ONLINE APPENDIX

References for studies included in this analysis (see end of document for list)

Phase 2: DFI11565 (1), CL-1003 (2). DFI12361 (3). DFI11566 (4).

Phase 3: LONG TERM (5), HIGH FH (6), FH I and FH II (7), COMBO I (8), COMBO

II (9), OPTIONS I (10), OPTIONS II (11), MONO (12), ALTERNATIVE (13).

Safety monitoring of LDL-C <25 mg/dL

A dedicated data monitoring committee member and independent physician were

provided access to unblinded low-density lipoprotein cholesterol (LDL-C) data to

monitor patients who achieved 2 consecutive calculated LDL-C values <25 mg/dL. At

their discretion, an alert was sent to the site, with sham alerts also used to preserve

the blind. The investigator would call the patient about occurrences of adverse

events and decide whether the patient should be requested to rapidly have an

unscheduled site visit, or if assessment could be done at the next scheduled visit. At

the site visit, the investigator assessed whether the patient needed additional work-

up, should see a specialist and whether the study treatment should be temporarily or

permanently discontinued.

Hemolytic anemia

Hemolytic anemia was assessed with specific algorithms in most studies. This

algorithm included review of laboratory parameters such as reticulocyte count,

lactate dehydrogenase, direct and indirect bilirubin, and haptoglobin. If needed and

based on special circumstances, further assessments with a peripheral blood smear

and Coombs test by a hematologist was requested.

Page 1

Propensity analysis

Baseline characteristics of patients who achieved at least 2 consecutive LDL-C <25

mg/dL and those who did not are different between these 2 post-randomization

subgroups. As an example, patients with 2 consecutive LDL-C <25 mg/dL are more

likely to be men, >65 years of age, with prior history of coronary heart disease (CHD)

or CHD risk equivalents, diabetic, with lower baseline LDL-C, lipoprotein (a) [Lp(a)],

high-density lipoprotein cholesterol (HDL-C), and with higher triglycerides. Those

differences in baseline characteristics could have an impact on the interpretation of

the comparison of the safety profile between the LDL-C subgroups (i.e. subgroup

with at least 2 consecutive LDL-C <25 mg/dL and the subgroup who did not achieve

2 consecutive LDL-C <25 mg/dL).

In this context, in order to limit the bias associated with comparison of post-

randomization subgroups, additional analyses based on propensity score adjustment

are provided (14). Of note, this methodology has also been used in the recently

published analysis on the safety profile of subjects from the JUPITER study who

achieved LDL-C levels <30 mg/dL with rosuvastatin 20 mg daily (15).

The first step of this method consists of the identification of prognostic factors for

achieving two consecutive LDL-C <25 mg/dL. The following factors were assessed:

• Age (years, continuous)

• Gender (reference: male)

• Race (White / Black or African American/Asian/Other; reference: White)

• Ethnicity (reference: not Hispanic)

• Body mass index (kg/m2, continuous)

• Weight (kg, continuous)

Page 2

• Baseline LDL-C (mg/dL, continuous)

• Baseline fasting triglycerides (mg/dL, continuous)

• Baseline Lp(a) (mg/dL, continuous)

• Baseline HDL-C (mg/dL, continuous)

• Baseline glomerular filtration rate (mL/min/1.73m2, continuous)

• Baseline systolic blood pressure (mmHg, continuous)

• Baseline diastolic blood pressure (mmHg, continuous)

• Background statin dose (no statin/low dose/high dose; reference: no background statin)

• Lipid-lowering therapy other than statin (reference: no)

• Prior history of myocardial infarction/stroke reported in the medical history (reference: no)

• Diabetes mellitus, type 1 or type 2 reported in the medical history (reference: no)

• Moderate chronic kidney disease (reference: no)

• Hypertension (reference: no)

• Baseline glycated hemoglobin (%, continuous)

• Starting dose of alirocumab (75 mg or 150 mg depending on the study;

reference: 75 mg)

The analysis was conducted on the global pool of Phase 3 studies as some factors,

such as pre-listed items for medical history, were not available in Phase 2 studies.

For each risk factor listed above, a univariate logistic regression was run. All factors

significant at the 0.15 level in the univariate analysis were included in a multivariate

logistic regression. The significant prognostic factors (p < 0.15) for achieving 2

consecutive LDL-C <25 mg/dL are described in Supplementary Table 2. As

expected, baseline LDL-C and the alirocumab starting dose are significant factors for

achieving 2 consecutive LDL-C <25 mg/dL values.

Page 3

The propensity scores (i.e. predicted probabilities to achieve 2 consecutive LDL-

C <25 mg/dL) were derived for each patient from this final multivariate model and

were divided into 5 quintiles. The second step of the propensity score analysis

consist of the comparison of the 2 post-randomization subgroups (<25 mg/dL, ≥25

mg/dL), after adjustment on the propensity score (e.g. stratification) in order to limit

the bias associated with this comparison and to adjust on potential confounding

factors.

For each grouping of interest (neurological, neurocognitive, ophthalmological,

diabetes), the time to the first TEAE is compared for patients with ≥2 consecutive

LDL-C <25 mg/dL versus ≥25 mg/dL, within the alirocumab group in the global pool

of Phase 3 studies, using a Cox model, including the covariate for 2 consecutive

LDL-C <25 mg/dL (Y/N) and stratified based on propensity score (quintile). Adjusted

hazard ratio (and 95% confidence interval) from this model are provided.

