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Association Between Major Adverse Cardiovascular Events and non-High-Density Lipoprotein Cholesterol and Apolipoprotein B
in Phase 3 Trials of Alirocumab
Michael H Davidson,1 Christopher P Cannon,2 Henry N Ginsberg,3 Robert Pordy,4 Laurence Bessac,5
Pascal Minini,6 Robert H Eckel,7 Kausik K Ray8
1Department of Medicine, University of Chicago Medicine, Chicago, IL, USA; 2Harvard Clinical Research Institute, Boston, MA, USA; 3Columbia University,
New York, NY, USA; 4Regeneron Pharmaceuticals, Tarrytown, NY, USA; 5Sanofi, Paris, France; 6Biostatistics and Programming, Sanofi, Chilly-Mazarin, France;
7University of Colorado, Anschutz Medical Campus, Aurora, CO, USA; 8Department of Primary Care and Public Health, School of Public Health, Imperial College,
London, UK
This study was funded by Sanofi and Regeneron Pharmaceuticals, Inc.
Disclosures
2
Author Disclosure Michael H Davidson Consultant/advisory board fees from Merck, Sanofi, Regeneron Pharmaceuticals,
Inc., Amgen, and Lipimedix.
Christopher P Cannon Grants from Arisaph, AstraZeneca, Bristol-Myers Squibb (BMS), Boehringer Ingelheim (BI), GlaxoSmithKline, Janssen, Merck and Takeda; consulting fees from Alnylam, Amgen, Arisaph, BI, BI/Lilly, BMS, GlaxoSmithKline, Kowa, Merck, Takeda, Lipimedix, Pfizer, Regeneron and Sanofi.
Henry N Ginsberg Grants and personal fees from Sanofi, grants from Regeneron Pharmaceuticals, Inc., consultant for Amgen and for Pfizer.
Robert Pordy Employee/stockholder, Regeneron Pharmaceuticals, Inc.
Laurence Bessac Employee/stockholder, Sanofi.
Pascal Minini Employee/stockholder, Sanofi.
Robert H Eckel Personal fees from Sanofi/Regeneron, Ionis Pharmaceuticals, UniQure, and Merck.
Kausik K Ray
Personal fees (data safety monitoring board) from AbbVie, Inc., consultant fees/honoraria from Aegerion, Algorithm, Amgen, AstraZeneca, BI, Cerenis, Eli Lily and Company, Ionis Pharmaceuticals, Kowa, Medicines Company, MSD, Novartis, Pfizer, Regeneron, Reservlogix, Sanofi, and Takeda, and research grants from Kowa, Pfizer, and Regeneron Pharmaceuticals, Inc.
LDL-C has been the primary focus of CV-risk management1
Other atherogenic particles [TG, VLDL-C, Lp(a)] also contribute to risk - accordingly, non-HDL-C is primary target in NLA guidelines2
– ApoB is also considered as a secondary treatment target2
We evaluated the impact of change in lipid parameters on CV outcomes using data from the alirocumab ODYSSEY clinical trial program
Non-HDL-C and apoB
3 1.Stone NJ et al. J Am Coll Cardiol. 2014;63:2889–2934. 2. Jacobson TA et al. J Clin Lipidol. 2015;9;129–169.
Continuous relationship between lower on-treatment LDL-
C levels and lower CV risk1
Emerging Evidence from ODYSSEY Program
4
Direct relationship between greater LDL-C % reduction from baseline and
lower ASCVD event rates2
Adjusted MACE rate by average LDL-C (absolute or % reduction from baseline) during treatment period. Multivariate analysis adjusted on baseline characteristics; pool of Phase 3 ODYSSEY trials. HR were calculated for each 39 mg/dL difference or 50% reduction in LDL-C. 1. Cannon CP et al., oral presentation [session 913], ACC 2016. 2. Ray KK et al. poster 1124M-05, ACC 2016.
Previous Data1 Suggests that Major CV Events Correlate More Closely with non-HDL-C than LDL-C
5
When discordant, risk follows non-HDL-C, not LDL-C
0.5 1.0 2.0 HR (95% CI)
1. Boekholdt SM et al. JAMA. 2012;307:1302-1309. Results are shown for 4 categories of statin-treated patients based on achievement of LDL-C <100 mg/dL and non-HDL-C <130 mg/dL. HRs were adjusted for sex, age, smoking, diabetes, systolic blood pressure, and trial. 2. Contois JH et al. Clin Chem. 2009;55:407–419.
