirocumab 150 mg Q2W, respectively,
had apolipoprotein B data available at baseline.
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Table 2
Baseline lipoprotein(a) levels in patients included in the pooled analysis
(pooled modified-intent-to-treat population*)
________Variable_____________ Placebo (n = 74)
Alirocumab 150 mg every 2 weeks
(n = 102)_______
Lipoprotein(a), median (interquartile range) (milligrams per deciliter)
19 (6–77) 30 (8–70)
Range, milligrams per deciliter 2–299 2–181
Patients subdivided by baseline lipoprotein(a)
≤50 mg/dl 49 (66%) 68 (67%)
>50 mg/dl 25 (34%) 36 (35%)
*Patients with Lp(a) data available at baseline and end of treatment (week 8/12 on-treatment
value or the last available on-treatment value carried forward).
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Supplementary Figure 1. Summary of design and dosing in the phase 2
studies included in this analysis.
Study 11566 included up-titration of ATV 10 mg to 80 mg in the placebo arm and 1 of the
alirocumab arms.
†Numbers indicate randomized population.
ATV = atorvastatin; FH = familial hypercholesterolemia; HC = hypercholesterolemia;
HeFH = heterozygous familial hypercholesterolemia; Q2W = every 2 weeks; Q4W = every 4 weeks.
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Supplementary Figure 2. Relationship between effects of alirocumab 150 mg
Q2W on change from baseline in Lp(a) and either the change from baseline in
LDL-C at end of study treatment (A) or achieved LDL-C (B) (pooled modified
intention-to-treat population).
LDL-C = low-density lipoprotein cholesterol; Lp(a) = lipoprotein(a); Q2W, every 2 weeks.
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