Page 4

Supplemental Table 1. Alirocumab Dose at Time of First LDL-C Value <25 or

<15 mg/dL (Safety Population; Phase 2 and 3 Studies)

Values are % (n) Alirocumab (n = 3,340)

Patients with 2 consecutive LDL-C <25 mg/dL 25.1 (839)

Alirocumab dose at time of first LDL-C value <25 mg/dL

75 mg Q2W (studies with dose increase) 23.7 (199/839)

75 mg Q2W (studies without dose increase)* 0.4 (3/839)

150 mg Q2W (studies with dose increase) 3.9 (33/839)

150 mg Q2W (studies without dose increase) 72.0 (604/839)

Patients with 2 consecutive LDL-C <15 mg/dL 9.4 (314)

Alirocumab dose at time of first LDL-C value <15 mg/dL

75 mg Q2W (studies with dose increase) 18.2 (57/314)

75 mg Q2W (studies without dose increase)* 0

150 mg Q2W (studies with dose increase) 4.1 (13/314)

150 mg Q2W (studies without dose increase) 77.7 (244/314)

*One study (Phase 2 study in Japanese patients, DFI12361) included an alirocumab 75 mg Q2W

treatment arm without the possibility of dose increase.

Page 5

Supplemental Table 2. Prognostic Factors for LDL-C <25 mg/dL (Safety

Population; Alirocumab-Treated Patients in Phase 3 Studies Only)

Alirocumab (n = 3,182)

Predictors

Adjusted OR

(95% CI)* p-value*

Baseline LDL-C (per 10 mg/dL decrement) 1.37 (1.32 to 1.42) <0.0001

Alirocumab starting dose (150 mg vs 75 mg) 4.37 (3.56 to 5.37) <0.0001

Baseline TG (per 10 mg/dL increment) 1.06 (1.05 to 1.07) <0.0001

Baseline Lp(a) (per 10 mg/dL decrement) 1.08 (1.05 to 1.10) <0.0001

Baseline BMI (per 1 kg/m² decrement) 1.06 (1.04 to 1.08) <0.0001

Sex Male vs Female 1.78 (1.43 to 2.23) <0.0001

Baseline HDL-C (per 10 mg/dL decrement) 1.20 (1.09 to 1.31) 0.0001

Baseline age (per 5 years increment) 1.08 (1.03 to 1.13) 0.0018

Stroke or MI (Yes vs No) 1.36 (1.12 to 1.65) 0.0022

Placebo-controlled studies: phase 3 (LONG TERM, FH I, FH II, HIGH FH, COMBO I). Ezetimibe-

controlled studies: phase 3 (COMBO II, MONO, OPTIONS I, OPTIONS II, ALTERNATIVE)

Table sorted by increasing p-value.

*OR, 95% CI and p-values are adjusted for all listed prognostic factors. Variables were first selected if

they showed p < 0.15 in univariate analyses and then a multivariate logistic regression was performed

using a stepwise selection at the 0.15 level for entry and stay. The individual propensity scores for

achieving 2 consecutive LDL-C <25 mg/dL are the probabilities predicted by the final multivariate

logistic regression.

CI = confidence interval; MI = myocardial infarction; OR = odds ratio.

Page 6

Supplemental Table 3. Prognostic Factors for LDL-C <15 mg/dL (Safety

Population; Phase 3 Studies Only)

Alirocumab

(n = 3,182)

Predictors

Adjusted OR

(95% CI)* p-value*

Baseline LDL-C (per 10 mg/dL decrement) 1.39 (1.32 to 1.47) <0.0001

Alirocumab starting dose (150 mg vs. 75 mg) 4.45 (3.26 to 6.07) <0.0001

Baseline TG (per 10 mg/dL increment) 1.07 (1.05 to 1.09) <0.0001

Baseline Lp(a) (per 10 mg/dL decrement) 1.10 (1.06 to 1.15) <0.0001

Baseline HDL-C (per 10 mg/dL decrement) 1.19 (1.04 to 1.37) 0.0125

Race (Asian vs. White) 1.70 (0.69 to 4.15)

0.0290Race (Black or African American vs. White) 0.51 (0.18 to 1.45)

Race (Other vs. White) 2.30 (1.18 to 4.50)

Baseline age (per 5 years increment) 1.07 (1.00 to 1.15) 0.0419

Sex Male vs Female 1.38 (1.00 to 1.91) 0.0471

Stroke or MI (Yes vs. No) 1.29 (0.98 to 1.69) 0.0699

LLT (Yes vs. No) 1.26 (0.93 to 1.70) 0.1420

Placebo-controlled studies: Phase 3 (LONG TERM, FH I, FH II, HIGH FH, COMBO I)

Ezetimibe-controlled studies: Phase 3 (COMBO II, MONO, OPTIONS I, OPTIONS II, ALTERNATIVE)

Table sorted by increasing p-value.

Page 7

*OR, 95% CI and p-values are adjusted for all listed prognostic factors. Variables were first selected if

they showed p<0.15 in univariate analyses and then a multivariate logistic regression was performed

using a stepwise selection at the 0.15 level for entry and stay. The individual propensity scores for

achieving two consecutive LDL-C <15 mg/dL are the probabilities predicted by the final multivariate

logistic regression.

