Public Disclosure Synopsis
Protocol B1481036 – 30 October 2017 – Final

PFIZER INC.
These results are supplied for informational purposes only.
Prescribing decisions should be made based on the approved package insert.
GENERIC DRUG NAME / COMPOUND NUMBER: Bococizumab / PF-04950615
PROTOCOL NO.: B1481036
PROTOCOL TITLE:
A Phase 2 Double Blind, Parallel Group, Placebo Controlled, Randomized, Dose Ranging
Study to Assess the Efficacy, Safety and Tolerability of PF-04950615 Following TwiceMonthly Subcutaneous Doses in Hypercholesterolemic Japanese Subjects Who Are
Receiving a Stable Dose of Atorvastatin or Treatment Naïve
Study Centers:

090177e18d079c7a\Approved\Approved On: 31-Oct-2017 02:32 (GMT)

A total of 9 centers in Japan took part in the study and randomized subjects.
Study Initiation and Final Completion Dates:
31 March 2014 to 08 January 2015
Phase of Development:
Phase 2
Study Objectives:
Primary Objectives:
To evaluate the low density lipoprotein-cholesterol (LDL-C) lowering effect of
PF-04950615 (bococizumab) administered subcutaneously (SC) once every 14 days
(Q14D) in hypercholesterolemic Japanese subjects whose fasting LDL-C was notcontrolled and was 100 mg/dL on background treatment with a stable dose of
atorvastatin (Population A);

To evaluate the LDL-C lowering effect of bococizumab administered SC Q14D in
hypercholesterolemic Japanese subjects who were naïve for a treatment by lipid lowering
drug and whose fasting LDL-C was 130 mg/dL (Population B).

Secondary Objectives:
To evaluate the effect of bococizumab administered SC on lipid parameters other thanLDL-C;

Template version 1.7

Page 1

Public Disclosure Synopsis
Protocol B1481036 – 30 October 2017 – Final

To evaluate the safety including injection site reaction, tolerability and immunogenicity(anti-drug antibody [ADA]) against bococizumab administered SC;

To evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) following
administration of bococizumab;To evaluate the effect of atorvastatin on PK and PD of bococizumab.

METHODS
Study Design:

090177e18d079c7a\Approved\Approved On: 31-Oct-2017 02:32 (GMT)This study was a double-blind, parallel-group, placebo-controlled, randomized, dose-ranging
study for 2 populations (Population A and Population B) with a treatment duration of
16 weeks (4 months). Population A comprised hypercholesterolemic subjects whose fasting
LDL-cholesterol was not controlled and was 100 mg/dL on background treatment with astable dose of atorvastatin. Population B consisted of hypercholesterolemic subjects who
were naïve for a treatment by lipid lowering drug and whose fasting LDL-C was130 mg/dL. A total of 9 arms in 2 populations, with 24 subjects per arm were planned. A
schematic of the study design is shown in Figure 1.

Template version 1.7

Page 2

Public Disclosure Synopsis
Protocol B1481036 – 30 October 2017 – Final

Figure 1. A Schematicchematic of the Study Design

090177e18d079c7a\Approved\Approved On: 31-Oct-2017 02:32 (GMT)

Population A:

Population B:

Atorva=atorvastatin; LDL-C=low ddensity lipoprotein-cholesterol; PF-04950615=bococizumab;
04950615=bococizumab; Q14D=once every
14 days.

In Population A, a subject who was receiving a stable dose of atorvastatin was randomized
into 1 out of 5 arms which consist
consisted of;

Arm 1: Atorvastatin plus bococizumab 50 mg Q14D SC;

Arm 2: Atorvastatin plus bococizumab 100 mg Q14D SC;

Template version 1.7

Page 3

Public Disclosure Synopsis
Protocol B1481036 – 30 October 2017 – Final

Arm 3: Atorvastatin plus bococizumab 150 mg Q14D SC;



Arm 4: Atorvastatin plus bococizumab Placebo Q14D SC;



Arm 5: Atorvastatin plus Ezetimibe 10 mg once a day (QD) per os (PO).

Subjects were on stable dosage of atorvastatin for at least 6 weeks prior to screening andthroughout the duration of this study. Atorvastatin plus Ezetimibe 10 mg arm (Arm 5) was
the only open arm because the purposes of this arm were to estimate the effect size ofezetimibe 10 mg on LDL-C reduction and to evaluate the effect on other lipid parameters andbiomarkers.

090177e18d079c7a\Approved\Approved On: 31-Oct-2017 02:32 (GMT)In Population B, a subject who was treatment naïve was randomly assigned to 1 of 4 arms
which comprised;Arm 6: Bococizumab 50 mg Q14D SC;



Arm 7: Bococizumab 100 mg Q14D SC;



Arm 8: Bococizumab 150 mg Q14D SC;



Arm 9: Bococizumab Placebo Q14D SC.

Subjects, except those in Arm 5, received bococizumab active dose or bococizumab placebo
by SC administration on Days 1, 15, 29, 43, 57, 71, 85 and 99. For the first 12 weeks, theassigned bococizumab active dose was administered. On or after Week 12 (Day 85), if
subjects met the dose adjustment criteria, a reduced dose was administered. Subjects in
Arm 5 took ezetimibe 10 mg tablet after food QD during treatment period (i.e., from Day 1 to112).
Subjects were seen periodically at the study site for safety assessment, collection of blood forsafety labs, lipid profiles, PK, PD, immunogenicity samples and to receive their dose of study
drug (bococizumab active or bococizumab placebo).
The co-primary efficacy endpoints were 1) the percent change of LDL-C from baseline at
Week 12 (Day 85) and 2) the percent change of LDL-C from baseline at Week 16 (Day 113).
Subjects who received at least 1 dose of study treatment (bococizumab active dose,
bococizumab placebo, or ezetimibe 10 mg) and withdrew from the study were not replaced
and were asked to remain in the study for safety follow-up and complete all scheduled visits
without receiving study treatment (bococizumab active dose, bococizumab placebo, or
ezetimibe 10 mg).
All evaluations and procedures are shown in Table 1, Table 2 and Table 3.

Template version 1.7

Page 4

Public Disclosure Synopsis
Protocol B1481036 – 30 October 2017 – Final

Table 1.

Subjects With Full Blood Collection for PK (Arm 1 to 4 in Population A, and Arm 6 to 9 in Population B)

090177e18d079c7a\Approved\Approved On: 31-Oct-2017 02:32 (GMT)

Study Phase
Week
Day

Screening−4 to −2 −1−28 to
−7
−8
3
X
X
X
X
X
X
X

Visit Window
Informed consent
General medical history
Physical exam
Vital signs
WeightHeight
Waist circumference
Randomization
Bococizumab/Placebo
administration

Treatment
Follow-Up
2 3 4 5 6 7 8 10 12 14 - 15 16 17 18 20 22 24
15 22 29 36 43 50 57 71 85 99 100 102 104 106 113 120 127 141 155 169
EO
EO
T
S
−3/+0 0 0 0 0 0 0 0 0 2 2 2 2 2 2 2 2 2 2 2a 2a 2a 2a 2 3 3 3 3 3

X

0
1

2

3

4

5

6

7

1
8

X
X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X
X

X

X

X

X

X

X

X

X

X

X

Blood for bococizumab PK

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

Blood for PCSK9

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X
X
X

X
X
X

X
X
X

X
X
X

X
X
X

X
X
X

X
X
X

X
X
X

X

X
X
X

X
X
X

X

X
X

X
X
X

X
X

X

X
X
X

X

X
X
X

X
X
X

X
X
X
X
X
X
X
X

X
X
X

X

X
X
X
X
X
X
X
X

X

X

X
X
X

X

X

X
X
X

X

b

c

Blood for atorvastatin PK
Concomitant medication
Blood for fasting lipid profile
Blood for LDL composition
Blood for Lp-PLA2
Adverse events
Hematology, biochemistry
Urinalysis
12-Lead ECG
Blood for ADA

X
X

X
X
X

HbA1c
Hormone monitoring
Neurological panel

X

Pregnancy test
Hepatitis screen
TSH

X
X
X
X

e

f

FSH
Banked biospecimen (PGx)

Template version 1.7

X
X

X
X
X
X
X
X
X
X
X
X
X
X
X

X

X

X
X

X
X

X

X
X
X

X

X
b

X
X
X

X

X

X

X
X
X

X

X

X

X

X

X

X

X

Page 5

X
X
X

X

X

X

X
X

X

X

X

X

X
X
X
X
X
X
X
X
X
X
X
X
X
X

X

d

X

Public Disclosure Synopsis
Protocol B1481036 – 30 October 2017 – Final

090177e18d079c7a\Approved\Approved On: 31-Oct-2017 02:32 (GMT)

Table 1.

Subjects With Full Blood Collection for PK (Arm 1 to 4 in Population A, and Arm 6 to 9 in Population B)

ADA=anti-drug antibody; ECG=electrocardiogram; EOS=end of study; EOT=end of treatment; FSH=follicle stimulating hormone; HbA1c=glycosylated hemoglobin;
IEC=Independent Ethics Committee; IRB=Institutional Review Board; LDL=low density lipoprotein; Lp-PLA2=lipoprotein-associated phospholipase A2;
PGx=pharmacogenomics; PCSK9=proprotein convertase subtilisin/kexin type 9; PK=pharmacokinetics; TSH=thyroid stimulating hormone.
a. Subjects visited the study site 1, 3, 5, 7 days after injection at Day 99.
b. About a half of subjects in each treatment arm (n=12) were allocated to full PK sampling group.
c. Only Population A.
d. Subjects found to have ADA still present at EOS were requested to return to the study site at up to 90 days intervals until antibody was not detected.
e. Pregnancy tests were also repeated as per request of IRB/IECs or if required by local regulations.
f. FSH to be done in postmenopausal females only.

Template version 1.7

Page 6

Public Disclosure Synopsis
Protocol B1481036 – 30 October 2017 – Final

Table 2.

Subjects Without Full Blood Collection for PK (Arm 1 to 4 in Population A, and Arm 6 to 9 in Population B)

Study Phase
Week

090177e18d079c7a\Approved\Approved On: 31-Oct-2017 02:32 (GMT)Day

Screening
−4 to
−1
−2
−28 to−8−7Treatment

Follow-Up

0

-

1

2

3

4

5

6

7

8

10

12

14

15

1

5

8

15

22

29

36

43

50

57

71

85

99

106

16
113
EO
T
2

18

20

22

127

141

155

a
Visit Window
3 -3/+0 0 0 0 2 2 2 2 2 2 2 2 2 2 2
3
3
3
Informed consent
X
General medical history
X
Physical exam
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
WeightX
X
X
HeightX
Waist circumference
X
X
X
Randomization
X
Bococizumab/placebo administration
X
X
X
X
X
X
X
X
Blood for bococizumab PK
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood for PCSK9
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood for atorvastatin PKb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood for fasting lipid profile
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood for LDL composition
X
X
X
X
Blood for Lp-PLA2
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology, biochemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
12-Lead ECG
X
XX
Blood for ADA
X
X
X
X
X
X
X
X
X
HbA1c
X
X
X
X
Hormone monitoring
X
X
X
X
Neurological panel
X
X
Pregnancy testd
X
X
X
Hepatitis screen
X
TSH
X
FSHe
X
Banked biospecimen (PGx)X
ADA=anti-drug antibody; ECG=electrocardiogram; EOS=end of study; EOT=end of treatment; FSH=follicle stimulating hormone; HbA1c=glycosylated hemoglobin;
IEC=Independent Ethics Committee; IRB=Institutional Review Board; LDL=low density lipoprotein; Lp-PLA2=lipoprotein-associated phospholipase A2;
PGx=pharmacogenomics; PCSK9=proprotein convertase subtilisin/kexin type 9; PK=pharmacokinetics; TSH=thyroid stimulating hormone.

Template version 1.7

Page 7

24
169
EO
S
3

X

X
X

X
X
X
Xc

Public Disclosure Synopsis
Protocol B1481036 – 30 October 2017 – Final

Table 2.

Subjects visited the study site 7 days after injection at Day 99.
Only Population A.
Subjects found to have ADA still present at EOS were requested to return to the study site at up to 90 days intervals until antibody was not detected.
Pregnancy tests were also repeated as per request of IRB/IECs or if required by local regulations.
FSH to be done in postmenopausal females only.

090177e18d079c7a\Approved\Approved On: 31-Oct-2017 02:32 (GMT)

a.
b.
c.
d.
e.

Subjects Without Full Blood Collection for PK (Arm 1 to 4 in Population A, and Arm 6 to 9 in Population B)

Template version 1.7

Page 8

Public Disclosure Synopsis
Protocol B1481036 – 30 October 2017 – Final

Table 3.

Open-Label Ezetimibe Arm (Arm 5 in Population A)

Study Phase
Week

090177e18d079c7a\Approved\Approved On: 31-Oct-2017 02:32 (GMT)Day

Screening
−4 to
−1
0
−2
−28 to−7
1−8
3 -3/+0 0
X
X
X
X
X
X
X
X
X
X
X
X

Treatment

Follow-Up

-

1

2

3

4

5

6

7

8

10

12

14

15

5

8

15

22

29

36

43

50

57

71

85

99

106

16
113
EOT
2

18

20

22

127

141

155

24
169
EOS
3

Visit Window
0 0 2 2 2 2 2 2 2 2 2 2 1
3
3
3
Informed consent
General medical history
Physical exam
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
WeightX
Height
Waist circumferenceX
Randomization
Ezetimibe 10 mg(only open ezetimibe arm)
Concomitant medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood for fasting lipid profile
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood for LDL composition
X
X
X
X
Blood for Lp-PLA2
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology, biochemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECG
X
X
X
HbA1c
X
X
X
X
Pregnancy testa
X
X
X
Hepatitis screen
X
TSH
X
FSHb
X
Banked biospecimen (PGx)X
ECG=electrocardiogram; EOS=end of study; EOT=end of treatment; FSH=follicle stimulating hormone; HbA1c=glycosylated hemoglobin; IEC=Independent Ethics
Committee; IRB=Institutional Review Board; LDL=low density lipoprotein; Lp-PLA2=lipoprotein-associated phospholipase A2; PGx=pharmacogenomics; TSH=thyroid
stimulating hormone.
a. Pregnancy tests were also repeated as per request of IRB/IECs or if required by local regulations.
b. FSH to be done in postmenopausal females only.