ApoB has also been shown to be a stronger predictor of risk than LDL-C in several epidemiological studies2
Risk for major CV events
LDL-C (mg/dL)
Non-HDL-C (mg/dL)
Total patients (N)
Major CV Events (n) HR (95% CI)
≥100 ≥130 10419 1877 1.21 (1.13–1.29)
≥100 <130 2873 467 1.02 (0.92–1.12)
<100 ≥130 1435 283 1.32 (1.17–1.50)
<100 <130 23426 2760 1.00 (Reference)
Methods: 10 Phase 3 ODYSSEY Trials Analyzed (n=4983)
6
OPTIONS I, 24 weeks†
Atorvastatin not at goal ALI 75/150 mg Q2W : n=104 EZE: n=102
COMBO II, 104 weeks* ALI 75/150 mg Q2W : n=479 EZE: n=241
OPTIONS II, 24 weeks† Rosuvastatin not at goal ALI 75/150 mg Q2W : n=103 EZE: n=101
COMBO I, 52 weeks ALI 75/150 mg Q2W : n=209 PBO: n=107
FH I, 78 weeks ALI 75/150 mg Q2W: n=323 PBO: n=163
FH II, 78 weeks ALI 75/150 mg Q2W : n=167 PBO: n=82
LONG TERM, 78 weeks ALI 150 mg Q2W : n=1553 PBO: n=788
HIGH FH, 78 weeks ALI 150 mg Q2W : n=72 PBO: n=35
MONO, 24 weeks No background LLTs ALI 75/150 mg Q2W : n=52 EZE: n=51
ALTERNATIVE, 24 weeks Statin intolerance ALI 75/150 mg Q2W : n=126 EZE: n=125
ALI 75/150 mg Q2W = studies initiated with ALI mg 75 Q2W, increasing to 150 mg Q2W at Week 12 if pre-specified LDL-C levels were not achieved by Week 8. In HIGH FH and LONG TERM, all patients randomized to ALI started on the 150 m Q2W dose. *Other LLTs not allowed at study entry in COMBO II; †moderate doses of atorvastatin/rosuvastatin at study entry. ALI, alirocumab; EZE, ezetimibe; HeFH, heterozygous familial hypercholesterolemia; LLT, lipid-lowering therapy; PBO, placebo; Q2W, every 2 weeks. Clinicaltrials.gov identifiers: LONG TERM, NCT01507831; FH I NCT01623115; FH II, NCT01709500; HIGH FH, NCT01617655; COMBO I, NCT01644175; COMBO II, NCT01644188; MONO, NCT01644474; OPTIONS I, NCT01730040; OPTIONS II, NCT01730053; ALTERNATIVE, NCT01709513.
HeFH population High CV risk population Additional populations Add-on to maximally tolerated
statin (±other LLT) Add-on to maximally tolerated
statin (±other LLT)
Placebo-controlled
Ezetimibe-controlled
Data from 4974 patients were analyzed (3182 treated with alirocumab, 1174 with placebo, 618 with ezetimibe)
MACE incidence correlated with average achieved apoB or non-HDL-C from baseline to time of MACE using multivariate analysis adjusted for baseline factors: age, sex, diabetes, prior MI/stroke, baseline LDL-C, smoking status
– Average apoB and non-HDL-C calculated from area under the curve (trapezoidal method) using all values until the end of the treatment period, or until an incident of MACE, if this occurred first
– For comparison with the LDL-C results, an 0.76 SD ratio was applied to non-HDL-C and apoB (these lipids evaluated per 42 and 27 mg/dL reduction, respectively).
– Similarly, non-HDL-C/apo B were assessed per 50% reduction as this corresponds with the increment used for the LDL-C analysis.
Methods
7 1. Schwartz GG et al. Am Heart J. 2014;168:682–689. CHD, coronary heart disease; MI, myocardial infarction; UA, unstable angina.