CI = confidence interval; LDL-C = low-density lipoprotein cholesterol; LLT = lipid-lowering therapy; MI

= myocardial infarction; OR = odds ratio.

Page 8

Supplemental Table 4. Percentage Incidence of TEAEs Occurring in ≥1%

Patients (Safety Population; Phase 2 and 3 Studies)

Alirocumab

Values are % (n)

[rate per 100 patient-

years‡]

Pooled

control

(n = 1,894)

Overall

alirocumab

(n = 3,340)

LDL-C

≥25 mg/dL*

(n = 2,501)

LDL-C

<25 mg/dL†

(n = 839)

LDL-C

<15 mg/dL†

(n = 314)

TEAEs with ≥1%

incidence in any group

System organ class

Preferred term

Infections and

infestations

40.0 (758)

[45.6]

41.5 (1387)

[44.5]

40.4 (1010)

[45.2]

37.1 (311)

[39.1]

37.6 (118)

[41.4]

Nasopharyngitis9.9 (188)

[8.6]

10.6 (353)

[8.5]

9.9 (248)

[8.4]

9.3 (78)

[7.8]

10.5 (33)

[9.1]

Upper respiratory tract

infection

7.2 (137)

[6.1]

6.8 (227)

[5.3]

6.7 (168)

[5.5]

5.1 (43)

[4.2]

6.1 (19)

[5.1]

Urinary tract infection4.8 (90)

[3.9]

4.5 (150)

[3.4]

4.0 (101)

[3.3]

5.0 (42)

[4.1]

4.8 (15)

[4.0]

Bronchitis4.1 (78)

[3.4]

4.2 (139)

[3.2]

4.0 (99)

[3.2]

4.5 (38)

[3.7]

3.5 (11)

[2.9]

Influenza4.5 (86)

[3.8]

5.5 (184)

[4.3]

5.8 (145)

[4.7]

3.9 (33)

[3.2]

4.8 (15)

[4.0]

Page 9

Sinusitis2.9 (55)

[2.4]

2.9 (98)

[2.2]

2.8 (71)

[2.3]

3.1 (26)

[2.5]

3.5 (11)

[2.9]

Lower respiratory tract

infection

1.5 (29)

[1.2]

1.6 (55)

[1.2]

1.4 (35)

[1.1]

2.1 (18)

[1.7]

2.5 (8)

[2.1]

Herpes zoster1.0 (18)

[0.8]

0.8 (28)

[0.6]

0.6 (16)

[0.5]

1.2 (10)

[0.9]

0.1 (3)

[0.8]

Cellulitis0.8 (15)

[0.6]

0.9 (31)

[0.7]

0.7 (18)

[0.6]

1.1 (9)

[0.8]0

Pharyngitis0.8 (16)

[0.7]

1.1 (37)

[0.8]

1.1 (27)

[0.9]

1.1 (9)

[0.8]

1.3 (4)

[1.0]

Pneumonia1.6 (30)

[1.3]

1.7 (56)

[1.3]

1.9 (4.7)

[1.5]

1.1 (9)

[0.8]

1.3 (4)

[1.0]

Tooth abscess0.8 (16)

[0.7]

1.0 (35)

[0.8]

1.0 (26)

[0.8]

1.1 (9)

[0.9]

1.3 (4)

[1.0]

Conjunctivitis0.7 (14)

[0.6]

0.8 (28)

[0.6]

0.7 (17)

[0.5]

1.0 (8)

[0.8]

0.3 (1)

[0.3]

Gastroenteritis2.6 (50)

[2.2]

2.0 (66)

[1.5]

2.2 (56)

[1.8]

0.8 (7)

[0.7]

1.3 (4)

[1.0]

Rhinitis1.2 (22)

[0.9]

0.9 (31)

[0.7]

0.7 (17)

[0.5]

0.8 (7)

[0.7]

0.6 (2)

[0.5]

Cystitis 1.1 (21) 0.8 (27) 0.8 (20) 0.7 (6) 0.6 (2)

Page 10

[0.9] [0.6] [0.6] [0.6] [0.5]

Gastroenteritis viral0.8 (15)

[0.6]

1.0 (35)

[0.8]

1.0 (26)

[0.8]

0.5 (4)

[0.4]

1.0 (3)

[0.8]

Neoplasms benign,

malignant, and

unspecified (including

cysts and polyps)

3.3 (63)

[2.7]

3.2 (108)

[2.5]

3.0 (75)

[2.4]

3.5 (29)

[2.8]

3.5 (11)

[2.9]

Basal cell carcinoma0.5 (9)

[0.4]

0.4 (15)

[0.3]

0.3 (7)

[0.2]

0.8 (7)

[0.7]

1.0 (3)

[0.8]

Blood and lymphatic

system disorders

3.1 (59)

[2.5]

2.6 (88)

[2.0]

2.6 (64)

[2.0]

2.1 (18)

[1.7]

1.6 (5)

[1.3]

Anemia0.9 (17)

[0.7]

1.0 (33)

[0.7]

1.0 (25)

[0.8]

0.6 (5)

[0.5]

0.6 (2)

[0.5]

Immune system

disorders

0.9 (17)