Template version 1.7

Page 9Public Disclosure Synopsis
Protocol B1481036 – 30 October 2017 – Final

Number of Subjects (Planned and Analyzed):
Initially a total of 9 arms in 2 populations, with 24 subjects per arm were planned. Out of
which a total of 121 subjects were randomized to either bococizumab 50 mg arm(25 subjects), bococizumab 100 mg arm (24 subjects), bococizumab 150 mg arm(24 subjects), placebo arm (26 subjects), or ezetimibe arm (22 subjects), and all of them wereadministered at least 1 dose of study treatment.
Diagnosis and Main Criteria for Inclusion and Exclusion:
Main Inclusion Criteria for Population A: Subjects whose LDL-C was not controlled by astable dose of atorvastatin were included in this study.

090177e18d079c7a\Approved\Approved On: 31-Oct-2017 02:32 (GMT)

Main Inclusion Criteria for Population B: Subjects who were naïve to a treatment by lipid
lowering drug and whose LDL-C was not controlled were included in this study.
Main Exclusion Criteria: Severe acute or chronic medical or psychiatric condition orlaboratory abnormality; pregnant females; breastfeeding females; males and females ofchildbearing potential who were unwilling or unable to use a highly effective method ofcontraception; subjects who were administered or prior exposed to bococizumab and/or antibody targeting proprotein convertase subtilisin/kexin Type 9 (PCSK9) were excluded fromthis study.
Study Treatment:
In Population A, a subject was administered bococizumab 50 mg Q14D SC (Arm 1),
bococizumab 100 mg Q14D SC (Arm 2), bococizumab 150 mg Q14D SC (Arm 3),
bococizumab placebo Q14D SC (Arm 4), and ezetimibe 10 mg QD PO (Arm 5), adding on
the stable dose of atorvastatin. All subjects in Population A kept the same dose of
atorvastatin as background treatment throughout the study. For Arm 1 to Arm 4, all subjects
were SC administered the same bococizumab or placebo dose as assigned for the first 12
weeks. On or after Week 12 (Day 85), if a subject met the dose adjustment criteria illustrated
below, the dose was reduced. A subject in Arm 5 took ezetimibe 10 mg tablet after food QD
during treatment period (i.e., from Day 1 to 112).
In Population B, a subject was administered bococizumab 50 mg Q14D SC (Arm 6),
bococizumab 100 mg Q14D SC (Arm 7), bococizumab 150 mg Q14D SC (Arm 8), andbococizumab placebo Q14D SC (Arm 9). For Arm 6 to Arm 9, all subjects were SC
administered the same bococizumab or placebo dose as assigned for the first 12 weeks. On
or after Week 12 (Day 85), if a subject met the dose adjustment criteria illustrated below, thedose was reduced.
Study drug administration including the following dose reduction was performed by thedesignated unblind pharmacist at the study site.
Efficacy and Pharmacokinetic Endpoints:
Primary Endpoints:
The co-primary efficacy endpoints wereTemplate version 1.7

Page 10

Public Disclosure Synopsis
Protocol B1481036 – 30 October 2017 – Final

Percent change from baseline (CFB) in fasting LDL-C at Week 12 (Day 85) following
randomization;

Percent CFB in fasting LDL-C at Week 16 (Day 113) following randomization.

090177e18d079c7a\Approved\Approved On: 31-Oct-2017 02:32 (GMT)

Secondary Endpoints:


LDL-C (actual value and CFB);

Actual value, CFB and percent CFB in

Total cholesterol;

Apolipoprotein B (ApoB), Apolipoprotein A-1 (ApoA1), Apolipoprotein A-2(ApoA2);

Lipoprotein (a) (Lp[a]);High density lipoprotein–cholesterol (HDL-C);

Very low density lipoprotein (VLDL)-cholesterol;Triglycerides (TG);

Non-HDL-cholesterol;

TC/HDL-C ratio;

ApoB/ApoA1 ratio;

Proportion of subjects having LDL-C less than particular limits(<100 mg/dL, <70 mg/dL, <40 mg/dL, <25 mg/dL, <10 mg/dL);Adverse events (AEs) (including injection site reaction) and clinical laboratory
abnormalities;



ADA;



Plasma bococizumab PK parameters;Plasma concentration of PCSK9.

Safety Evaluations:
Safety was assessed by physical examinations, neurological examinations, vital signs,
electrocardiograms (ECGs), clinical laboratory results, and the spontaneous reporting of AEs
in all subjects who received at least 1 dose of study drug. Additionally, blood samples werecollected to assay the development of ADAs.

Template version 1.7

Page 11

Public Disclosure Synopsis
Protocol B1481036 – 30 October 2017 – Final

Statistical Methods:
The full analysis set (FAS) which included all subjects who were randomized and wereadministered at least 1 dose of study treatment, was the primary analysis set for efficacy
analysis. Subjects were analyzed according to their randomized dose. The per-protocol
analysis set (PPS) was a subset of the FAS and consisted of subjects who were compliant
with the protocol. The safety analysis set included all randomized subjects who wereadministered at least 1 dose of study treatment. The PK concentration population was
defined as subjects in the FAS who had at least 1 concentration of bococizumab, PCSK9 or
atorvastatin and its active metabolites. The PK parameter analysis population was defined as
subjects with full PK sampling in the FAS who had at least 1 of the bococizumab PK
parameters of interest calculated. The PD analysis population was defined as subjects in the
FAS who had at least 1 PD measurement.
In statistical inferences for Population A, data from Arm 5 were not used. Data from Arm 5
were only summarized descriptively.

090177e18d079c7a\Approved\Approved On: 31-Oct-2017 02:32 (GMT)For each population (Population A and Population B) separately, each bococizumab dosearm was compared with placebo. For the statistical test of the co-primary endpoints in each
population, the following sequence testing was performed (type I error at =0.025 1-sided,
Bonferroni correction):Superiority of each bococizumab dose arm over placebo at Week 12 was tested at
=0.025/3.



If superiority of a bococizumab dose arm over placebo at Week 12 was demonstrated,superiority of the bococizumab dose arm over placebo at Week 16 was tested at the1-sided α=0.025/3.

The primary endpoint of percent CFB in LDL-C at Week 12 and Week 16, was analyzed
using a mixed-effects model for repeated measures (MMRM) analysis using all observed
measures. The least squares means with their 95% confidence intervals (CIs) were plotted bytreatment arm. There was no imputation for missing data.
The analyses of secondary endpoints were conducted using only the FAS. For each
population separately, the following lipid endpoints of absolute and percent CFB wereanalyzed in a MMRM. The respective baseline value of the endpoint was used in the model
as a continuous covariate.
Absolute and percent CFB in LDL-C other than the co-primary endpoints (percent CFB
in LDL-C at Week 12 and Week 16)Absolute and percent CFB in the following endpoints: total cholesterol, ApoB, ApoA1,
ApoA2, Lp(a), HDL-C, VLDL-C, TG, non-HDL-C, total cholesterol/HDL-C ratio, and
ApoB/ApoA1 ratio

Template version 1.7

Page 12

Public Disclosure Synopsis
Protocol B1481036 – 30 October 2017 – Final

Descriptive statistics summaries were provided by treatment and dosing day for the PK
parameters, plasma concentrations of PCSK9 were summarized and the mean percent change
from baseline of PCSK9 concentration were plotted by treatment arm and visit.

090177e18d079c7a\Approved\Approved On: 31-Oct-2017 02:32 (GMT)

A 3-tier approach was used to summarize AEs.


Tier 1 events were pre-specified events of clinical importance and were maintained in alist in the product’s Safety Review Plan. For tier 1 events, the percentage of subjects
with treatment-emergent adverse event, the risk difference and/or risk ratio versus
placebo, its 95% CI, and p-value were provided. The CIs and p-values were not adjusted
for multiplicity and were provided for screening purposes only.



Tier 2 events were defined as common (5%) events. For tier 2 events, the percentage ofsubjects with incident AE, the risk difference and/or risk ratio versus placebo, its 95% CI
were provided. The CIs were for estimation purposes only.



Tier 3 events were all other AEs. For tier 3 events, the percentage of subjects withincident AE was provided.

The number and percentage of subjects with detectable ADAs were summarized by treatment
arm and visit and also any post-baseline visit during the entire study. Subjects in Arm 5 were
not included in this summary because blood for ADA was not collected in Arm 5.
The number and percentage of subjects with laboratory test abnormalities observed at any
time during the study were tabulated by treatment arm following the Sponsor’s data
standards. Absolute values and CFB in continuous laboratory parameters were summarized
by treatment arm.
Absolute values and CFB in vital sign parameters were summarized by treatment arm andvisit following the sponsor’s data standards.
RESULTS
Subject Disposition and Demography:
Population A:
A total of 121 subjects were randomized to either bococizumab 50 mg arm (25 subjects),
bococizumab 100 mg arm (24 subjects), bococizumab 150 mg arm (24 subjects), placeboarm (26 subjects), or ezetimibe arm (22 subjects), and all of them were administered at least
1 dose of study treatment. Of the 121 treated subjects, 117 subjects (25, 23, 22, 25, and22 subjects in the bococizumab 50 mg, 100 mg and 150 mg, placebo, and ezetimibe arms,
respectively) completed study treatment, and 4 subjects (1, 2, and 1 subject in the
bococizumab 100 mg and 150 mg, and placebo arms, respectively) permanently discontinued
study treatment.
The reasons for discontinuation from the study are summarized in Table 4.

Template version 1.7

Page 13

Public Disclosure Synopsis
Protocol B1481036 – 30 October 2017 – Final

Table 4.

Reasons for Discontinuation From Study (Population A)

Number (%) of Subjects
Placebo

Atorvastatin +Bococizumab
50 mg
100 mg
150 mg(N=25)(N=24)(N=24)

Ezetimibe
10 mg(N=22)

Total(N=26)(N=121)
Discontinuations
Relation to study drug not defined
1 (3.8)00
1 (4.2)0
2 (1.7)a0
0
00
1 (0.8)Other
1 (4.2)
Does not meet inclusion/exclusion
0
0
0
0
0
0
criteria
Lost to follow-up
1 (3.8)0000
1 (0.8)
Not related to study drug
0
0
0
0
0
0
Adverse event
0
0
0
0
0
0
Total
1 (3.8)00
1 (4.2)0
2 (1.7)
N=number of subjects.
a. One (1) subject discontinued the study because the subject could no longer visit the study center due to thesubject’s parent care.

090177e18d079c7a\Approved\Approved On: 31-Oct-2017 02:32 (GMT)

Population B:
A total of 97 subjects were randomized to bococizumab 50 mg arm (25 subjects),
bococizumab 100 mg arm (25 subjects), bococizumab 150 mg arm (24 subjects), or placeboarm (23 subjects), and all of them were administered at least 1 dose of study treatment. Of
the 97 treated subjects, 92 subjects (23, 22, 24, and 23 subjects in the bococizumab 50 mg,
100 mg and 150 mg, and placebo arms, respectively) completed study treatment, and5 subjects (2 and 3 subjects in the bococizumab 50 mg and 100 mg arms, respectively)
permanently discontinued the study treatment.
The reasons for discontinuation from the study are summarized in Table 5.
In Population A, the mean age ranged from 55.9 to 59.6 years across the treatment arms, andminimum and maximum ages were 31 and 80 years, respectively. Across treatment arms, thetotal number of male and female subjects were 68 and 53, respectively.
Table 5.

Reasons for Discontinuation From Study (Population B)

Number (%) of Subjects
Discontinuations
Relation to study drug not defined
Other
Does not meet inclusion/exclusion
criteria
Lost to follow-up
Not related to study drug
Adverse event
Total
N=number of subjects.

Template version 1.7

Placebo(N=23)

50 mg(N=25)

Bococizumab
100 mg(N=25)

150 mg(N=24)(N=97)

0
0
0

0
0
0

1 (4.0)0
1 (4.0)000

1 (1.0)0
1 (1.0)00000
1 (4.0)1 (4.0)1 (4.0)0
1 (4.0)1 (4.0)2 (8.0)00000
2 (2.1)2 (2.1)3 (3.1)Page 14Total

Public Disclosure Synopsis
Protocol B1481036 – 30 October 2017 – Final

In Population B, the mean age ranged from 53.3 to 60.1 years across the treatment arms, andminimum and maximum ages were 26 and 76 years, respectively. Across treatment arms, thetotal number of male and female subjects were 50 and 47, respectively.
Efficacy and Pharmacokinetic Results:
Population A:
The results showed that bococizumab significantly reduced the LDL-C for all bococizumab
dose arms (p<0.001) at Weeks 12 and 16 compared to placebo (Table 6). The adjusted meandifferences from placebo in percent CFB at Week 12 in LDL-C in the FAS were −49.838%,−66.754% and −71.534% in the bococizumab 50 mg, 100 mg and 150 mg arms, respectively.
The corresponding values at Week 16 were −42.293%, −56.262%, and −61.384% in the
bococizumab 50 mg, 100 mg and 150 mg arms, respectively. Dose response is evident as thetreatment arm differences from placebo become more pronounced as dose increases inPopulation A.

090177e18d079c7a\Approved\Approved On: 31-Oct-2017 02:32 (GMT)

Additionally, the mean percent change (standard deviation [SD]) from baseline in LDL-C
was −18.56% (15.968) and −20.55% (18.682) in the ezetimibe arm at Week 12 and Week 16,
respectively.

Template version 1.7

Page 15

Public Disclosure Synopsis
Protocol B1481036 – 30 October 2017 – Final

Table 6.

Comparison of Percent Change From Baseline at Weeks 12 and 16 in
LDL-C (mg/dL) Using MMRM Analysis Based on Observed Case Data
(Population A) – FAS

Time Point

Treatment arm(Atorvastatin +)090177e18d079c7a\Approved\Approved On: 31-Oct-2017 02:32 (GMT)

Raw
Mean
Percent
ChangeAdjusted Mean
Percent Change(95% CI)

Adjusted Mean
Difference vs.
Placebo(95% CI)

p-valuea
Unadjusted Adjusted forfor
Multiplicity
Multiplicity−5.18(−10.453, 0.102)
Bococizumab−55.01−49.838
25 −55.65<0.001<0.00150 mg(−60.388, −49.639) (−57.335, −42.340)
Bococizumab−71.93−66.754
23 −70.76<0.001<0.001
100 mg(−77.547, −66.313) (−74.523, −58.986)
Bococizumab−76.71−71.534
22 −75.99<0.001<0.001150 mg(−82.354, −71.066) (−79.284, −63.784)
Placebo−11.77
Week 16
25 −12.10(−16.783, −6.749)
Bococizumab−54.06−42.293
24 −54.41<0.001<0.00150 mg(−59.168, −48.949) (−49.417, −35.168)
Bococizumab−68.03−56.262
23 −67.51<0.001<0.001
100 mg(−73.305, −62.751) (−63.603, −48.921)
Bococizumab−73.15−61.384
22 −72.78<0.001<0.001150 mg(−78.487, −67.813) (−68.733, −54.035)% change=100% × [LDL-C (mg/dL) − LDL-C (mg/dL) at baseline] / LDL-C (mg/dL) at baseline.
CI=confidence interval; FAS=full analysis set; LDL-C=low density lipoprotein-cholesterol; MMRM=mixed-effects model
for repeated measures; N=number of subjects with non-missing values collected except the off-drug follow-up period;
vs=versus.
a. p-value obtained from mixed model: % change from baseline=treatment + visit + baseline value + treatment × visit +baseline value × visit (covariance structure=unstructured, Newton-Raphson algorithm). Unadjusted for multiplicity:
1-sided, 0.025/3 significance level. Adjusted for multiplicity: 1-sided, 0.025 significance level.
Week 12

Placebo

N

26

−5.91

Population B
The results showed that bococizumab significantly reduced the LDL-C for all bococizumab
dose arms (p<0.001) at Weeks 12 and 16 compared to placebo (Table 7). The adjusted meandifferences from placebo in percent CFB at Week 12 in LDL-C in the FAS were −47.531%,−62.624%, and −64.268% in the bococizumab 50 mg, 100 mg and 150 mg arms, respectively.
The corresponding values at Week 16 were −47.578%, −63.346%, and −66.691% in the
bococizumab 50 mg, 100 mg and 150 mg arms, respectively. At both Weeks 12 and 16, thetreatment arm differences from placebo were larger in the bococizumab 100 mg and 150 mg
arms compared with the bococizumab 50 mg arm.