Definition of MACE (ODYSSEY OUTCOMES primary endpoint)1:
CHD death
non-fatal MI
ischemic stroke
unstable angina requiring hospitalization*
MACE adjudicated by Clinical Events Committee
*UA requiring hospitalization = limited to cases with definite evidence of progression of the ischemic condition, i.e. small proportion of UAs
Baseline Characteristics
8
Placebo-controlled trials Ezetimibe-controlled trials Alirocumab
(n=2324) Placebo (n=1175)
Alirocumab (n=864)
Ezetimibe (n=620)
Age, years, mean ± SD 58.7 ± 11.6 58.8 ± 11.4 61.9 ± 9.4 62.1 ± 9.5 Males, % 60.9 60.6 67.2 62.6 Race, white, % 92.0 91.2 86.2 88.4 BMI, kg/m2, mean ± SD 30.1 ± 5.6 30.3 ± 5.6 30.2 ± 6.0 30.0 ± 5.7 HeFH, % 36.1 35.7 4.6 6.9 Diabetes, % 30.1 30.2 32.8 31.0 ASCVD, % 69.5 71.0 75.3 66.3
CHD 62.6 65.2 70.7 62.9 Ischemic stroke/TIA 8.6 7.3 7.8 6.8 PAD 4.2 4.8 3.8 3.1
Current smoker, % 19.5 19.7 16.9 19.0
LDL-C, mg/dL, mean ± SD 126.8 ± 46.3 126.8 ± 44.8 123.2 ± 51.5 125.5 ± 56.9
Non-HDL-C, mg/dL, mean ± SD 155.7 ± 49.6 155.5 ± 48.5 154.2 ± 57.2 156.9 ± 64.1
Apo B, mg/dL, mean ± SD 104.3 ± 29.0 104.0 ± 28.5 101.8 ± 30.7 102.5 ± 32.2
ASCVD, atherosclerotic cardiovascular disease; BMI, body mass index; CHD, coronary heart disease, HeFH, heterozygous familial hypercholesterolemia, PAD, peripheral artery disease, SD, standard deviation, TIA, transient ischemic attack.
84.7% on background of maximally tolerated statin
02468
101214
20–<
30
30–<
40
40–<
50
50–<
60
60–<
70
70–<
80
80–<
90
90–<
100
100–
<110
11
0–<1
20
120–
<130
13
0–<1
40
140–
<150
15
0–<1
60
160–
<170
17
0–<1
80
180–
<190
19
0–<2
00
200-
<210
210-
<220
220-
<230
230-
<240
240-
<250
250+
All treatment groups(n=4974)
02468
101214
20-<
3030
–<40
40
–<50
50
–<60
60
–<70
70
–<80
80
–<90
90
–<10
0 10
0–<1
10
110–
<120
12
0–<1
30
130–
<140
14
0–<1
50
150–
<160
16
0–<1
70
170–
<180
18
0–<1
90
190–
<200
20
0-<2
1021
0-<2
2022
0-<2
3023
0-<2
4024
0-<2
5025
0+
% p
atie
nts
All treatment groups(n=4974)
9
Distribution of Average non-HDL-C At Baseline And During Treatment
% p
atie
nts
Average non-HDL-C during treatment, mg/dL
Baseline non-HDL-C, mg/dL
Baseline
During treatment
Data pooled from patients treated with alirocumab
(n=3182), placebo
(n=1174), and ezetimibe (n=618)
Adjusted MACE Rate by Average Achieved non-HDL-C During Treatment
Multivariate analysis adjusted on baseline characteristics; pool of Phase 3 trials
10
HR [95% CI]: 0.77 [0.65 to 0.93] per 42 mg/dL difference; p=0.0056
50 100 125 Average non-HDL-C during the treatment period (mg/dL)
Adju
sted
rate
of M
ACE
(per
100
pat
ient
-yea
rs)
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
175 150 75
Event rate 95% CI
4974 patients (84.7% on background maximally tolerated statin) were treated with ALI, PBO or EZE for total follow-up of 6699 patient-yrs
104 patients reported MACE (median time to event: 36 wks)
LDL-C
Adjusted MACE Rate by Average non-HDL-C % Change from Baseline During Treatment
Multivariate analysis adjusted on baseline characteristics; pool of Phase 3 trials
11
HR [95% CI]: 0.71 [0.52 to 0.97] per 50% reduction; p=0.0323
0 30 40 Percent reduction in average non-HDL-C during the
treatment period (%)
0.0
0.5
1.0
1.5
2.0
2.5
3.0
100 70 10 20 60 90 50 80
Event rate 95% CI
Adju
sted
rate
of M
ACE
(per
100
pat
ient
-yea
rs)
LDL-C
02468
1012141618
% p
atie
nts
All groups(n=4974)
12
Distribution of Average ApoB At Baseline And During Treatment for All Groups Combined
% p
atie
nts
Average apoB during treatment, mg/dL