[0.7]

1.4 (46)

[1.0]

1.4 (36)

[1.1]

0.8 (7)

[0.7]

1.0 (3)

[0.8]

Endocrine disorders0.7 (13)

[0.6]

0.8 (28)

[0.6]

0.7 (18)

[0.6]

1.2 (10)

[0.9]

1.9 (6)

[1.6]

Hypothyroidism0.4 (8)

[0.3]

0.3 (10)

[0.2]

0.2 (6)

[0.2]

0.5 (4)

[0.4]

1.0 (3)

[0.8]

Metabolism and nutrition

disorders

7.6 (143)

[6.3]

8.2 (274)

[6.5]

7.6 (189)

[6.2]

8.3 (70)

[6.9]

8.9 (28)

[7.6]

Type 2 diabetes

mellitus

1.3 (25) 1.4 (46) 1.1 (28) 1.9 (16) 1.3 (4)

Page 11

[1.1] [1.0] [0.9] [1.5] [1.0]

Diabetes mellitus1.1 (21)

[0.9]

1.3 (45)

[1.0]

1.2 (30)

[0.9]

1.8 (15)

[1.4]

2.5 (8)

[2.1]

Gout1.0 (19)

[0.8]

1.1 (38)

[0.9]

1.0 (25)

[0.8]

1.2 (10)

[0.9]

0.6 (2)

[0.5]

Diabetes mellitus

inadequate control

0.6 (11)

[0.5]

0.4 (15)

[0.3]

0.3 (7)

[0.2]

1.0 (8)

[0.8]

0.6 (2)

[0.5]

Hyperuricemia0.2 (4)

[0.2]

0.3 (11)

[0.2]

0.2 (5)

[0.2]

0.6 (5)

[0.5]

1.0 (3)

[0.8]

Hypoglycemia0.6 (11)

[0.5]

0.5 (18)

[0.4]

0.5 (13)

[0.4]

0.5 (4)

[0.4]

1.3 (4)

[1.0]

Psychiatric disorders6.3 (119)

[5.3]

5.7 (192)

[4.5]

5.9 (148)

[4.8]

4.4 (37)

[3.6]

3.8 (12)

[3.1]

Depression2.0 (38)

[1.6]

1.6 (55)

[1.2]

1.6 (41)

[1.3]

1.4 (12)

[1.1]

1.0 (3)

[0.8]

Anxiety1.7 (33)

[1.4]

1.1 (36)

[0.8]

1.0 (24)

[0.8]

1.2 (10)

[0.9]

1.6 (5)

[1.3]

Insomnia1.5 (29)

[1.2]

1.6 (53)

[1.2]

1.8 (44)

[1.4]

1.0 (8)

[0.8]

0.3 (1)

[0.3]

Nervous system

disorders

16.7 (317)

[15.2]

16.9 (566)

[14.3]

17.3 (433)

[15.4]

11.9 (100)

[10.2]

11.5 (36)

[10.0]

Dizziness 4.2 (79) 3.7 (122) 3.9 (97) 2.3 (19) 1.6 (5)

Page 12

[3.4] [2.8] [3.1][1.8]

[1.3]

Headache4.8 (91)

[4.0]

5.1 (169)

[3.9]

5.5 (138)

[4.5]

1.8 (15)

[1.4]

1.9 (6)

[1.6]

Sciatica1.0 (18)

[0.8]

0.9 (31)

[0.7]

0.7 (18)

[0.6]

1.3 (11)

[1.0]

0.6 (2)

[0.5]

Paraesthesia0.7 (14)

[0.6]

1.1 (37)

[0.8]

1.1 (27)

[0.9]

0.6 (5)

[0.5]

0.6 (2)

[0.5]

Syncope1.2 (22)

[0.9]

0.8 (26)

[0.6]

0.8 (21)

[0.7]

0.6 (5)

[0.5]

0.6 (2)

[0.5]

Hypoaesthesia0.8 (15)

[0.6]

0.8 (26)

[0.6]

1.0 (24)

[0.8]

0.2 (2)

[0.2]0

Eye disorders4.4 (83)

[3.6]

5.3 (176)

[4.1]

4.8 (119)

[3.9]

5.6 (47)

[4.6]

7.0 (22)

[5.9]

Cataract1.0 (19)

[0.8]

1.0 (35)

[0.8]

0.7 (17)

[0.5]

1.9 (16)

[1.5]

2.5 (8)

[2.1]

Vision blurred0.4 (7)

[0.3]

0.5 (16)

[0.4]

0.4 (10)

[0.3]

0.7 (6)

[0.6]

1.0 (3)

[0.8]

Ear and labyrinth

disorders

3.5 (66)

[2.9]

2.1 (69)

[1.6]

2.1 (52)

[1.6]

1.9 (16)

[1.5]

1.6 (5)

[1.3]

Vertigo 1.7 (32) 1.0 (32) 1.0 (24) 1.0 (8) 1.0 (3)

Page 13

[1.4] [0.7] [0.8] [0.8] [0.8]

Cardiac disorders9.8 (185)

[8.3]

9.9 (330)

[7.8]

9.5 (238)

[7.9]

9.3 (78)

[7.7]

7.0 (22)

[5.8]

Angina pectoris2.0 (38)

[1.6]

1.9 (62)

[1.4]