Template version 1.7

Page 16

Public Disclosure Synopsis
Protocol B1481036 – 30 October 2017 – Final

Table 7.

Time
Point

Treatment
arm

Placebo

N

Raw
Mean
Percent
ChangeAdjusted Mean
Percent Change(95% CI)

Adjusted Mean
Difference vs.
Placebo(95% CI)ap-value
Unadjusted
Adjusted forfor
Multiplicity
Multiplicity−1.62(−7.246, 4.014)
Bococizumab−49.15−47.53123−49.37<0.001<0.00150 mg(−54.729, −43.565)(−55.511, −39.551)
Bococizumab−64.24−62.62422−64.64<0.001<0.001
100 mg(−69.845, −58.635)(−70.557, −54.691)
Bococizumab−65.88−64.26824−65.89<0.001<0.001150 mg(−71.367, −60.401)(−72.128, −56.409)
Placebo−0.13
Week 16
23
0.39(−6.119, 5.868)
Bococizumab−47.70−47.57823−47.96<0.001<0.00150 mg(−53.637, −41.770)(−56.067, −39.088)
Bococizumab−63.47−63.34622−63.97<0.001<0.001
100 mg(−69.419, −57.524)(−71.776, −54.915)
Bococizumab−66.82−66.69123−66.98<0.001<0.001150 mg(−72.692, −60.942)(−75.088, −58.295)% change=100% × [LDL-C (mg/dL) − LDL-C (mg/dL) at baseline] / LDL-C (mg/dL) at baseline.
CI=confidence interval; FAS=full analysis set; LDL-C=low density lipoprotein-cholesterol; MMRM=mixed-effects model
for repeated measures; N=number of subjects with non-missing values collected except the off-drug follow-up period;
vs=versus.
a. p-value obtained from mixed model: % change from baseline=treatment + visit + baseline value + treatment × visit +baseline value × visit (covariance structure=unstructured, Newton-Raphson algorithm). Unadjusted for multiplicity: 1-sided,
0.025/3 significance level. Adjusted for multiplicity: 1-sided, 0.025 significance level.
Week 12090177e18d079c7a\Approved\Approved On: 31-Oct-2017 02:32 (GMT)

Comparison of Percent Change From Baseline at Weeks 12 and 16 in
LDL-C (mg/dL) Using MMRM Analysis Based on Observed Case Data
(Population B) – FAS

23

−1.21

Secondary Endpoints:
Low Density Lipoprotein-Cholesterol: The summary of observed value and change fromBaseline in LDL-C (mg/dL) at Weeks 12 and 16 in Population A and Population B in FAS issummarized in Table 8 and Table 9 respectively.

Template version 1.7

Page 17

Public Disclosure Synopsis
Protocol B1481036 – 30 October 2017 – Final

Table 8.

Summary of Observed Value and Change From Baseline in LDL-C (mg/dL)
at Weeks 12 and 16 (Population A) – FAS

090177e18d079c7a\Approved\Approved On: 31-Oct-2017 02:32 (GMT)LDL-C (mg/dL)
Mean (SD)

Atorvastatin +Bococizumab
Ezetimibe
10 mg
50 mg
100 mg
150 mgObserved value at baseline
135.90135.36123.85129.19135.36(24.697)(23.652)(20.585)(17.769)(24.745)
N
26
25
24
24
22
Observed value at Week 12
126.38
58.96
38.00
33.91
110.64(21.478)(19.650)(19.077)(19.400)(33.530)
N
26
25
24
23
22
Change from baseline at Week 12−9.52−76.40−85.85−95.11−24.73(21.041)(26.447)(28.977)(21.145)(23.125)
N
26
25
24
23
22
Observed value at Week 16
118.88
62.17
42.88
38.48
107.32(22.883)(20.417)(19.427)(24.346)(30.459)
N
25
24
24
23
22
Change from baseline at Week 16−17.48−73.33−80.98−90.54−28.05(20.767)(18.047)(28.902)(28.496)(23.663)
N
25
24
24
23
22
Baseline was defined as the mean of the last 2 non-missing measurements collected within 10 days prior to
randomization. If only 1 measurement was available 10 days prior to randomization, that measurement served.
FAS=full analysis set; LDL-C=low density lipoprotein-cholesterol; N=number of subjects with non-missing
values collected including the off-drug follow-up period in the analysis set; SD=standard deviation.

Table 9.

Placebo

Summary of Observed Value and Change From Baseline in LDL-C (mg/dL)
at Weeks 12 and 16 (Population B) – FAS

Placebo
Bococizumab
LDL-C (mg/dL)
Mean (SD)50 mg
100 mg
150 mgObserved value at baseline
155.22 (23.096) 164.22 (25.839) 158.00 (20.004) 159.90 (19.800)
N
23
25
25
24
Observed value at Week 12
151.30 (21.137) 86.64 (30.447)
59.83 (27.495)
54.71 (18.388)
N
23
25
23
24
Change from baseline at Week 12−3.91 (23.632) −77.58 (29.943) −99.28 (32.550) −105.19 (19.833)
N
23
25
23
24
Observed value at Week 16
153.30 (16.255) 89.44 (29.798)
61.48 (28.511)
53.39 (20.954)
N
23
25
23
23
Change from baseline at Week 16−1.91 (20.147) −74.78 (34.970) −97.63 (25.545) −107.57 (21.765)
N
23
25
23
23
Baseline was defined as the mean of the last 2 non-missing measurements collected within 10 days prior to
randomization. If only 1 measurement was available 10 days prior to randomization, that measurement served.
FAS=full analysis set; LDL-C=low density lipoprotein-cholesterol; N=number of subjects with non-missing
values collected including the off-drug follow-up period in the analysis set; SD=standard deviation.

Template version 1.7

Page 18

Public Disclosure Synopsis
Protocol B1481036 – 30 October 2017 – Final

Total Cholesterol:
Population A: The comparison of percent change from Baseline at Weeks 12 and 16 in totalcholesterol (mg/dL) using MMRM for Population A is summarized in (Table 10).
The mean (SD) baseline total cholesterol values were 214.16 (30.658), 210.29 (21.594),
211.71 (23.065), 222.44 (31.317) and 222.84 (25.395) mg/dL in the bococizumab 50 mg,
100 mg and 150 mg, placebo, and ezetimibe arms, respectively. At Week 12, the mean (SD)
CFB were −78.64 (28.525), −90.71 (31.705), −101.43 (25.436), −13.56 (22.346) and−24.02 (26.166) mg/dL in the bococizumab 50 mg, 100 mg and 150 mg, placebo, andezetimibe arms, respectively; the corresponding values at Week 16 were −73.44 (21.242),−85.71 (30.263), −95.83 (27.765), −21.68 (23.686) and −31.11 (24.992) mg/dL. Doserelated decreases over time were observed in the bococizumab dose arms.
Table 10. Comparison of Percent Change From Baseline at Weeks 12 and 16 in Total
Cholesterol (mg/dL) Using MMRM Analysis Based on Observed Case Data
(Population A) – FASaAdjusted Mean
Adjusted Meanp-Value
Percent Change
Difference vs. Placebo(95% CI) (%)(95% CI) (%)
Week 12
Placebo26−4.70(−8.496, −0.909)
Bococizumab 50 mg
25−36.26−36.34−31.642<0.001(−40.174, −32.515)(−37.039, −26.246)
Bococizumab 100 mg
23−44.27−44.58−39.880<0.001(−48.557, −40.608)(−45.403, −34.358)
Bococizumab 150 mg
22−49.77−50.59−45.889<0.001(−54.619, −46.564)(−51.450, −40.329)
Week 16
Placebo
25
−9.18
−8.95
(−12.705, −5.192)
Bococizumab 50 mg
24−34.28−34.32−25.374<0.001(−38.112, −30.533)(−30.717, −20.032)
Bococizumab 100 mg
23−42.35−42.44−33.490<0.001(−46.340, −38.537)(−38.934, −28.047)
Bococizumab 150 mg
22−47.30−47.71−38.760<0.001(−51.687, −43.730)(−44.262, −33.258)% change=100% x [total cholesterol (mg/dL) − total cholesterol (mg/dL) at baseline] / total cholesterol (mg/dL) at baseline.
MMRM=mixed-effects model for repeated measures; FAS=full analysis set; N=number of subjects with non-missing values
collected except the off-drug follow-up period; CI=confidence interval.
a. Unadjusted for multiplicity. P-value obtained from mixed model: % change from baseline=treatment + visit + baseline
value + treatment•visit + baseline value •visit (covariance structure=unstructured, Newton-Raphson algorithm). 1-sided,
0.025/3 significance level.

090177e18d079c7a\Approved\Approved On: 31-Oct-2017 02:32 (GMT)Time Point

Treatment arm(Atorvastatin +)N

Raw Mean
Percent
Change (%)−5.47

Population B: The comparison of percent change from Baseline at Weeks 12 and 16 in totalcholesterol (mg/dL) using MMRM for Population B is summarized in (Table 11).
The mean (SD) baseline total cholesterol values were 245.94 (30.425), 243.26 (21.967),
244.19 (29.987) and 242.04 (22.956) mg/dL in the bococizumab 50 mg, 100 mg and 150 mg,
and placebo arms, respectively. At Week 12, the mean (SD) CFB were −80.50 (31.851),−102.80 (34.603), −110.02 (24.119) and −10.52 (26.111) mg/dL in the bococizumab 50 mg,
100 mg and 150 mg, and placebo arms, respectively; the corresponding values at Week 16
were −76.22 (36.301), −97.89 (29.274), −111.96 (24.871) and −5.22 (20.333) mg/dL. In all

Template version 1.7

Page 19

Public Disclosure Synopsis
Protocol B1481036 – 30 October 2017 – Final

bococizumab dose arms, total cholesterol values decreased after start of study treatment. The
magnitude of the changes at Weeks 12 and 16 was larger in the bococizumab 100 mg and
150 mg arms compared with the bococizumab 50 mg arm. There was no observable CFB in
the placebo arm.
Table 11. Comparison of Percent Change From Baseline at Weeks 12 and 16 in Total
Cholesterol (mg/dL) Using MMRM Analysis Based on Observed Case Data
(Population B) – FASaAdjusted Mean
Adjusted Meanp-Value
Percent Change
Difference vs. Placebo(95% CI) (%)(95% CI) (%)
Week 12
Placebo23−3.92(−8.153, 0.322)
Bococizumab 50 mg
23−33.99−34.05−30.137<0.001(−38.249, −29.855)(−36.110, −24.164)
Bococizumab 100 mg
22−43.58−43.44−39.525<0.001(−47.685, −39.197)(−45.520, −33.531)
Bococizumab 150 mg
24−45.28−45.29−41.372<0.001(−49.431, −41.143)(−47.299, −35.445)
Week 16
Placebo
23
−1.62
−1.72
(−5.778, 2.345)
Bococizumab 50 mg
23−32.52−32.56−30.847<0.001(−36.580, −28.548)(−36.568, −25.127)
Bococizumab 100 mg
22−41.94−41.74−40.019<0.001(−45.788, −37.684)(−45.754, −34.285)
Bococizumab 150 mg−45.66−43.94723−45.71<0.001(−49.662, −41.666)(−49.647, −38.247)% change = 100% x [total cholesterol (mg/dL) − total cholesterol (mg/dL) at baseline] / total cholesterol (mg/dL) atbaseline.
MMRM = mixed-effects model for repeated measures; FAS = full analysis set; N = number of subjects with non-missing
values collected except the off-drug follow-up period; CI = confidence interval.
a. Unadjusted for multiplicity. P-value obtained from mixed model: % change from baseline = treatment + visit +baseline value + treatment*visit + baseline value *visit (covariance structure = unstructured, Newton-Raphson algorithm).
1-sided, 0.025/3 significance level.