Baseline LDL-C, mg/dL
02468
10121416
All groups(n=4974)
Baseline
During treatment
Adjusted MACE Rate by Average Achieved ApoB During Treatment
Multivariate analysis adjusted on baseline characteristics; pool of Phase 3 trials
13
HR [95% CI]: 0.72 [0.60 to 0.86] per 27 mg/dL difference; p=0.0002
40 70 80 Average Apo B during the treatment period (mg/dL)
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
120 100 50
Event rate 95% CI
60 90 110
Adju
sted
rate
of M
ACE
(per
100
pat
ient
-yea
rs)
LDL-C
Adjusted MACE Rate by Average ApoB % Change from Baseline During Treatment
Multivariate analysis adjusted on baseline characteristics; pool of Phase 3 trials
14
HR [95% CI]: 0.68 [0.54 to 0.85] per 50% reduction; p=0.0008
0 30 40 0.0
0.5
1.0
1.5
2.0
2.5
3.0
100 70 10 20 60 90 50 80
Event rate 95% CI
Percent reduction in average Apo B during the treatment period (%)
Adju
sted
rate
of M
ACE
(per
100
pat
ient
-yea
rs)
LDL-C
Comparison of Effect on MACE of Average achieved LDL-C, Non-HDL-C and ApoB
15
ApoB (per 27 mg/dL difference)
LDL-C (per 39 mg/dL difference)
Non-HDL-C (per 42 mg/dL difference)
Hazard ratio (95% CI) 0.50 0.60 0.70 0.80 0.90 1.00 1.10
0.63 0.76 0.91
0.65 0.77 0.93
0.60 0.72 0.86
Comparison of Effect on MACE of Average % Change in LDL-C, Non-HDL-C and ApoB
16
Hazard ratio (95% CI) 0.50 0.60 0.70 0.80 0.90 1.00 1.10
0.57 0.71 0.89
0.52 0.71 0.97
0.54 0.68 0.85 ApoB (per 50% reduction)
LDL-C (per 50% reduction)
Non-HDL-C (per 50% reduction)
Safety Summary of the 10 Trials Used in this Analysis
17
Values are % (n)
Placebo-controlled trials Ezetimibe-controlled trials Alirocumab
(n=2318) Placebo (n=1174)
Alirocumab (n=864)
Ezetimibe (n=618)
TEAEs 79.9 (1851) 81.3 (954) 76.0 (657) 73.9 (457) Treatment-emergent SAEs 16.6 (385) 17.2 (202) 17.0 (147) 13.9 (86) TEAEs leading to death 0.7 (16) 1.1 (13) 0.7 (6) 1.5 (9) TEAEs leading to discontinuation 6.2 (144) 5.7 (67) 9.7 (84) 10.7 (66) TEAEs in ≥5% of patients Nasopharyngitis 12.6 (291) 12.1 (142) 6.0 (52) 6.6 (41) Injection site reaction 7.2 (167) 5.3 (62) 2.9 (25) 2.1 (13) Upper respiratory tract infection 7.0 (162) 8.0 (94) 7.2 (62) 6.5 (40) Influenza 6.3 (147) 5.4 (63) 4.3 (37) 3.7 (23) Urinary tract infection 5.5 (128) 5.5 (65) 2.4 (21) 4.0 (25) Back pain 5.3 (123) 6.0 (70) 3.8 (33) 4.2 (26) Diarrhoea 5.3 (123) 4.9 (57) 3.5 (30) 3.4 (21) Headache 5.1 (119) 5.5 (64) 5.0 (43) 3.9 (24) Arthralgia 5.1 (118) 6.5 (76) 4.9 (42) 4.2 (26)
Myalgia 4.8 (111) 3.9 (46) 7.2 (62) 7.8 (48)
Accidental overdose 1.3 (30) 1.4 (17) 6.3 (54) 3.9 (24) SAE, serious adverse event; TEAE, treatment-emergent adverse event
Limitations: small # events, hence CI is broad; analysis not pre-specified (hypothesis generating)
Data pooled from 4974 patients (most on maximally tolerated statin) in the ODYSSEY program
Lower MACE rate directly related to both lower on-treatment levels and greater % reduction in non-HDL-C and apoB
The ODYSSEY OUTCOMES trial (~18,000 patients) is evaluating the effect on MACE with alirocumab treatment
Conclusions
18
Back up slide
19
Average LDL-C
Average Non-HDL-C
Average ApoB
Average LDL-C during the treatment period - 0.973 (p<0.0001)
0.922 (p<0.0001)
Average non-HDL-C during the treatment period 0.973 (p<0.0001) - 0.948
(p<0.0001)
Average ApoB during the treatment period 0.922 (p<0.0001)
0.948 (p<0.0001) -
Correlation between average LDL-C, Non-HDL-C and ApoB during the treatment period
20
Pearson correlation coefficient
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