1.7 (43)

[1.4]

1.7 (14)

[1.3]

1.6 (5)

[1.3]

Atrial fibrillation1.7 (32)

[1.4]

1.4 (46)

[1.0]

1.3 (32)

[1.0]

1.5 (13)

[1.2]

1.3 (4)

[1.0]

Angina unstable1.0 (19)

[0.8]

1.5 (50)

[1.1]

1.4 (34)

[1.1]

1.3 (11)

[1.0]

1.6 (5)

[1.3]

Vascular disorders8.3 (158)

[7.1]

7.6 (253)

[5.9]

7.7 (193)

[6.4]

5.1 (43)

[4.1]

4.8 (15)

[3.9]

Hypertension4.0 (76)

[3.3]

3.9 (130)

[3.0]

4.1 (102)

[3.3]

2.4 (20)

[1.9]

2.9 (9)

[2.3]

Hypotension0.7 (13)

[0.6]

0.9 (29)

[0.7]

0.8 (20)

[0.6]

1.0 (8)

[0.8]

0.6 (2)

[0.5]

Respiratory, thoracic, and

mediastinal disorders

10.6 (201)

[9.1]

10.5 (352)

[8.5]

10.3 (258)

[8.7]

8.6 (72)

[7.1]

10.5 (33)

[9.0]

Cough2.3 (44)

[1.9]

2.6 (88)

[2.0]

2.5 (62)

[2.0]

2.0 (17)

[1.6]

2.5 (8)

[2.1]

Chronic obstructive

pulmonary disease

1.1 (21)

[0.9]

1.0 (35)

[0.8]

1.0 (25)

[0.8]

1.2 (10)

[0.9]

1.3 (4)

[1.0]

Asthma 0.6 (12) 0.7 (24) 0.7 (17) 0.7 (6) 1.0 (3)

Page 14

[0.5] [0.5] [0.5][0.6]

[0.8]

Epistaxis1.1 (21)

[0.9]

0.8 (28)

[0.6]

0.8 (21)

[0.7]

0.6 (5)

[0.5]

0.6 (2)

[0.5]

Dyspnea1.8 (35)

[1.5]

1.0 (33)

[0.7]

1.1 (27)

[0.9]

0.5 (4)

[0.4]

0.3 (1)

[0.3]

Nasal congestion0.3 (5)

[0.2]

0.4 (14)

[0.3]

0.3 (8)

[0.3]

0.5 (4)

[0.4]

1.0 (3)

[0.8]

Oropharyngeal pain0.6 (12)

[0.5]

1.1 (36)

[0.8]

1.2 (29)

[0.9]

0.5 (4)

[0.4]

0.3 (1)

[0.3]

Gastrointestinal

disorders

18.9 (358)

[17.3]

19.5 (650)

[16.7]

19.0 (476)

[17.2]

15.6 (131)

[13.7]

13.4 (42)

[11.9]

Diarrhea4.3 (82)

[3.6]

4.7 (158)

[3.6]

4.5 (112)

[3.6]

3.8 (32)

[3.1]

2.5 (8)

[2.1]

Constipation1.7 (32)

[1.4]

2.0 (66)

[1.5]

1.9 (48)

[1.5]

1.4 (12)

[1.1]

1.6 (5)

[1.3]

Dyspepsia1.3 (24)

[1.0]

1.0 (35)

[0.8]

0.8 (21)

[0.7]

1.4 (12)

[1.1]

1.3 (4)

[1.0]

Abdominal pain upper1.2 (22)

[0.9]

1.0 (35)

[0.8]

0.9 (23)

[0.7]

1.2 (10)

[0.9]

1.0 (3)

[0.8]

Nausea2.8 (53)

[2.3]

2.4 (81)

[1.8]

2.8 (70)

[2.2]

1.0 (8)

[0.8]

1.0 (3)

[0.8]

Page 15

Vomiting1.3 (24)

[1.0]

1.2 (39)

[0.9]

1.2 (30)

[0.9]

1.0 (8)

[0.8]

1.6 (5)

[1.3]

Gastroesophageal

reflux disease

1.7 (33)

[1.4]

1.4 (47)

[1.1]

1.6 (39)

[1.2]

0.8 (7)

[0.7]

0.3 (1)

[0.3]

Toothache1.1 (21)

[0.9]

1.0 (34)

[0.8]

1.0 (26)

[0.8]

0.7 (6)

[0.6]

1.3 (4)

[1.0]

Gastritis1.2 (23)

[1.0]

0.7 (25)

[0.6]

0.6 (16)

[0.5]

0.6 (5)

[0.5]

0.3 (1)

[0.3]

Abdominal pain1.2 (23)

[1.0]

1.4 (48)

[1.1]

1.7 (43)

[1.4]

0.4 (3)

[0.3]

1.0 (3)

[0.8]

Hepatobiliary disorders1.7 (33)

[1.4]

1.4 (47)

[1.1]

1.4 (34)

[1.1]

1.4 (12)

[1.1]

1.6 (5)

[1.3]

Skin and subcutaneous

tissue disorders

7.6 (144)

[6.4]

9.1 (303)

[7.2]

8.8 (220)

[7.3]

7.7 (65)

[6.4]

8.6 (27)

[7.4]

Rash1.2 (23)

[1.0]