090177e18d079c7a\Approved\Approved On: 31-Oct-2017 02:32 (GMT)Time Point

Treatment Arm

N

Raw Mean
Percent
Change (%)
−3.82

ApoB
Population A:
The mean (SD) baseline ApoB values were 92.76 (14.383), 92.54 (12.362), 90.40 (12.732),
95.65 (13.229) and 96.70 (13.382) mg/dL in the bococizumab 50 mg, 100 mg and 150 mg,
placebo, and ezetimibe arms, respectively. At Week 12, the mean (SD) CFB were
−41.44 (16.385), −53.33 (19.097), −56.43 (17.650), −2.19 (10.703) and −9.93 (14.350)
mg/dL in the bococizumab 50 mg, 100 mg and 150 mg, placebo, and ezetimibe arms,
respectively; the corresponding values at Week 16 were −39.56 (12.011), −49.71 (18.699),−53.61 (16.526), −7.70 (12.436) and −13.93 (12.650) mg/dL. In all bococizumab dose arms,
ApoB values decreased after the start of study treatment. The magnitude of the changes at
Weeks 12 and 16 was larger in the bococizumab 100 mg and 150 mg arms compared withthe bococizumab 50 mg arm. There was no observable CFB in the placebo arm.
At Week 12, the adjusted mean differences (95% CI) from placebo in percent CFB in ApoB
were −43.265% (−50.347%, −36.183%), −57.962% (−65.167%, −50.758%) and −64.729%

Template version 1.7

Page 20

Public Disclosure Synopsis
Protocol B1481036 – 30 October 2017 – Final(−72.039%, −57.419%) in the bococizumab 50 mg, 100 mg and 150 mg arms, respectively.
At Week 16, the adjusted mean differences (95% CI) from placebo in percent CFB were−35.288% (−42.059%, −28.516%), −48.845% (−55.709%, −41.982%) and −55.114%(−62.116%, −48.112%) in the bococizumab 50 mg, 100 mg and 150 mg arms, respectively.
Population B:

090177e18d079c7a\Approved\Approved On: 31-Oct-2017 02:32 (GMT)The mean (SD) baseline ApoB values were 106.54 (15.800), 104.02 (14.652),
101.88 (11.494) and 103.13 (13.608) mg/dL in the bococizumab 50 mg, 100 mg and 150 mg,
and placebo arms, respectively. At Week 12, mean (SD) CFB were −37.86 (18.125),−54.33 (21.080), −56.75 (14.506) and −1.04 (13.020) mg/dL in the bococizumab 50 mg, 100
mg and 150 mg, and placebo arms, respectively; the corresponding values at Week 16 were−37.46 (18.504), −51.15 (16.855), −56.83 (15.501) and 2.48 (11.107) mg/dL. In all
bococizumab dose arms, ApoB values decreased after the start of study treatment. The
magnitude of the changes at Weeks 12 and 16 was larger in the bococizumab 100 mg and
150 mg arms compared with the bococizumab 50 mg arm. There was no observable CFB in
the placebo arm.
At Week 12, the adjusted mean differences (95% CI) from placebo in percent CFB in ApoB
were −36.428% (−43.451%, −29.405%), −53.296% (−60.325%, −46.267%) and −55.489%(−62.436%, −48.542%) in the bococizumab 50 mg, 100 mg and 150 mg arms, respectively.
At Week 16, the adjusted mean differences (95% CI) from placebo in percent CFB were−40.045% (−47.118%, −32.971%), −53.810% (−60.883%, −46.737%) and −58.620%(−65.640%, −51.600%) in the bococizumab 50 mg, 100 mg and 150 mg arms, respectively.
ApoA1
Population A:
The mean (SD) baseline ApoA1 values were 137.02 (13.235), 142.60 (16.507), 140.31(18.813), 145.65 (21.908) and 145.34 (16.171) mg/dL in the bococizumab 50 mg, 100 mg
and 150 mg, placebo, and ezetimibe arms, respectively. At Week 12, the mean (SD) CFB
were 1.02 (9.479), 5.56 (10.575), 3.63 (11.155), −9.65 (9.495) and −1.11 (11.118) mg/dL in
the bococizumab 50 mg, 100 mg and 150 mg, placebo, and ezetimibe arms, respectively; thecorresponding values at Week 16 were 2.52 (9.226), 6.56 (12.310), 3.72 (11.977),−7.86 (13.052) and −0.34 (10.783) mg/dL. No meaningful CFB were found in all treatment
arms.
At Week 12, the adjusted mean differences (95% CI) from placebo in percent CFB in ApoA1
were 6.079% (2.296%, 9.863%), 10.786% (6.976%, 14.597%) and 9.069% (5.206%,
12.932%) in the bococizumab 50 mg, 100 mg and 150 mg arms, respectively. At Week 16,
the adjusted mean differences (95% CI) from placebo in percent CFB in ApoA1 were
5.936% (1.435%, 10.437%), 10.213% (5.702%, 14.724%) and 8.056% (3.484%, 12.629%) in
the bococizumab 50 mg, 100 mg and 150 mg arms, respectively.

Template version 1.7

Page 21

Public Disclosure Synopsis
Protocol B1481036 – 30 October 2017 – Final

Population B:
The mean (SD) baseline ApoA1 values were 138.90 (21.808), 145.38 (19.260),
146.75 (25.587) and 150.13 (16.834) mg/dL in the bococizumab 50 mg, 100 mg and 150 mg,
and placebo arms, respectively. At Week 12, the mean (SD) CFB were −6.02 (11.069),−2.09 (12.040), −0.17 (11.897) and −13.83 (10.602) mg/dL in the bococizumab 50 mg,
100 mg and 150 mg, and placebo arms, respectively; the corresponding values at Week 16
were −0.50 (9.512), 1.87 (9.328), −3.54 (8.982) and −10.09 (11.236) mg/dL. No meaningful
CFB were found in all treatment arms.
At Week 12, the adjusted mean differences (95% CI) from placebo in percent CFB in ApoA1
were 4.859% (0.541%, 9.178%), 7.331% (3.037%, 11.624%) and 9.075% (4.856%,
13.293%) in the bococizumab 50 mg, 100 mg and 150 mg arms, respectively. At Week 16,
the adjusted mean differences (95% CI) from placebo in percent CFB in ApoA1 were5.846% (2.312%, 9.380%), 6.910% (3.400%, 10.421%) and 4.168% (0.693%, 7.642%) in the
bococizumab 50 mg, 100 mg and 150 mg arms, respectively.
ApoA2090177e18d079c7a\Approved\Approved On: 31-Oct-2017 02:32 (GMT)

Population A:
The mean (SD) baseline ApoA2 values were 30.700 (3.6817), 30.223 (2.8992),
30.471 (2.8918), 31.515 (3.8373) and 32.189 (3.2855) mg/dL in the bococizumab 50 mg, 100
mg and 150 mg, placebo, and ezetimibe arms, respectively. At Week 12, the mean (SD)
CFB were −0.216 (2.2274), 0.073 (2.6605), −0.450 (2.3906), −0.938 (1.8339) and 0.907(2.6785) mg/dL in the bococizumab 50 mg, 100 mg and 150 mg, placebo, and ezetimibe
arms, respectively; the corresponding values at Week 16 were −0.073 (2.0937), 0.090(2.3882), −0.637 (2.2412), −1.104 (4.0438) and 0.370 (2.2388) mg/dL. No meaningful CFB
were found in all treatment arms.
At Week 12, the adjusted mean differences (95% CI) from placebo in percent CFB in ApoA2
were 2.0813% (−1.9730%, 6.1356%), 3.2608% (−0.9035%, 7.4250%) and 0.8224%(−3.3733%, 5.0182%) in the bococizumab 50 mg, 100 mg and 150 mg arms, respectively.
At Week 16, the adjusted mean differences (95% CI) from placebo in percent CFB in ApoA2
were 2.1827% (−2.6334%, 6.9988%), 2.1376% (−2.7718%, 7.0469%) and 0.3113%(−4.6358%, 5.2584%) in the bococizumab 50 mg, 100 mg and 150 mg arms, respectively.
Population B:
The mean (SD) baseline ApoA2 values were 29.940 (3.3630), 31.232 (3.9681),
30.294 (3.0541) and 31.354 (3.9552) mg/dL in the bococizumab 50 mg, 100 mg and 150 mg,
and placebo arms, respectively. At Week 12, the mean (SD) CFB were −0.904 (2.3894),
0.354 (3.3769), 0.240 (3.1812) and −1.698 (2.9589) mg/dL in the bococizumab 50 mg,
100 mg and 150 mg, and placebo arms, respectively; the corresponding values at Week 16
were −0.640 (2.0394), 0.759 (2.2739), 0.002 (2.8256) and −1.228 (3.4404) mg/dL. No
meaningful CFB were found in all treatment arms.

Template version 1.7

Page 22

Public Disclosure Synopsis
Protocol B1481036 – 30 October 2017 – Final

At Week 12, the adjusted mean differences (95% CI) from placebo in percent CFB in ApoA2
were 2.3254% (−3.1801%, 7.8310%), 6.1048% (0.5833%, 11.6263%) and 5.2393%(−0.2058%, 10.6845%) in the bococizumab 50 mg, 100 mg and 150 mg arms, respectively.
At Week 16, the adjusted mean differences (95% CI) from placebo in percent CFB in ApoA2
were 0.6078% (−4.0274%, 5.2431%), 5.7096% (1.0659%, 10.3532%) and 2.4558%(−2.1608%, 7.0724%) in the bococizumab 50 mg, 100 mg and 150 mg arms, respectively.
Lp(a)090177e18d079c7a\Approved\Approved On: 31-Oct-2017 02:32 (GMT)

Population A:
The mean (SD) baseline Lp(a) values were 18.452 (13.1792), 20.998 (17.2111),
18.840 (16.7289), 19.265 (14.3646) and 19.468 (18.4181) mg/dL in the bococizumab 50 mg,
100 mg and 150 mg, placebo, and ezetimibe arms, respectively. At Week 12, mean (SD)
CFB were −7.492 (5.1400), −10.119 (5.4374), −10.239 (8.2471), −2.746 (3.1292) and−1.859 (3.0759) mg/dL in the bococizumab 50 mg, 100 mg and 150 mg, placebo, andezetimibe arms, respectively; the corresponding values at Week 16 were −6.815 (4.6182),−9.815 (5.0568), −9.913 (6.6763), −3.574 (4.0251) and −2.655 (3.1725) mg/dL. In all
bococizumab dose arms, Lp(a) values decreased after the start of study treatment. The
magnitude of the changes at Weeks 12 and 16 was larger in the bococizumab 100 mg and
150 mg arms compared with the bococizumab 50 mg arm. Small decreases from baseline
were also found in the placebo arm, but the magnitude of the change was larger in all
bococizumab dose arms compared with the placebo arm.
At Week 12, the adjusted mean differences (95% CI) from placebo in percent CFB in Lp(a)were −27.4492% (−47.7872%, −7.1112%), −40.5908% (−61.3577%, −19.8240%) and−27.1630% (−48.0927%, −6.2332%) in the bococizumab 50 mg, 100 mg and 150 mg arms,
respectively. At Week 16, the adjusted mean differences (95% CI) from placebo in percent
CFB were −18.3898% (−28.6698%, −8.1097%), −36.7882% (−47.2423%, −26.3341%) and−36.8453% (−47.3864%, −26.3041%) in the bococizumab 50 mg, 100 mg and 150 mg arms,
respectively.
Population B:
The mean (SD) baseline Lp(a) values were 14.080 (11.9369), 15.458 (12.6296),
13.400 (9.0719) and 16.239 (10.1883) mg/dL in the bococizumab 50 mg, 100 mg and 150
mg, and placebo arms, respectively. At Week 12, the mean (SD) CFB were −5.272 (5.1528),−7.100 (5.9402), −6.763 (5.3474) and −3.513 (3.6550) mg/dL in the bococizumab 50 mg,
100 mg and 150 mg, and placebo arms, respectively; the corresponding values at Week 16
were −6.060 (4.5477), −8.074 (6.0886), −7.098 (4.5025) and −3.326 (3.4975) mg/dL. In all
bococizumab dose arms, Lp(a) values decreased after the start of study treatment. The
magnitude of the changes at Weeks 12 and 16 was similar among the 3 dose arms. A small
decrease from baseline was also found in the placebo arm, but the magnitude of the change
was larger in all bococizumab dose arms compared with the placebo arm.
At Week 12, the adjusted mean differences (95% CI) from placebo in percent CFB in Lp(a)were −24.1677% (−41.8023%, −6.5332%), −19.2255% (−36.9471%, −1.5038%) andTemplate version 1.7

Page 23

Public Disclosure Synopsis
Protocol B1481036 – 30 October 2017 – Final−26.5155% (−44.0795%, −8.9515%) in the bococizumab 50 mg, 100 mg and 150 mg arms,
respectively. At Week 16, the adjusted mean differences (95% CI) from placebo in percent
CFB were −32.9411% (−48.5748%, −17.3075%), −31.3176% (−47.0238%, −15.6114%) and−32.8470% (−48.4650%, −17.2289%) in the bococizumab 50 mg, 100 mg and 150 mg arms,
respectively.
HDL-C
Population A: The comparison of percent change from Baseline at Weeks 12 and 16 in
HDL-C (mg/dL) using MMRM for population A is summarized in (Table 12).

090177e18d079c7a\Approved\Approved On: 31-Oct-2017 02:32 (GMT)The mean (SD) baseline HDL-C values were 54.58 (9.048), 54.75 (11.789), 57.00 (12.858),
58.54 (14.683) and 56.98 (9.607) mg/dL in the bococizumab 50 mg, 100 mg and 150 mg,
placebo, and ezetimibe arms, respectively. At Week 12, the mean (SD) CFB were 3.66
(6.216), 4.79 (5.568), 2.63 (5.394), −4.58 (4.573) and 2.80 (6.223) mg/dL in the
bococizumab 50 mg, 100 mg and 150 mg, placebo, and ezetimibe arms, respectively; thecorresponding values at Week 16 were 3.90 (6.437), 6.29 (7.003), 2.33 (8.053), −3.28 (7.264)
and 3.34 (5.702) mg/dL. In all bococizumab dose arms and ezetimibe arms, small increases
in HDL-C values were observed after the start of study treatment. HDL-C values in theplacebo arm slightly decreased.
Table 12. Comparison of Percent Change From Baseline at Weeks 12 and 16 in HDLC (mg/dL) Using MMRM Analysis Based on Observed Case Data
(Population A) – FAS
Time Point

Treatment arm(Atorvastatin +)N

Week 12

Placebo26

Raw Mean
Percent
Change (%)−7.31

Bococizumab 50 mg

25

7.26

Bococizumab 100 mg

23

10.39

Bococizumab 150 mg

22

6.40

Placebo25−4.83

Bococizumab 50 mg

24

7.39

Bococizumab 100 mg

23

12.75

Bococizumab 150 mg

22

5.42

Week 16

Adjusted Mean
Percent Change(95% CI) (%)−6.64(−10.142, −3.135)
6.75(3.185, 10.317)
9.91(6.197, 13.619)
6.65(2.861, 10.438)−3.99(−8.599, 0.623)
6.02(1.316, 10.715)
12.26(7.438, 17.089)
5.58(0.672, 10.493)

aAdjusted Mean
Difference vs. Placebo(95% CI) (%)-

p-Value

13.389(8.373, 18.405)
16.546(11.430, 21.663)
13.288(8.137, 18.438)-<0.00110.004(3.395, 16.612)
16.252(9.560, 22.943)
9.571(2.847, 16.295)

0.002

-

<0.001<0.001-<0.0010.003% change=100% x [HDL-C (mg/dL) − HDL-C (mg/dL) at baseline]/ HDL-C (mg/dL) at baseline.
HDL-C=high density lipoprotein-cholesterol; MMRM=mixed-effects model for repeated measures; FAS=fullanalysis set; N=number of subjects with non-missing values collected except the off-drug follow-up period;
CI=confidence interval.
a. Unadjusted for multiplicity. P-value obtained from mixed model: % change from baseline=treatment +visit + baseline value + treatment*visit + baseline value *visit (covariance structure=unstructured, NewtonRaphson algorithm). 1-sided, 0.025/3 significance level.

