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

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All treatment groups(n=4974)

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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

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0.0

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2.5

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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

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Event rate 95% CI

Adju

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ACE

(per

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LDL-C

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% p

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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

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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

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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