1.4 (47)

[1.1]

1.3 (32)

[1.0]

1.1 (9)

[0.8]

1.9 (6)

[1.6]

Pruritus0.4 (8)

[0.3]

1.2 (39)

[0.9]

1.4 (34)

[1.1]

0.5 (4)

[0.4]

0.6 (2)

[0.5]

Musculoskeletal and

connective tissue

disorders

27.8 (527)

[27.3]

27.6 (923)

[25.5]

27.3 (683)

[26.5]

24.1 (202)

[22.8]

22.9 (72)

[21.8]

Back pain 5.1 (97) 4.8 (159) 4.3 (108) 5.2 (44) 5.1 (16)

Page 16

[4.2] [3.7] [3.5] [4.3] [4.2]

Arthralgia5.5 (105)

[4.6]

4.8 (161)

[3.7]

5.0 (126)

[4.1]

3.5 (29)

[2.8]

2.5 (8)

[2.1]

Myalgia5.0 (95)

[4.1]

5.2 (174)

[4.0]

5.4 (136)

[4.4]

3.1 (26)

[2.5]

3.8 (12)

[3.2]

Muscle spasms2.9 (54)

[2.3]

3.2 (107)

[2.4]

3.2 (79)

[2.5]

2.9 (24)

[2.3]

3.5 (11)

[2.9]

Pain in extremity3.6 (69)

[3.0]

2.8 (95)

[2.2]

2.8 (69)

[2.2]

2.4 (20)

[1.9]

1.9 (6)

[1.6]

Osteoarthritis2.6 (50)

[2.1]

2.5 (83)

[1.9]

2.4 (61)

[1.9]

2.1 (18)

[1.7]

1.3 (4)

[1.0]

Musculoskeletal pain1.5 (28)

[1.2]

2.2 (72)

[1.6]

2.2 (54)

[1.7]

1.4 (12)

[1.1]

1.3 (4)

[1.0]

Intervertebral disc

protrusion

0.3 (5)

[0.2]

0.8 (27)

[0.6]

0.6 (15)

[0.5]

1.1 (9)

[0.8]

1.0 (3)

[0.8]

Plantar fasciitis0.1 (2)

[0.1]

0.5 (17)

[0.4]

0.4 (9)

[0.3]

0.8 (7)

[0.7]

1.0 (3)

[0.8]

Rotator cuff syndrome0.6 (12)

[0.5]

0.5 (18)

[0.4]

0.4 (9)

[0.3]

0.8 (7)

[0.7]

1.3 (4)

[1.0]

Spinal osteoarthritis0.4 (8)

[0.3]

0.6 (19)

[0.4]

0.5 (12)

[0.4]

0.7 (6)

[0.6]

1.0 (3)

[0.8]

Neck pain 1.4 (26) 0.7 (22) 0.6 (15) 0.6 (5) 0.6 (2)

Page 17

[1.1] [0.5] [0.5][0.5]

[0.5]

Musculoskeletal chest

pain

1.0 (19)

[0.8]

0.7 (24)

[0.5]

0.9 (22)

[0.7]

0.2 (2)

[0.2]

0.3 (1)

[0.3]

Renal and urinary

disorders

5.0 (95)

[4.1]

4.9 (165)

[3.8]

4.9 (122)

[3.9]

4.4 (37)

[3.6]

4.5 (14)

[3.7]

Hematuria0.6 (12)

[0.5]

0.9 (29)

[0.7]

0.8 (20)

[0.6]

0.8 (7)

[0.7]

1.0 (3)

[0.8]

Urinary retention0.2 (4)

[0.2]

0.2 (7)

[0.2]

0.2 (4)

[0.1]

0.4 (3)

[0.3]

1.0 (3)

[0.8]

Reproductive system and

breast disorders

2.6 (50)

[2.1]

3.1 (103)

[2.3]

3.0 (76)

[2.4]

2.7 (23)

[2.2]

3.5 (11)

[2.9]

Benign prostatic

hyperplasia

0.7 (14)

[0.6]

0.6 (21)

[0.5]

0.6 (15)

[0.5]

0.6 (5)

[0.5]

1.0 (3)

[0.8]

General disorders and

administration site

conditions

15.8 (300)

[14.2]

16.2 (541)

[13.7]

16.6 (416)

[14.9]

10.8 (91)

[9.3]

8.0 (25)

[6.8]

Injection site reaction4.0 (76)

[3.3]

5.9 (196)

[4.6]

6.1 (153)

[5.0]

3.1 (26)

[2.5]

3.2 (10)

[2.6]

Fatigue2.7 (51)

[2.2]

3.0 (99)

[2.3]

2.9 (72)

[2.3]

2.6 (22)

[2.1]

2.2 (7)

[1.8]

Non-cardiac chest pain 2.2 (42) 2.3 (77) 2.1 (52) 2.6 (22) 1.3 (4)

Page 18

[1.8] [1.7] [1.7] [2.1] [1.0]

Edema peripheral1.3 (25)

[1.1]

1.6 (53)

[1.2]

1.6 (41)

[1.3]

1.1 (9)

[0.9]

0.6 (2)

[0.5]

Influenza like illness1.5 (28)

[1.2]

1.3 (43)

[1.0]

1.4 (36)

[1.1]

0.6 (5)

[0.5]