Template version 1.7

Page 24

Public Disclosure Synopsis
Protocol B1481036 – 30 October 2017 – Final

Population B: The comparison of percent change from Baseline at Weeks 12 and 16 in
HDL-C (mg/dL) using MMRM for population B is summarized in (Table 13).
The mean (SD) baseline HDL-C values were 57.22 (14.146), 60.40 (13.228), 62.02 (21.455)
and 60.87 (10.606) mg/dL in the bococizumab 50 mg, 100 mg and 150 mg, and placebo arms,
respectively. At Week 12, the mean (SD) CFB were −2.18 (6.065), 1.46 (7.408), −0.02(7.575) and −4.52 (5.191) mg/dL in the bococizumab 50 mg, 100 mg and 150 mg, andplacebo arms, respectively; the corresponding values at Week 16 were 0.70 (6.489),
1.37 (7.799), −0.63 (6.995) and −4.70 (5.045) mg/dL. In all bococizumab dose arms, small
increases in HDL-C values were observed except some evaluation points after the start ofstudy treatment. HDL-C values in the placebo arm slightly decreased.
Table 13. Comparison of Percent Change From Baseline at Weeks 12 and 16 in HDLC (mg/dL) Using MMRM Analysis Based on Observed Case Data
(Population B) – FASaAdjusted Mean
Adjusted Meanp-Value
Percent Change
Difference vs. Placebo(95% CI) (%)(95% CI) (%)
Week 12
Placebo23−7.04(−11.132, −2.956)
Bococizumab 50 mg
23
−2.05
-2.93
4.112
0.081
(−7.017, 1.152)(−1.671, 9.895)
Bococizumab 100 mg
22
2.90
2.52
9.560
<0.001(−1.624, 6.656)(3.743, 15.377)
Bococizumab 150 mg
24
2.35
2.78
9.826
<0.001(−1.226, 6.789)(4.103, 15.548)
Week 16
Placebo
23
−7.53
-7.44
(−11.450, −3.427)
Bococizumab 50 mg
23
2.25
1.59
9.029
0.001
(−2.426, 5.607)(3.348, 14.710)
Bococizumab 100 mg
22
1.44
1.10
8.543
0.002
(−2.969, 5.179)(2.827, 14.260)
Bococizumab 150 mg
23
1.05
1.46
8.898
0.001
(−2.517, 5.436)(3.252, 14.544)% change=100% x [HDL-C (mg/dL) − HDL-C (mg/dL) at baseline] / HDL-C (mg/dL) at baseline.
HDL-C=high density lipoprotein-cholesterol; MMRM=mixed-effects model for repeated measures; FAS=full analysis set;
N=number of subjects with non-missing values collected except the off-drug follow-up period; CI=confidence interval.
a. Unadjusted for multiplicity. P-value obtained from mixed model: % change from baseline=treatment + visit + baseline
value + treatment•visit + baseline value•visit (covariance structure=unstructured, Newton-Raphson algorithm). 1-sided,
0.025/3 significance level.

090177e18d079c7a\Approved\Approved On: 31-Oct-2017 02:32 (GMT)Time Point

Treatment arm

N

Raw Mean
Percent
Change (%)−7.16

VLDL-C
Population A:
The mean (SD) baseline VLDL-C values were 19.92 (9.312), 23.79 (11.286), 20.92 (7.651),
21.42 (6.858) and 22.48 (7.869) mg/dL in the bococizumab 50 mg, 100 mg and 150 mg,
placebo, and ezetimibe arms, respectively. At Week 12, the mean (SD) CFB were −5.68(6.973), −6.17 (7.171), −6.57 (6.726), 1.15 (4.841) and −2.70 (7.069) mg/dL in the
bococizumab 50 mg, 100 mg and 150 mg, placebo, and ezetimibe arms, respectively; thecorresponding values at Week 16 were −4.29 (8.538), −7.25 (9.067), −5.35 (6.619),
0.34 (10.957) and −3.98 (8.873) mg/dL. In all bococizumab dose arms, decreases in VLDL-

Template version 1.7

Page 25

Public Disclosure Synopsis
Protocol B1481036 – 30 October 2017 – Final

C values were observed except some evaluation points after the start of study treatment. The
magnitude of the changes at Weeks 12 and 16 was similar among the 3 dose arms. There
was no meaningful CFB in the placebo and ezetimibe arms.
At Week 12, the adjusted mean differences (95% CI) from placebo in percent CFB in
VLDL-C were −31.880% (−45.925%, −17.836%), −29.187% (−43.571%, −14.803%) and−39.657% (−54.136%, −25.178%) in the bococizumab 50 mg, 100 mg and 150 mg arms,
respectively. At Week 16, the adjusted mean differences (95% CI) from placebo in percent
CFB were −12.911% (−33.411%, 7.589%), −23.119% (−43.923%, −2.315%) and −17.159%(−38.108%, 3.789%) in the bococizumab 50 mg, 100 mg and 150 mg arms, respectively.
Population B:

090177e18d079c7a\Approved\Approved On: 31-Oct-2017 02:32 (GMT)The mean (SD) baseline VLDL-C values were 17.44 (7.509), 17.66 (9.090), 16.63 (6.273)
and 17.50 (8.549) mg/dL in the bococizumab 50 mg, 100 mg and 150 mg, and placebo arms,
respectively. At Week 12, the mean (SD) CFB were −0.76 (5.114), −2.63 (9.497),−2.58 (7.290) and −1.07 (4.989) mg/dL in the bococizumab 50 mg, 100 mg and 150 mg, andplacebo arms, respectively; the corresponding values at Week 16 were −1.52 (5.771),−0.76 (9.276), −2.98 (6.998) and 1.89 (5.762) mg/dL. No meaningful CFB were found in alltreatment arms.
At Week 12, the adjusted mean differences (95% CI) from placebo in percent CFB in VLDLC were −4.681% (−31.713%, 22.350%), 10.227% (−16.774%, 37.228%) and−2.646% (−29.206%, 23.915%) in the bococizumab 50 mg, 100 mg and 150 mg arms,
respectively. At Week 16, the adjusted mean differences (95% CI) from placebo in percent
CFB in VLDL-C were −24.416% (−49.696%, 0.865%), −6.287% (−31.541%, 18.968%) and−32.443% (−57.400%, −7.485%) in the bococizumab 50 mg, 100 mg and 150 mg arms,
respectively.
TG
Population A: The comparison of percent change from Baseline at Weeks 12 and 16 in TG(mg/dL) Using MMRM for Population A is summarized in (Table 14).
The mean (SD) baseline TG values were 121.04 (56.152), 158.21 (71.477),127.65 (59.878),
140.23 (51.283) and 152.59 (50.105) mg/dL in the bococizumab 50 mg, 100 mg and 150 mg,
placebo, and ezetimibe arms, respectively. At Week 12, mean (SD) CFB were
−28.68 (41.898), −27.96 (49.754), −29.52 (40.669), 2.58 (35.796) and −10.14(43.129) mg/dL in the bococizumab 50 mg, 100 mg and 150 mg, placebo, and ezetimibe
arms, respectively; the corresponding values at Week 16 were −20.02 (41.197),−45.33 (53.285), −30.13 (48.592), −0.58 (63.896) and −23.45 (51.443) mg/dL. In all
bococizumab dose arms, decreases in TG values were observed except some evaluation
points after the start of study treatment. There was no meaningful CFB in the placebo arm.

Template version 1.7

Page 26

Public Disclosure Synopsis
Protocol B1481036 – 30 October 2017 – Final

Table 14. Comparison of Percent Change From Baseline at Weeks 12 and 16 in TG(mg/dL) Using MMRM Analysis Based on Observed Case Data
(Population A) – FAS
Adjusted Mean
Adjusted MeanaPercent Change
Difference vs. Placebo p-Value(95% CI) (%)(95% CI) (%)
4.03
Week 12
Placebo26
3.74(−6.580, 14.633)−21.95−25.974
Bococizumab 50 mg
25−21.00<0.001(−32.842, −11.052)(−41.217, −10.731)−17.08−21.110
Bococizumab 100 mg
23−18.520.004(−28.536, −5.630)(−36.665, −5.555)−27.01−31.034
Bococizumab 150 mg
22−26.26<0.001(−38.573, −15.441)(−46.758, −15.310)−3.22
Week 16
Placebo25−3.82(−15.390, 8.946)−13.28−10.056
Bococizumab 50 mg
24−14.440.128(−25.767, −0.788)(−27.549, 7.437)−27.57−24.352
Bococizumab 100 mg
23−28.770.004(−40.486, −14.662)(−42.008, −6.695)−18.22−14.994
Bococizumab 150 mg
22−17.550.049(−31.229, −5.203)(−32.858, 2.870)% change=100% x [TG (mg/dL) − TG (mg/dL) at baseline] / TG (mg/dL) at baseline.
TG=triglyceride; MMRM = mixed-effects model for repeated measures; FAS=full analysis set; N=number of subjects with
non-missing values collected except the off-drug follow-up period; CI=confidence interval.
a. Unadjusted for multiplicity. P-value obtained from mixed model: % change from baseline=treatment + visit + baseline
value + treatment•visit + baseline value•visit (covariance structure=unstructured, Newton-Raphson algorithm). 1-sided,
0.025/3 significance level.

090177e18d079c7a\Approved\Approved On: 31-Oct-2017 02:32 (GMT)Time Point

Treatment arm(Atorvastatin +)N

Raw Mean
Percent
Change (%)

Population B: The comparison of percent change from Baseline at Weeks 12 and 16 in TG(mg/dL) Using MMRM for Population B is summarized in (Table 15).
The mean (SD) baseline TG values were 122.40 (50.578), 124.40 (59.717), 111.58 (42.354)
and 130.39 (49.826) mg/dL in the bococizumab 50 mg, 100 mg and 150 mg, and placeboarms, respectively. At Week 12, the mean (SD) CFB were −3.76 (37.502), −15.87 (48.341),−11.67 (42.519) and −11.22 (23.797) mg/dL in the bococizumab 50 mg, 100 mg and 150 mg,
and placebo arms, respectively; the corresponding values at Week 16 were −10.68 (27.488),
0.35 (48.858), −12.46 (44.128) and 6.22 (32.888) mg/dL. No meaningful CFB were found in
all treatment arms.

Template version 1.7

Page 27

Public Disclosure Synopsis
Protocol B1481036 – 30 October 2017 – Final

Table 15. Comparison of Percent Change From Baseline at Weeks 12 and 16 in TG(mg/dL) Using MMRM Analysis Based on Observed Case Data
(Population B) – FASaAdjusted Mean
Adjusted Meanp-Value
Percent Change
Difference vs. Placebo(95% CI) (%)(95% CI) (%)
Week 12
Placebo23−7.43(−20.958, 6.106)
Bococizumab 50 mg
23
−0.27
0.61
8.034
0.799
(−12.777, 13.991)(−10.948, 27.015)
Bococizumab 100 mg
22
−8.65
−9.94
−2.5110.398(−23.565, 3.691)(−21.748, 16.727)
Bococizumab 150 mg
24
−5.21
−7.06
0.369
0.515
(−20.303, 6.188)(−18.668, 19.407)
Week 16
Placebo
23
4.57
4.96
(−8.221, 18.145)
Bococizumab 50 mg
23
−8.98
−8.87
−13.830
0.071(−21.976, 4.240)(−32.368, 4.709)
Bococizumab 100 mg
22
1.99
1.58
−3.3780.361(−11.796, 14.963)(−22.191, 15.435)
Bococizumab 150 mg
23−8.47−10.07−15.035
23(−23.168, 3.022)(−33.698, 3.629)% change=100% x [TG (mg/dL) − TG (mg/dL) at baseline] / TG (mg/dL) at baseline.
TG=triglyceride; MMRM=mixed-effects model for repeated measures; FAS=full analysis set; N=number of subjects with
non-missing values collected except the off-drug follow-up period; CI=confidence interval.
a. Unadjusted for multiplicity. P-value obtained from mixed model: % change from baseline=treatment + visit + baseline
value + treatment•visit + baseline value•visit (covariance structure=unstructured, Newton-Raphson algorithm). 1-sided,
0.025/3 significance level.

090177e18d079c7a\Approved\Approved On: 31-Oct-2017 02:32 (GMT)Time Point

Treatment arm

N

Raw Mean
Percent
Change (%)−9.33

Non-HDL-C
Population A:
The mean (SD) baseline non-HDL-C values were 159.58 (29.033), 155.54 (20.706),
154.71 (22.511), 163.90 (25.271) and 165.86 (26.655) mg/dL in the bococizumab 50 mg,
100 mg and 150 mg, placebo, and ezetimibe arms, respectively. At Week 12, the mean (SD)
CFB were −82.30 (30.323), −95.50 (32.345), −104.07 (27.573), −8.98 (20.888) and−26.82 (28.796) mg/dL in the bococizumab 50 mg, 100 mg and 150 mg, placebo, andezetimibe arms, respectively; the corresponding values at Week 16 were −77.33 (22.371),−92.00 (32.099), −98.15 (28.798), −18.40 (22.784) and −34.45 (26.242) mg/dL. In all
bococizumab dose arms, non-HDL-C values decreased after the start of study treatment. The
magnitude of the changes at Weeks 12 and 16 was larger in the bococizumab 100 mg and
150 mg arms compared with the bococizumab 50 mg arm. There was no meaningful CFB in
the placebo arm.
At Week 12, the adjusted mean differences (95% CI) from placebo in percent CFB in
non-HDL-C were −46.772% (−53.671%, −39.874%), −59.200% (−66.257%, −52.143%) and−66.868% (−74.007%, −59.730%) in the bococizumab 50 mg, 100 mg and 150 mg arms,
respectively. At Week 16, the adjusted mean differences (95% CI) from placebo in percent
CFB were −37.991% (−44.721%, −31.260%), −50.856% (−57.709%, −44.002%) and−56.354% (−63.315%, −49.393%) in the bococizumab 50 mg, 100 mg and 150 mg arms,
respectively.

Template version 1.7

Page 28

Public Disclosure Synopsis
Protocol B1481036 – 30 October 2017 – Final

Population B:
The mean (SD) baseline non-HDL-C values were 188.72 (30.222), 182.86 (22.842),
182.17 (21.217) and 181.17 (23.577) mg/dL in the bococizumab 50 mg, 100 mg and 150 mg,
and placebo arms, respectively. At Week 12, the mean (SD) CFB were −78.32 (33.436),−104.26 (34.056), −110.00 (24.274) and −6.00 (24.009) mg/dL in the bococizumab 50 mg,
100 mg and 150 mg, and placebo arms, respectively; the corresponding values at Week 16
were −76.92 (35.588), −99.26 (27.347), −111.33 (24.646) and −0.52 (20.267) mg/dL. In all
bococizumab dose arms, non-HDL-C values decreased after the start of study treatment. The
magnitude of the changes at Weeks 12 and 16 was larger in the bococizumab 100 mg and
150 mg arms compared with the bococizumab 50 mg arm. There was no meaningful CFB in
the placebo arm.

090177e18d079c7a\Approved\Approved On: 31-Oct-2017 02:32 (GMT)At Week 12, the adjusted mean differences (95% CI) from placebo in percent CFB in
non-HDL-C were −40.051% (−47.195%, −32.908%), −56.009% (−63.135%, −48.882%) and−57.576% (−64.618%, −50.533%) in the bococizumab 50 mg, 100 mg and 150 mg arms,
respectively. At Week 16, the adjusted mean differences (95% CI) from placebo in percent
CFB were −43.172% (−50.417%, −35.926%), −56.698% (−63.916%, −49.480%) and−61.305% (−68.477%, −54.134%) in the bococizumab 50 mg, 100 mg and 150 mg arms,
respectively.
Total Cholesterol/HDL-C ratio
Population A
The mean (SD) baseline total cholesterol/HDL-C ratio were 4.0118 (0.82813),
4.0154 (0.92478), 3.8500 (0.72414), 3.9629 (0.77435) and 4.0223 (0.81145) in the
bococizumab 50 mg, 100 mg and 150 mg, placebo, and ezetimibe arms, respectively. At
Week 12, the mean (SD) CFB were −1.6394 (0.69058), −1.9433 (0.90358),−1.9835 (0.78766), 0.0879 (0.43755) and −0.6236 (0.66072) in the bococizumab 50 mg,
100 mg and 150 mg, placebo, and ezetimibe arms, respectively; the corresponding values at
Week 16 were −1.5671 (0.65875), −1.9113 (0.93385), −1.8704 (0.73630), −0.1560 (0.53286)
and −0.7864 (0.60966). In all bococizumab dose arms, total cholesterol/HDL-C ratio
decreased after the start of study treatment. The magnitude of the changes at Weeks 12 and
16 was larger in the bococizumab 100 mg and 150 mg arms compared with the bococizumab
50-mg arm. There was no meaningful CFB in the placebo arm.
At Week 12, the adjusted mean differences (95% CI) from placebo in percent CFB in totalcholesterol/HDL-C ratio were −41.92915% (−47.55052%, −36.30778%),−51.08604% (−56.81235%, −45.35973%) and −55.51600% (−61.29424%, −49.73777%) in
the bococizumab 50 mg, 100 mg and 150 mg arms, respectively. At Week 16, the adjusted
mean differences (95% CI) from placebo in percent CFB were −33.52920% (−39.42015%,−27.63826%), −43.85680% (−49.82617%, −37.88744%) and −46.36865% (−52.40589%,−40.33142%) in the bococizumab 50 mg, 100 mg and 150 mg arms, respectively.

Template version 1.7

Page 29

Public Disclosure Synopsis
Protocol B1481036 – 30 October 2017 – Final

Population B
The mean (SD) baseline total cholesterol/HDL-C ratio were 4.5408 (1.11809),
4.2558 (1.15512), 4.2610 (1.08481) and 4.1076 (0.88524) in the bococizumab 50 mg, 100
mg and 150 mg, and placebo arms, respectively. At Week 12, mean (SD) CFB were −1.4204(0.91892), −1.8407 (0.85260), −2.0469 (0.96230) and 0.1537 (0.47755) in the bococizumab
50 mg, 100 mg and 150 mg, and placebo arms, respectively; the corresponding values at
Week 16 were −1.4648 (0.83864), −1.7563 (0.74752), −2.0461 (0.92038) and
0.2493 (0.43772). In all bococizumab dose arms, total cholesterol/HDL-C ratio decreased
after the start of study treatment. The magnitude of the changes at Weeks 12 and 16 waslarger in the bococizumab 100 mg and 150 mg arms compared with the bococizumab 50 mg
arm. There was no meaningful CFB in the placebo arm.

090177e18d079c7a\Approved\Approved On: 31-Oct-2017 02:32 (GMT)At Week 12, the adjusted mean differences (95% CI) from placebo in percent CFB in totalcholesterol/HDL-C ratio were −33.30375% (−39.41376%, −27.19373%),−47.85210% (−53.92668%, −41.77751%) and −48.65686% (−54.66060%, −42.65313%) in
the bococizumab 50 mg, 100 mg and 150 mg arms, respectively. At Week 16, the adjusted
mean differences (95% CI) from placebo in percent CFB were −38.06019% (−44.29176%,−31.82863%), −48.57807% (−54.76397%, −42.39217%) and −51.87214% (−58.01968%,−45.72460%) in the bococizumab 50 mg, 100 mg and 150 mg arms, respectively.
ApoB/ApoA1 ratio
Population A:
The mean (SD) baseline ApoB/ApoA1 ratio were 0.6846 (0.14145), 0.6606 (0.13665),
0.6567 (0.12772), 0.6687 (0.12269) and 0.6775 (0.14076) in the bococizumab 50 mg,
100 mg and 150 mg, placebo, and ezetimibe arms, respectively. At Week 12, the mean (SD)
CFB were −0.3078 (0.13144), −0.3910 (0.15635), −0.4211 (0.16147), 0.0337 (0.09054) and−0.0643 (0.11318) in the bococizumab 50 mg, 100 mg and 150 mg, placebo, and ezetimibe
arms, respectively; the corresponding values at Week 16 were −0.2998 (0.12105), −0.3698(0.16194), −0.3998 (0.15163), −0.0170 (0.10303) and −0.0998 (0.09487). In all
bococizumab dose arms, ApoB/ApoA1 ratio decreased after the start of study treatment. The
magnitude of the changes at Weeks 12 and 16 was slightly larger in the bococizumab 100 mg
and 150 mg arms compared with the bococizumab 50 mg arm. There was no meaningful
CFB in the placebo and ezetimibe arm.
At Week 12, the adjusted mean differences (95% CI) from placebo in percent CFB in
ApoB/ApoA1 ratio were −49.42411% (−56.83019%, −42.01803%),−66.63383% (−74.16086%, −59.10681%) and −71.72901% (−79.30431%, −64.15371%) in
the bococizumab 50 mg, 100 mg and 150 mg arms, respectively. At Week 16, the adjusted
mean differences (95% CI) from placebo in percent CFB were −40.52435% (−47.81299%,−33.23571%), −56.14495% (−63.52668%, −48.76322%) and −61.56370% (−69.02510%,−54.10230%) in the bococizumab 50 mg, 100 mg and 150 mg arms, respectively.

Template version 1.7

Page 30

Public Disclosure Synopsis
Protocol B1481036 – 30 October 2017 – Final

Population B:
The mean (SD) baseline ApoB/ApoA1 ratio were 0.7890 (0.17841), 0.7324 (0.16556),
0.7167 (0.16058) and 0.6980 (0.13867) in the bococizumab 50 mg, 100 mg and 150 mg, andplacebo arms, respectively. At Week 12, mean (SD) CFB were −0.2626 (0.16341),−0.3748 (0.17224), −0.4042 (0.14894) and 0.0685 (0.10818) in the bococizumab 50 mg,
100 mg and 150 mg, and placebo arms, respectively; the corresponding values at Week 16
were −0.2750 (0.15604), −0.3626 (0.14553), −0.3965 (0.15431) and 0.0702 (0.09306). In all
bococizumab dose arms, ApoB/ApoA1 ratio decreased after the start of study treatment. The
magnitude of the changes at Weeks 12 and 16 was slightly larger in the bococizumab 100 mg
and 150 mg arms compared with the bococizumab 50 mg arm. There was no meaningful
CFB in the placebo arm.

090177e18d079c7a\Approved\Approved On: 31-Oct-2017 02:32 (GMT)At Week 12, the adjusted mean differences (95% CI) from placebo in percent CFB in
ApoB/ApoA1 ratio were −43.56596% (−51.35899%, −35.77293%),−62.34926% (−70.02607%, −54.67245%) and −65.06617% (−72.65818%, −57.47415%) in
the bococizumab 50 mg, 100 mg and 150 mg arms, respectively. At Week 16, the adjusted
mean differences (95% CI) from placebo in percent CFB were −46.34109% (−54.61427%,−38.06792%), −61.37890% (−69.52338%, −53.23443%) and −64.67274% (−72.75728%,−56.58820%) in the bococizumab 50 mg, 100 mg and 150 mg arms, respectively.
Low Density Lipoprotein-Cholesterol Proportion Analysis
The proportion of subjects reaching LDL-C of <100, <70, <40, <25 and <10 mg/dL during
the treatment period in the FAS is shown in Table 16 for Population A and Table 17 forPopulation B.
Population A:
Table 16. Proportion of Subjects Reaching LDL-C of <100, <70, <40, <25 and<10 mg/dL During Treatment Period (Population A) – FAS
LDL-CPercentage Responders, n/N (%)
Atorvastatin +Placebo
Bococizumab
50 mg
100 mg
150 mg<100 mg/dL
6/26 (23.1)
25/25 (100.0)
24/24 (100.0)
24/24 (100.0)<70 mg/dL
0/26 (0.0)
24/25 (96.0)
24/24 (100.0)
24/24 (100.0)<40 mg/dL
0/26 (0.0)
21/25 (84.0)
22/24 (91.7)
23/24 (95.8)<25 mg/dL
0/26 (0.0)
3/25 (12.0)
16/24 (66.7)
14/24 (58.3)<10 mg/dL
0/26 (0.0)
0/25 (0.0)
1/24 (4.2)
0/24 (0.0)
FAS=full analysis set; LDL-C=low density lipoprotein-cholesterol; n=number of responders; N=number ofsubjects in study population with at least 1 non-missing data at any visit during treatment period.

Template version 1.7

Page 31

Public Disclosure Synopsis
Protocol B1481036 – 30 October 2017 – Final

Population B:
Table 17. Proportion of Subjects Reaching LDL-C of <100, <70, <40, <25 and<10 mg/dL During Treatment Period (Population B) – FAS
LDL-CPercentage Responders, n/N (%)
PF-04950615
50 mg
100 mg
150 mg<100 mg/dL
1/23 (4.3)
23/25 (92.0)
25/25 (100.0)
24/24 (100.0)<70 mg/dL
0/23 (0.0)
16/25 (64.0)
23/25 (92.0)
21/24 (87.5)<40 mg/dL
0/23 (0.0)
3/25 (12.0)
9/25 (36.0)
10/24 (41.7)<25 mg/dL
0/23 (0.0)
0/25 (0.0)
0/25 (0.0)
5/24 (20.8)<10 mg/dL
0/23 (0.0)
0/25 (0.0)
0/25 (0.0)
0/24 (0.0)
FAS = full analysis set; LDL-C=low density lipoprotein-cholesterol; n=number of responders; N=number ofsubjects in study population with at least 1 non-missing data at any visit during treatment period.
Placebo

090177e18d079c7a\Approved\Approved On: 31-Oct-2017 02:32 (GMT)

Population A and Population B:
To assess the robustness of the primary analysis, the same analysis was conducted in the PPS
which was a subset of the FAS and consisted of subjects who were compliant with theprotocol. The analysis revealed consistent results with those in the FAS, in which
comparison of percent CFB at Weeks 12 and 16 in LDL-C showed statistically significant
differences from placebo in all bococizumab dose arms in both populations.
Additionally, the study showed that subjects receiving bococizumab 100 mg or 150 mg had
the high proportion of subjects obtaining LDL-C levels less than the specified limit values.
In Population A, including subjects whose fasting LDL-C was 100 mg/dL at screening,>90% of subjects receiving bococizumab 100 mg and 150 mg had LDL-C of <40 mg/dL
during the treatment period (91.7% and 95.8%, respectively), and approximately 60% of
subjects had LDL-C of <25 mg/dL (66.7% and 58.3%, respectively) during the treatment
period. In Population B, including subjects whose fasting LDL-C was 130 mg/dL atscreening, approximately 90% of subjects had LDL-C of <70 mg/dL (92.0% and 87.5%,
respectively), and approximately 40% of subjects had LDL-C of <40 mg/dL (36.0% and41.7%, respectively) during the treatment period.
Consistent with LDL-C lowering, other lipids (including, total cholesterol, ApoB, Lp(a), andnon-HDL-C) were also lowered in both populations. LDL-C particles were decreased acrossall estimated size categories (small LDL-C and large LDL-C) in both populations. In
Population A, there was a trend towards increases in HDL-C.
Pharmacokinetic Results:
Pharmacokinetic parameters for Days 1 and 99 are summarized descriptively in Table 18 andTable 19 for Populations A and B respectively.

Template version 1.7

Page 32

Public Disclosure Synopsis
Protocol B1481036 – 30 October 2017 – Final

Table 18. Summary of Plasma Bococizumab Pharmacokinetic Parameters Following
Single and Multiple SC Doses (Population A)

090177e18d079c7a\Approved\Approved On: 31-Oct-2017 02:32 (GMT)

Parameter (Units)aParameter Summary Statistics by Dose and Treatment
Atorvastatin +Atorvastatin +Atorvastatin +Bococizumab 50 mg
Bococizumab 100 mg
Bococizumab 150 mg

Day 1 (Single dose)
N
12
12
13
32.98 (57)52.33 (49)77.11 (43)
AUCtau (g•day/mL)
0.6595 (57)0.5233 (49)0.5139 (43)
AUCtau (dn) (g•day/mL/mg)
3.173 (61)5.074 (50)7.382 (45)Cmax (g/mL)
0.06344 (61)0.05074 (50)0.04921 (45)Cmax (dn) (g/mL/mg)
Tmax (Day)4.01 (3.00-5.96)
4.97 (3.94-7.00)
5.94 (1.94-7.00)
Day 99 (multiple dose)
N, n
10,10
8,7
8,8
63.54 (40)92.46 (127)242.5 (81)
AUCtau (g•day/mL)
1.270 (40)0.9246 (127)1.617 (81)
AUCtau (dn) (g•day/mL/mg)
87.86 (49)140.3 (145)434.2 (91)
AUClast (g•day/mL)
1.759 (49)1.403 (145)
2.892 (91)
AUClast (dn) (g•day/mL/mg)
94.83 (46)176.9 (144)469.5 (90)
AUCinf (g•day/mL)
6.197(36)
8.343
(119)
21.91 (76)Cmax (g/mL)
0.1239 (36)0.08343 (119)0.1461 (76)Cmax (dn) (g/mL/mg)
2.176 (65)4.041 (147)
12.95 (94)
Cmin (g/mL)
Tmax (day)3.03 (2.92-6.98)
2.98 (1.00-4.97)
2.97 (0.964-4.99)
t½ (day)
7.716±1.759
9.471±2.289
10.56±1.593
PTR
2.847 (42)2.063 (25)
1.692 (16)Rac
2.027 (47)1.889 (60)
3.176 (56)Rac, Cmax
2.057 (46)1.794 (64)2.998 (49)
CL/F (L/day)
0.7870 (40)1.082 (127)0.6184 (81)Vz/F (L)8.552 (48)
12.48 (107)9.330 (94)
AUCtau=area under the concentration-time profile from time 0 to time tau, the dosing interval, where tau=14 days;
AUClast=area under the concentration-time profile from time 0 to the time of the last quantifiable concentration (Clast);
AUCinf=area under the concentration-time profile from time 0 extrapolated to infinite time; %CV=percent coefficient ofvariation; Cmax=maximum plasma concentration; Cmin=lowest concentration observed during the dosing interval;
CL/F=apparent clearance; dn=dose normalized; PTR=peak-to-trough ratio; SC=subcutaneously; SD=standard deviation;
Tmax=time for Cmax; t½=terminal half-life; N=number of subjects in the treatment group and contributing to the mean; n=number of subjects where t½, AUCinf and Vz/F, were reported; Rac= observed accumulation ratio; Vz/F= volume of
distribution.
a. Geometric mean (geometric %CV) for all except: median (range) for Tmax; arithmetic mean  SD for t½.