1.3 (4)

[1.0]

Asthenia1.1 (21)

[0.9]

0.7 (22)

[0.5]

0.6 (16)

[0.5]

0.4 (3)

[0.3]0

Investigations7.4 (141)

[6.2]

8.2 (275)

[6.4]

8.7 (218)

[7.2]

5.8 (49)

[4.7]

4.8 (15)

[3.9]

Alanine

aminotransferase

increased

0.9 (17)

[0.7]

1.0 (35)

[0.8]

1.1 (27)

[0.9]

0.7 (6)

[0.6]

1.0 (3)

[0.8]

Blood creatine

phosphokinase

increased

1.2 (23)

[1.0]

1.0 (34)

[0.8]

1.1 (27)

[0.9]

0.5 (4)

[0.4]

0.3 (1)

[0.3]

Injury, poisoning, and

procedural complications

14.6 (277)

[13.0]

15.3 (510)

[12.7]

15.4 (384)

[13.5]

12.3 (103)

[10.4]

14.0 (44)

[12.3]

Fall3.0 (57)

[2.5]

2.6 (88)

[2.0]

2.6 (66)

[2.1]

2.1 (18)

[1.7]

2.5 (8)

[2.1]

Accidental overdose2.2 (41)

[1.8]

2.7 (89)

[2.0]

2.8 (71)

[2.3]

1.5 (13)

[1.2]

1.0 (3)

[0.8]

Laceration 0.8 (15) 1.0 (34) 0.7 (18) 1.4 (12) 1.0 (3)

Page 19

[0.6] [0.8] [0.6] [1.1] [0.8]

Contusion1.2 (23)

[1.0]

2.1 (69)

[1.6]

2.2 (55)

[1.7]

1.3 (11)

[1.0]

1.3 (4)

[1.0]

Arthropod bite0.8 (15)

[0.6]

0.6 (21)

[0.5]

0.6 (15)

[0.5]

0.6 (5)

[0.5]

1.0 (3)

[0.8]

Ligament sprain1.2 (22)

[0.9]

0.9 (31)

[0.7]

1.0 (24)

[0.8]

0.6 (5)

[0.5]

1.3 (4)

[1.0]

Muscle strain1.0 (18)

[0.8]

0.8 (26)

[0.6]

0.9 (22)

[0.7]

0.5 (4)

[0.4]

0.6 (2)

[0.5]

*Patients who did not have two or more consecutive LDL-C values <25 mg/dL during treatment.

†Patients with 2 or more consecutive LDL-C values <25 or <15 mg/dL during treatment. Values are

considered consecutive if spaced out by at least 21 days. Only TEAEs that occurred, worsened or

became serious on the day or after the first of two consecutive LDL-C values <25 or <15 mg/dL are

considered.

‡Number of patients with an event per patient year, calculated as number of patients with an event

divided by total patient-years. For patients with an event, number of patient-years is calculated up to

date of the first event; for patients without an event, it corresponds to the length of the TEAE period.

LDL-C = low-density lipoprotein cholesterol; TEAE = treatment-emergent adverse event.

Page 20

Supplemental Table 5. Impact on Hormone Levels, as Measured in ODYSSEY

LONG TERM (Safety Population)

Laboratory parameter, % (n/N) Placebo (n = 788) Alirocumab (n = 1,550)

Cortisol

<LLN 22.9 (176/767) 21.6 (325/1506)

<LLN and ACTH >ULN 0.6 (1/176) 0.6 (2/325)

<LLN and ACTH >ULN and normal

ACTH stimulation test100 (1/1) 50.0 (1/2)

<LLN and ACTH >ULN and

abnormal ACTH stimulation test*0/1 50.0 (1/2)†

Gonadal hormones (men only) Placebo (n = 474) Alirocumab (n = 982)

Total testosterone <LLN regardless

of baseline status16.9 (74/439) 20.7 (188/909)

Luteinizing hormone >ULN

regardless of baseline status14.1 (62/439) 13.2 (120/910)

Follicle-stimulating hormone >ULN

regardless of baseline status8.2 (36/439) 7.3 (66/910)

*Abnormal ACTH stimulation test is defined as cortisol value <18 µg/dL (<497 nmol/L) at both 30 and

60 minutes after ACTH administration.

†Patient with Addison’s disease at baseline.

ACTH = adrenocorticotropic hormone; LLN = lower limit of normal; ULN = upper limit of normal.

Page 21

Supplemental Table 6. Patients With Abnormalities in Estimated Glomerular

Filtration Rate (Safety Population; Phase 3 Studies Only)

Alirocumab

eGFR, regardless of the baseline status

Values are % (n/N)

LDL-C

≥25 mg/dL* (n =

2,371)

LDL-C

<25 mg/dL†

(n = 811)

≥60–<90 mL/min/1.73m2 (mild decrease in eGFR) 64.6 (1477/2286) 63.5 (514/809)

≥30–<60 mL/min/1.73m2 (moderate decrease in eGFR) 24.2 (553/2286) 28.3 (229/809)

≥15–<30 mL/min/1.73m2 (severe decrease in eGFR) 1.0 (23/2286) 0.5 (4/809)

<15 mL/min/1.73m2 (end stage renal disease) <0.1 (1/2286) 0/809

*Patients who did not have 2 or more consecutive LDL-C values <25 mg/dL during treatment.