Template version 1.7

Page 33

Public Disclosure Synopsis
Protocol B1481036 – 30 October 2017 – Final

Table 19. Summary of Plasma Bococizumab Pharmacokinetic Parameters Following
Single and Multiple SC Doses (Population B)

090177e18d079c7a\Approved\Approved On: 31-Oct-2017 02:32 (GMT)

Parameter (Units)aParameter Summary Statistics by Dose and Treatment
Bococizumab 50 mg
Bococizumab 100 mg
Bococizumab 150 mg

Day 1 (single dose)
N
11
12
12
32.97 (42)51.49 (46)82.05 (45)
AUCtau, (g•day/mL)
0.6595 (42)0.5149 (46)0.5472 (45)
AUCtau (dn) (g•day/mL/mg)
2.994 (44)4.744 (47)7.726 (42)Cmax (g/mL)
0.05983(44)0.04744(47)0.05156(42)
Cmax (dn) (g/mL/mg)
Tmax (day)5.94 (3.94-6.95)
5.45 (2.95-6.94)
6.94 (2.96-14.0)
Day 99 (multiple dose)
N, n
10,9
11, 1112,763.74 (57)
136.6 (32)273.5 (100)
AUCtau (g•day/mL)
1.275 (57)1.366 (32)1.822 (100)
AUCtau (dn) (g•day/mL/mg)
96.32 (65)220.9 (39)486.7 (143)
AUClast (g•day/mL)
1.927 (65)2.209 (39)3.246 (143)
AUClast (dn) (g•day/mL/mg)
111.7 (63)237.4 (41)248.4 (76)
AUCinf (g•day/mL)
5.874 (55)
12.22 (29)23.64 (88)Cmax (g/mL)
0.1174 (55)0.1222 (29)0.1575 (88)Cmax (dn) (g/mL/mg)
2.858 (64)6.571 (40)
13.47 (139)
Cmin (g/mL)
Tmax (day)2.99 (0.985-7.06)
2.98 (0.988-4.98)
4.98 (2.97-7.00)
t½ (day)
9.404±2.145
9.570±2.234
9.333±2.754
PTR
2.054 (32)1.858 (22)1.755 (35)Rac
1.920 (35)2.665 (46)3.330 (57)Rac, Cmax
1.961 (41)2.557 (44)3.057 (56)
CL/F (L/day)
0.7845 (57)0.7317 (32)0.5490 (100)Vz/F (L)9.866 (65)9.881 (39)12.77 (45)
AUCtau=area under the concentration-time profile from time 0 to time tau, the dosing interval, where tau=14 days;
AUClast=area under the concentration-time profile from time 0 to the time of the last quantifiable concentration (Clast);
AUCinf=area under the concentration-time profile from time 0 extrapolated to infinite time; Cmax=maximum plasma
concentration; Cmin=lowest concentration observed during the dosing interval; CL/F=apparent clearance; dn=dose
normalized; PTR=peak-to-trough ratio; %CV=percent coefficient of variation; Tmax=time for Cmax; t½=terminal half-life;
N=number of subjects in the treatment group and contributing to the mean; n=number of subjects where t½, AUCinf and
Vz/F, were reported; Rac=observed accumulation ratio; SC=subcutaneously; SD=standard deviation; Vz/F= volume of
distribution.
a. Geometric mean (geometric %CV) for all except: median (range) for Tmax; arithmetic meanSD for t½.

Single Dose Administration (Day 1)
Following a single SC administration of bococizumab at doses of 50 mg, 100 mg, and
150 mg to hypercholesterolemic subjects, absorption of bococizumab into the systemic
circulation was slow, with mean maximum plasma concentrations (Cmax) achieved within amedian Tmax of 4-7 days postdose for both Population A and Population B across all doselevels.
There were no apparent differences in the PK profiles between Population A andPopulation B following a single SC dose of bococizumab. Exposure based on geometricmean area under the concentration-time profile from time 0 to time tau, the dosing interval(AUCτ) and Cmax values increased in a slightly less than dose proportional manner across the50-150 mg doses. However, the dose related exposure was interpreted with caution sincelarge variability in bococizumab was observed across all dose groups and populations.

Template version 1.7

Page 34

Public Disclosure Synopsis
Protocol B1481036 – 30 October 2017 – Final

Multiple Dose Administration (Day 99)
Following multiple SC administration of bococizumab at doses of 50 mg, 100 mg, and
150 mg Q14D for a period of 16 weeks, mean Cmax was achieved within a median Tmax of
3-5 days postdose across all dose levels for both Population A and Population B. Following
the attainment of Cmax, plasma concentrations appeared to decline in a mono-phasic manner,with mean terminal t½ values ranging between 8-11 days.
Bococizumab PK profiles for Population A and Population B were generally similar acrossall doses following multiple SC administration. An upward trend was observed in
bococizumab exposure with an increase in dose with greater than dose proportional increases
for both mean AUCτ and Cmax values across the 50-150 mg dose range in both subject
populations. However, the dose related exposure should be interpreted with caution sincelarge variability in bococizumab was observed across all dose groups and populations.

090177e18d079c7a\Approved\Approved On: 31-Oct-2017 02:32 (GMT)

Exposure on Day 99 based on mean AUCτ and Cmax was higher compared to that observed on
Day 1. Mean accumulation ratios on Day 99 based on mean AUCτ (observed accumulation
ratio [Rac]) and Cmax (Rac, Cmax) values ranged between 1.9 -3.3 and 1.8-3.1 respectively, withthe higher values observed for the 150-mg dose indicating that there is some drug
accumulation following multiple dosing every 2 weeks at higher doses.
Apparent clearance (CL/F) and volume of distribution (Vz/F) geometric mean values on
Day 99 were generally similar between the 2 populations, with mean CL/F and Vz/F values
ranging between 0.549 -1.08 L/day and 8.6-12.8 L, respectively. The lower mean CL/F
values were observed for the higher dose 150 mg.
Based on median trough plasma bococizumab concentrations, steady state for the 50 mg and
100 mg doses appeared to have been reached by the third dose (Day 43) for both Population
A and Population B, however, for the 150 mg dose steady state did not appear to have beenreached by Day 113 (2 weeks after last dose on Day 99). However, due to the small sample
size and large variability, this data was interpreted with caution.
Total Plasma PCSK9The mean (SD) percent CFB in PCSK9 for Populations A and B, are shown in Figure 2.
Similar mean (SD) total plasma PCSK9 concentrations were seen at baseline across placebo
and bococizumab treatment groups with values ranging from 261.2 (72.4) to 286.0 (75.8)
ng/mL in Population A and from 210.2 (48.6) to 234.4 (77.5) ng/mL in Population B. At
Day 85, mean total plasma PCSK9 concentrations increased by 10- to 15-fold from baseline
in Population A and by 11- to 13-fold from baseline in Population B. In both Population A
and B, percent change in PCSK9 from baseline quickly reached steady state at Day 15 or
Day 22 for all dose groups as shown in Figure 2. Total PCSK9 on Day 141 remained close
to steady-state concentrations in the 150 mg dose group.

Template version 1.7

Page 35

Public Disclosure Synopsis
Protocol B1481036 – 30 October 2017 – Final

090177e18d079c7a\Approved\Approved On: 31-Oct-2017 02:32 (GMT)

Figure 2. Mean (SD) Percent Change from Baseline (%CFB) in Plasma PCSK9
Concentration-Time Profiles (Upper panel: Population A; Lower panel:
Population B)

CFB=change from baseline; PCSK= proprotein convertase subtilisin/kexin ; SD=standard deviation.

Safety Results:
Serious adverse events (SAEs): Treatment-emergent SAEs by system organ class (SOC) andpreferred term (PT) are summarized in Table 20.
Deaths: There were no deaths reported during the study.
Discontinuations due to AEs:

Template version 1.7

Page 36

Public Disclosure Synopsis
Protocol B1481036 – 30 October 2017 – Final

Permanent Discontinuations due to AEs:
Population A
In total, 2 subjects in the bococizumab dose arms discontinued study treatment due totreatment-emergent AEs. These events included gastrointestinal disorder in 1 subject in the
bococizumab 100 mg arm, and nausea and dizziness in 1 subject in the bococizumab 150 mg
arm. All these events were considered by the investigator to be related to the study drug.
These subjects continued and completed the study. No treatment-emergent AEs leading totreatment discontinuation were reported in the bococizumab 50 mg, placebo, and ezetimibe
arms.

090177e18d079c7a\Approved\Approved On: 31-Oct-2017 02:32 (GMT)

Population B
In total, 4 subjects in the bococizumab dose arms discontinued study treatment due totreatment-emergent AEs. These events included injection site erythema and myalgia in
1 subject each in the bococizumab 50 mg arm, and hepatic function abnormal and spinal
compression fracture in 1 subject each in the bococizumab 100 mg arm. All these eventswere considered by the investigator to be related to the study drug, except for spinal
compression fracture. No treatment-emergent AEs leading to treatment discontinuation werereported in the bococizumab 150 mg and placebo arms.
No treatment-emergent AEs which led to dose reductions or temporary discontinuation werereported in this study.

Template version 1.7

Page 37

Public Disclosure Synopsis
Protocol B1481036 – 30 October 2017 – Final

Table 20. Treatment-Emergent Serious Adverse Events by System Organ Class and Preferred Term (All Causalities)

090177e18d079c7a\Approved\Approved On: 31-Oct-2017 02:32 (GMT)

Number (%) of Subjects With
Adverse Events by:
System Organ Class and MedDRA(Version 17.1) Preferred Term

Bococizumab
50 mg
n (%)

Population A
Atorvastatin +Bococizumab
Bococizumab
100 mg
150 mgn (%)
n (%)

Placebon (%)
Number (%) of Subjects:
Evaluable for Adverse Events
25
24
24
26
With Adverse Events
1 (4.0)001 (3.8)
Cardiac disorders000
1 (3.8)
Angina pectoris
000
1 (3.8)Infections and infestations
1 (4.0)0
00Cellulitis
1 (4.0)000Injury, poisoning and procedural0000complications
Spinal compression fracture0000Subjects were only counted once per treatment for each row.
Includes data up to 9999 days after last dose of study drug.
Percentages of gender specific events were calculated using the corresponding gender count as denominator.
MedDRA (Version 17.1) coding dictionary applied.
MedDRA=Medical Dictionary for Regulatory Activities; n=number of subjects.

Template version 1.7

Page 38

Population B
Bococizumab
100 mg
150 mgPlacebo

Ezetimibe
10 mg
n (%)

50 mg
n (%)

n (%)

n (%)

n (%)

22
0
0
0
0
0
0

25
0
0
0
0
0
0

25
1 (4.0)0000
1 (4.0)

24
0
0
0
0
0
0

23
0
0
0
0
0
0

0

0

1 (4.0)00Public Disclosure Synopsis
Protocol B1481036 – 30 October 2017 – Final

090177e18d079c7a\Approved\Approved On: 31-Oct-2017 02:32 (GMT)

Adverse events (AEs): Treatment-emergent nonserious AEs by SOC and PT are summarizedin Table 21.

Template version 1.7

Page 39

Public Disclosure Synopsis
Protocol B1481036 – 30 October 2017 – Final

090177e18d079c7a\Approved\Approved On: 31-Oct-2017 02:32 (GMT)

Table 21. Treatment-Emergent Nonserious Adverse Events by System Organ Class and Preferred Term (All Causalities) in>5% of Subjects
Number (%) of Subjects With
Adverse Events by:
System Organ Class and
MedDRA (Version 17.1) Preferred
Term
Number (%) of Subjects:
Evaluable for Adverse Events
With Adverse Events
General disorders and administrationsite conditions
Injection site erythema
Injection site haemorrhage
Injection site pain
Injection site pruritus
Injection site swelling
Infections and infestations
Nasopharyngitis
Pharyngitis
Injury, poisoning and procedural
complications
Contusion
Fall
Investigations
Blood alkaline phosphataseincreased
Musculoskeletal and connective
tissue disorders
Back pain
Myalgia
Nervous system disorders
Dizziness
HeadacheReproductive system and breast
disordersEjaculation disorder
Respiratory, thoracic andmediastinal disorders

Template version 1.7

Bococizumab
50 mg
n (%)
25
10 (40.0)

Population A
Atorvastatin +Bococizumab Bococizumab
100 mg
150 mg
n (%)
n (%)
24
24
12 (50.0)
12 (50.0)

Placebo

50 mg

Population B
Bococizumab
100 mg
150 mgPlacebon (%)
26
10 (38.5)

Ezetimibe
10 mg
n (%)
22
2 (9.1)n (%)
25
11 (44.0)n (%)
25
11 (44.0)n (%)
24
11 (45.8)n (%)
23
9 (39.1)

2 (8.0)6 (25.0)

9 (37.5)

2 (7.7)0

5 (20.0)

7 (28.0)

7 (29.2)

1 (4.3)2 (8.0)002 (8.0)05 (20.0)
5 (20.0)
1 (4.0)1 (4.0)6 (25.0)0
1 (4.2)4 (16.7)
01 (4.2)
1 (4.2)0
1 (4.2)8 (33.3)
1 (4.2)0
7 (29.2)2 (8.3)2 (8.3)1 (4.2)
1 (4.2)00
2 (7.7)000
5 (19.2)
5 (19.2)01 (3.8)00
000
1 (4.5)1 (4.5)00

4 (16.0)
1 (4.0)0
4 (16.0)03 (12.0)
3 (12.0)00

7 (28.0)
1 (4.0)0
6 (24.0)04 (16.0)
4 (16.0)03 (12.0)

6 (25.0)03 (12.5)5 (20.8)
1 (4.2)7 (29.2)2 (8.3)5 (20.8)
01 (4.3)00
00
4 (17.4)
4 (17.4)
02 (8.7)0
1 (4.0)1 (4.0)1 (4.0)1 (4.2)
1 (4.2)
0
0

0
0
0
0

0
1 (3.8)
0
0

0
0
0
0

0
0
0
0

1 (4.0)3 (12.0)00002 (8.3)2 (8.3)2 (8.7)1 (4.3)00

1 (4.0)1 (4.2)0

3 (11.5)0

3 (12.0)

1 (4.0)0

1 (4.3)0
1 (4.0)1 (4.0)0
1 (4.0)001 (4.2)2 (8.3)0
2 (8.3)000
2 (8.3)2 (8.3)0
1 (8.3)2 (7.7)
1 (3.8)
0
0
0
0

0
0
0
0
0
0

0
3 (12.0)
1 (4.0)0
1 (4.0)0

1 (4.0)
0
0
0
0
0

0
0
1 (4.2)0
1 (4.2)00
1 (4.3)2 (8.7)02 (8.7)00
2 (8.0)0
3 (12.5)

1 (8.3)00
2 (7.7)

0
0

0
0

0
0

0
0

0
0

Page 40

Public Disclosure Synopsis
Protocol B1481036 – 30 October 2017 – Final

090177e18d079c7a\Approved\Approved On: 31-Oct-2017 02:32 (GMT)

Table 21. Treatment-Emergent Nonserious Adverse Events by System Organ Class and Preferred Term (All Causalities) in>5% of Subjects
Number (%) of Subjects With
Population A
Adverse Events by:
Atorvastatin +System Organ Class andBococizumab
Bococizumab Bococizumab
Placebo
MedDRA (Version 17.1) Preferred
50 mg
100 mg
150 mg
Term
n (%)
n (%)
n (%)
n (%)
Upper respiratory tract
2 (8.0)3 (12.5)
02 (7.7)inflammation
Skin and subcutaneous tissue
1 (4.0)2 (8.3)00disordersEczema1 (4.0)000Pruritus
02 (8.3)00Subjects were only counted once per treatment for each row.
Includes data up to 9999 days after last dose of study drug.
Percentages of gender specific events were calculated using the corresponding gender count as denominator.
MedDRA (Version 17.1) coding dictionary applied.
MedDRA=Medical Dictionary for Regulatory Activities; n=number of subjects.

Template version 1.7

Page 41

Population B
Bococizumab
100 mg
150 mgPlacebo

Ezetimibe
10 mg
n (%)
0

50 mg
n (%)
0

n (%)
0

n (%)
0

n (%)
0

1 (4.5)

3 (12.0)00

1 (4.3)1 (4.5)0

3 (12.0)
1 (4.0)0000

1 (4.3)0

Public Disclosure Synopsis
Protocol B1481036 – 30 October 2017 – Final

Adverse Events by Treatment Relationship:
Population A:

090177e18d079c7a\Approved\Approved On: 31-Oct-2017 02:32 (GMT)

Treatment-emergent treatment-related AEs (number [%] of subjects) observed in5% subjects in any bococizumab dose arm by PT are presented in Table 22. These eventswere not reported in the placebo and ezetimibe arms.


Injection site erythema: bococizumab 50 mg, 2 (8.0%); 100 mg, 6 (25.0%); 150 mg,
8 (33.3%);

Injection site pruritus: bococizumab 50 mg, 2 (8.0%); 100 mg, 4 (16.7%); 150 mg,
7 (29.2%);

Injection site swelling: bococizumab 50 mg, 0; 100 mg, 0; 150 mg, 2 (8.3%);

Pruritus: bococizumab 50 mg, 0; 100 mg, 2 (8.3%); 150 mg, 0.

The dose-response relationship was observed in the incidence of injection site erythema andinjection site pruritus increased with increasing the dose of bococizumab. Injection site
swelling occurred only in the highest dose (150 mg) arm.

Template version 1.7

Page 42

Public Disclosure Synopsis
Protocol B1481036 – 30 October 2017 – Final

Table 22. Treatment-Emergent Adverse Events (Treatment-Related per Investigator
Causality Assessment) (Population A) – Safety Analysis Set

090177e18d079c7a\Approved\Approved On: 31-Oct-2017 02:32 (GMT)

System Organ Class
Preferred Term
(MedDRA Version 17.1)

PlaceboNumber (%) of Subjects
Atorvastatin +Bococizumab
50 mg
100 mg
150 mg(N=25)(N=24)(N=24)
4 (16.0)
7 (29.2)
9 (37.5)
00
1 (4.2)00
1 (4.2)0
1 (4.2)
1 (4.2)0
1 (4.2)000
1 (4.2)Ezetimibe
10 mg(N=22)000000(N=26)Total
3 (11.5)
Cardiac disorders
0
Ventricular extrasystoles
0
Gastrointestinal disorders
0
Gastrointestinal disorder0
Nausea0
General disorders and administration site
3 (11.5)
3 (12.0)
6 (25.0)
9 (37.5)0conditions
Asthenia0
1 (4.0)000Injection site discolouration
1 (3.8)0000Injection site erythema0
2 (8.0)6 (25.0)
8 (33.3)
0Injection site haemorrhage
1 (3.8)00
1 (4.2)0Injection site hypersensitivity
1 (3.8)0000Injection site pain00
1 (4.2)00Injection site pruritus
02 (8.0)4 (16.7)
7 (29.2)
0Injection site swelling000
2 (8.3)0Investigations
0
1 (4.0)000White blood cell count decreased0
1 (4.0)0
0
0
Nervous system disorders000
1 (4.2)0
Dizziness
000
1 (4.2)0
Skin and subcutaneous tissue disorders00
3 (12.5)00Pruritus
00
2 (8.3)
0
0
Rash
0
0
1 (4.2)00
Urticaria
00
1 (4.2)00Serious adverse events and nonserious adverse event results were not separated out.
Subjects were only counted once per treatment for each row.
MedDRA=Medical Dictionary for Regulatory Activities; N=number of subjects evaluable for adverse events.

Population B:
Treatment-emergent treatment-related AEs (number [%] of subjects) observed in5% subjects in any bococizumab dose arm by PT are presented in Table 23 and are as
follows:

Injection site erythema: bococizumab 50 mg, 4 (16.0%); 100 mg, 7 (28.0%); 150 mg,
6 (25.0%); placebo, 1 (4.3%);

Injection site pruritus: bococizumab 50 mg, 4 (16.0%); 100 mg, 6 (24.0%); 150 mg,
5 (20.8%); placebo, 0;Injection site pain: bococizumab 50 mg, 0; 100 mg, 0; 150 mg, 3 (12.5%); placebo, 0.

Template version 1.7

Page 43

Public Disclosure Synopsis
Protocol B1481036 – 30 October 2017 – Final

The incidence of injection site erythema was higher in the bococizumab dose arms comparedwith the placebo arm. All events of injection site pruritus were reported in the
3 bococizumab dose arms. Injection site pain occurred only in the highest dose (150 mg)
arm.
Table 23. Treatment-Emergent Adverse Events (Treatment-Related per Investigator
Causality Assessment) (Population B) – Safety Analysis Set
System Organ Class
Preferred term
(MedDRA Version. 17.1)

Placebo

090177e18d079c7a\Approved\Approved On: 31-Oct-2017 02:32 (GMT)(N=23)
3 (13.0)
1 (4.3)1 (4.3)

Number (%) of Subjects
Bococizumab
50 mg
100 mg(N=25)(N=25)
7 (28.0)
10 (40.0)0000150 mg(N=24)
7 (29.2)
00

Total
Gastrointestinal disorders
Abdominal pain
General disorders and administration site
2 (8.7)5 (20.0)
9 (36.0)
7 (29.2)
conditions
Feeling hot
0
1 (4.0)00Injection site bruising
1 (4.3)0
1 (4.0)0Injection site eczema
0
1 (4.0)00Injection site erythema
1 (4.3)4 (16.0)
7 (28.0)
6 (25.0)
Injection site haemorrhage
0
1 (4.0)1 (4.0)0Injection site induration
00
1 (4.0)0Injection site nodule00
1 (4.0)0Injection site pain000
3 (12.5)
Injection site pruritus0
4 (16.0)
6 (24.0)
5 (20.8)
Injection site swelling000
1 (4.2)
Injection site warmth0001 (4.2)
Hepatobiliary disorders00
1 (4.0)0
Hepatic function abnormal
00
1 (4.0)0Metabolism and nutrition disorders0
1 (4.0)00Hyperuricaemia
01 (4.0)0
0Musculoskeletal and connective tissue0
1 (4.0)00disorders
Myalgia0
1 (4.0)
0
0
Nervous system disorders
1 (4.3)0
0
0
Headache
1 (4.3)000Skin and subcutaneous tissue disorders
1 (4.3)1 (4.0)00Eczema1 (4.3)1 (4.0)00Pruritus
0
1 (4.0)00Serious adverse events and nonserious adverse event results were not separated out.
Subjects were only counted once per treatment for each row.
MedDRA=Medical Dictionary for Regulatory Activities; N=number of subjects evaluable for adverse events.

Anti-drug Antibody
Incidence:
Incidence of positive ADA and positive neutralizing antibody (nAb) are summarized in Table
24. Of 147 subjects who received bococizumab treatment, 74 (50.3%) subjects were ADA
positive. A dose dependent relationship was not observed for ADA incidence and there wasno difference in ADA incidence between Populations A and B. Due to interference by
Template version 1.7

Page 44

Public Disclosure Synopsis
Protocol B1481036 – 30 October 2017 – Final

bococizumab concentration and/or PCSK9, nAb was assayed for only 55 of 74 ADA positive
subjects. Thirty-five (35) of the 55 ADA positive subjects (63.6%) tested in the nAb assay
showed positive nAb titers, resulting in an overall nAb incidence of 23.8% (out of 147
bococizumab treated subjects). The nAb incidence across the 3 dose groups ranged from
8.3% to 34.0% when Populations A and B data were combined. However since samples
from 19 ADA positive subjects were not tested in the nAb assay, the true incidence of
positive nAb may be underestimated.
Table 24. Immunogenicity Incidence Following Q14D SC PF-04950615
AdministrationaBococizumabN
ADA PositivenAb Positive
N
b
Dose
n (%)
n (% )
50 mg
25
14 (56.0)
14
8 (32.0)
Population A
Uncontrolled by a
100 mg24
6 (25.0)43 (12.5)
stable dose of
150 mg24
14 (58.3)
83 (12.5)
atorvastatin
All Doses
73
34 (46.6)
26
14 (19.2)50 mg
25
13 (52.0)129 (36.0)
Population B
Treatment naïve
100 mg25
16 (64.0)
13
11 (44.0)
150 mg24
11 (45.8)
4
1 (4.2)All Doses74
40 (54.1)
29
21 (28.4)50 mg
5027 (54.0)
26
17 (34.0)
Population A + B
100 mg49
22 (44.9)
17
14 (28.6)
150 mg48
25 (52.1)
12
4 (8.3)All Doses
147
74 (50.3)
55
35 (23.8)
Overall
ADA Negative: Titer < 6.23; ADA Positive: Titer 6.23.
ADA=anti-drug antibody; nAb=neutralizing antibody; Q14D=once every 14 days; SC=subcutaneous.
a. Number of ADA positive subject data tested in the nAb assay.
b. Percent nAb positive subjects calculated using total N in each treatment arm.
c. Percent nAb positive subjects calculated as % of ADA positive subjects tested in the nAb assay.

090177e18d079c7a\Approved\Approved On: 31-Oct-2017 02:32 (GMT)

PopulationnAb Positivecn/N (% )8/14 (57.1)
3/4 (75.0)
3/8 (37.5)
14/26 (53.8)
9/12 (75.0)
11/13 (84.6)
1/4 (25.0)
21/29 (72.4)
17/26 (65.4)
14/17 (82.3)
4/12 (33.3)
35/55 (63.6)

CONCLUSIONS:
Primary Objective:

Bococizumab administered SC Q14D to hypercholesterolemic subjects on backgroundtreatment with a stable dose of atorvastatin resulted in a statistically significant reductionin LDL-C (Weeks 12 and 16) at all 3 doses tested compared to placebo. A clear dose
response was observed at Weeks 12 and 16.

Bococizumab administered SC Q14D to hypercholesterolemic subjects who were naïve
for a treatment by lipid lowering drug resulted in a statistically significant reduction in
LDL-C (Weeks 12 and 16) at all 3 doses tested compared to placebo.

Secondary Objectives:

The decreases in serum levels of other lipids (including total cholesterol, ApoB, Lp(a),and non-HDL-C) in subjects who received bococizumab were generally consistent withthe effect of LDL-C lowering.



There were no apparent differences in the PK profiles between Population A andPopulation B following single and multiple SC doses of bococizumab. Exposure based

Template version 1.7

Page 45

Public Disclosure Synopsis
Protocol B1481036 – 30 October 2017 – Final

090177e18d079c7a\Approved\Approved On: 31-Oct-2017 02:32 (GMT)on geometric mean AUC and Cmax values appeared to increase in a slightly less thandose proportional manner across the 50 mg -150 mg doses following a single SC dose on
Day 1 and they appeared to increase in a greater than dose proportional manner following
multiple SC doses on Day 99. However, the dose related exposure should be interpretedwith caution since large variability in bococizumab was observed across all dose groups
and populations. Mean terminal t½ values ranged between 8-11 days. Apparent steadystate was achieved by Day 43 for the 50 and 100 mg dose groups, however, apparent
steady state was not observed for the 150 mg dose group in both populations even by
Day 113.


Similar total plasma PCSK9 concentrations were seen at baseline across placebo andbococizumab treatment groups in Population A and B, respectively. Percent change in
PCSK9 from baseline quickly reached steady state at Day 15 or Day 22 for all dosegroups, and the increase in mean total plasma PCSK9 concentrations from baseline
ranged from 10- to 15-fold in Population A and 11- to 13-fold in Population B.

SC Q14D administration of bococizumab at a dose of up to 150 mg in
hypercholesterolemic subjects was generally well-tolerated at each dose in both
populations.



Of 147 subjects who received bococizumab treatment, 74 subjects were ADA positive.
There was no apparent dose dependent relationship for ADA incidence and no differencein ADA incidence between the 2 populations.

Template version 1.7

Page 46