†Patients with 2 or more consecutive LDL-C values <25 mg/dL during treatment. Values are

considered consecutive if spaced out by at least 21 days. Only values measured on the day or after

the first of 2 consecutive LDL-C values <25 mg/dL are considered.

eGFR = estimated glomerular filtration rate; LDL-C = low-density lipoprotein cholesterol.

Page 22

Supplemental Figure 1. Mean HbA1c Over Time According to Achievement of

LDL-C <25 mg/dL and Diabetes Status (Safety Population; Phase 3 Studies

Only)

Baseline W12 W24 W52 W78 Last

Hem

oglob

in A

1Cm

ean

(+/-S

E) (%

)

5.0

5.5

6.0

6.5

7.0

7.5

8.0

Time point

Hem

oglob

in A

1Cm

ean

(+/-S

E) (%

)

5.0

5.5

6.0

6.5

7.0

7.5

8.0

Time point

With diabetes-Alirocumab-LDL-C>=25 mg/dL (N=451)With diabetes-Alirocumab-LDL-C<25 mg/dL (N=247)Without diabetes-Alirocumab-LDL-C>=25 mg/dL (N=1217)Without diabetes-Alirocumab-LDL-C<25 mg/dL (N=403)

With diabetes-Alirocumab-LDL-C>=25 mg/dL (N=451)With diabetes-Alirocumab-LDL-C<25 mg/dL (N=247)Without diabetes-Alirocumab-LDL-C>=25 mg/dL (N=1217)Without diabetes-Alirocumab-LDL-C<25 mg/dL (N=403)

LDL-C = low-density lipoprotein cholesterol; W = week

Page 23

References for supplement

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and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine

protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving

ongoing stable atorvastatin therapy. J Am Coll Cardiol 2012;59:2344-2353.

2. Stein EA, Gipe D, Bergeron J, et al. Effect of a monoclonal antibody to PCSK9,

REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with

heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe

therapy: a phase 2 randomised controlled trial. Lancet 2012;380:29-36.

3. Teramoto T, Kobayashi M, Uno K, et al. Efficacy and Safety of Alirocumab in

Japanese Subjects (Phase 1 and 2 Studies). Am J Cardiol 2016;118:56-63.

4. Roth EM, McKenney JM, Hanotin C, Asset G, Stein EA. Atorvastatin with or without

an antibody to PCSK9 in primary hypercholesterolemia. N Engl J Med 2012;367:1891-1900.

5. Robinson JG, Farnier M, Krempf M, et al. Efficacy and Safety of Alirocumab in

Reducing Lipids and Cardiovascular Events. N Engl J Med 2015;372:1489-1499.

6. Ginsberg HN, Rader DJ, Raal FJ, et al. Efficacy and Safety of Alirocumab in Patients

with Heterozygous Familial Hypercholesterolemia and LDL-C of 160 mg/dl or Higher.

Cardiovasc Drugs Ther 2016;30:473-483.

7. Kastelein JJ, Ginsberg HN, Langslet G, et al. ODYSSEY FH I and FH II: 78 week

results with alirocumab treatment in 735 patients with heterozygous familial

hypercholesterolaemia. Eur Heart J 2015;36:2996-3003.

Page 24

8. Kereiakes DJ, Robinson JG, Cannon CP, et al. Efficacy and safety of the PCSK9

inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin

therapy: the ODYSSEY COMBO I study. Am Heart J 2015;169:906-915.e13.

9. Cannon CP, Cariou B, Blom D, et al. Efficacy and safety of alirocumab in high

cardiovascular risk patients with inadequately controlled hypercholesterolaemia on

maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial.

Eur Heart J 2015;36:1186-94.

10. Bays H, Gaudet D, Weiss R, et al. Alirocumab as add-on to atorvastatin versus other

lipid treatment strategies: ODYSSEY OPTIONS I randomized trial. J Clin Endocrinol Metab

2015;100:3140-3148.

11. Farnier M, Jones P, Severance R, et al. Efficacy and safety of adding alirocumab to

rosuvastatin versus adding ezetimibe or doubling the rosuvastatin dose in high

cardiovascular-risk patients: the ODYSSEY OPTIONS II randomized trial. Atherosclerosis

2016;244:138-146.

12. Roth EM, Taskinen MR, Ginsberg HN, et al. Monotherapy with the PCSK9 inhibitor

alirocumab versus ezetimibe in patients with hypercholesterolemia: results of a 24 week,

double-blind, randomized Phase 3 trial. Int J Cardiol 2014;176:55-61.

13. Moriarty PM, Thompson PD, Cannon CP, et al. Efficacy and safety of alirocumab vs

ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY

ALTERNATIVE randomized trial. J Clin Lipidol 2015;9:758-769.

14. D’Agostino RB, Jr. Propensity score methods for bias reduction in the comparison of

a treatment to a non-randomized control group. Stat Med 1998;17:2265-81.

Page 25

15. Everett BM, Mora S, Glynn RJ, MacFadyen J, Ridker PM. Safety profile of subjects

treated to very low low-density lipoprotein cholesterol levels (<30 mg/dl) with rosuvastatin 20

mg daily (from JUPITER). Am J Cardiol 2014;114:1682-1689.

Page 26