Public Disclosure Synopsis
Protocol B3461010 – 21 April 2015 – Final

PFIZER INC.
These results are supplied for informational purposes only.
Prescribing decisions should be made based on the approved package insert.
PROPRIETARY DRUG NAME®/GENERIC DRUG NAME: Vyndaqel® / Tafamidis
meglumine
PROTOCOL NO.: B3461010
PROTOCOL TITLE: The Effect on Transthyretin Stabilization, Safety, Tolerability,
Efficacy and Pharmacokinetics of Orally Administered Tafamidis in Transthyretin Amyloid
Polyneuropathy Patients With V30M or Non-V30M Transthyretin: a Phase III, Open-Label
Study
Study Center(s): 2 centers in Japan

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Study Initiation and Final Completion Dates: 28 November 2011 to 26 February 2014
Phase of Development: Phase 3
Study Objective(s): The objective of this study was to determine transthyretin (TTR)
stabilization as well as tafamidis safety and tolerability, efficacy and pharmacokinetics inpatients with V30MNote a and non-V30M transthyretin familial amyloid polyneuropathy(TTR-FAP).
Primary Objective
To determine TTR stabilization at steady-state, as measured in patients with V30M and nonV30M TTR-FAP.
Secondary Objectives
To evaluate the safety, tolerability and efficacy of tafamidis in patients with V30M and
non-V30M TTR-FAP.



To characterize tafamidis pharmacokinetics using a population pharmacokinetic approachin patients with V30M and non-V30M TTR-FAP.

Note a: The most common variant associated with polyneuropathy is V30M (valine replaced by methionine atposition 30).

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Public Disclosure Synopsis
Protocol B3461010 – 21 April 2015 – Final

METHODS
Study Design: This was a single-arm, open-label, multicenter study designed to determine
TTR stabilization as well as tafamidis safety and tolerability, efficacy and population
pharmacokinetics in patients with V30M and non-V30M TTR-FAP.

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The duration was to continue to be until available from market (up to 3 years). Clinical visits
for assessment of TTR stabilization, safety, tolerability, efficacy and tafamidis concentration
were scheduled at screening (Days −30 and −1), baseline (Day 0) and at Week 2, Week 4,
Week 8, Week 12, Week 26, Week 39, Week 52, Week 78 and then 26-week interval visit
and the end of study. The study flowchart is presented in Table 1.

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Study Flowchart

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Informed consent
Medical history/demographics
Review of entrance criteria
Registration
Biopsy to confirm amyloid a
Confirmation of V30M or non-V30M genotype
QST for vibration perception in the feet utilizing
CASE IV
Physical examination
Abbreviated physical examination
Body height
Body weight
Vital signs
Blood sample for TTR stabilization assay
Blood sample for pharmacokinetic analysis
Laboratory tests (hematology, coagulation panel,
serum chemistry, and urinalysis)
Serology (HbsAg, anti-HCV, HIV)
Serum pregnancy test (females of child-bearing
potential only)
Urine pregnancy test (females of child-bearing
potential only)
Serum follicle-stimulating hormone e
12-Lead ECG
Echocardiography
NIS h
QST (CASE IV), HRDB, NCS
Norfolk QOL-DN
Ambulatory status
Concomitant medications j
Study medication compliance j
AEs j

Allowable window

Table 1.

Public Disclosure Synopsis
Protocol B3461010 – 21 April 2015 – Final

X

X
X

X
X

X

X
X
X

X

Day -30 toDay -1
X
X
X
X
X
X
X

Screening

X
Xf
Xf
Xf
Xf
Xf
X

X

X

X
X
X

X
X

Baseline
Day 0

X
X

Xc
X

Xc

Page 3

X
X

X

X

X

X

±2
days

4 Wk

X

X

±2
days

2 Wk

X
X

X

X

X
X
Xb
Xc
X

X

±7
days

8 Wk

X
X

X

X

X

X

X

±7
days

12 Wk

X

X
X

X
X
X
X
X
X

X

X

X

X

±14
days

X

X

X
X
Xb
Xd
X

X

±14
days

Treatment phase
26 Wk 39 Wk

X
X
X
X
X
X
X
X

X

X
X
Xb
Xb
X

X

±14
days

52 Wk

X
X
X
X
X
X

X

X

X
X
Xb
Xb
X

X

±14
days

78 Wk

X
X

X
Xg

X

X

X

X

26 Wk
interval
±14
days

X
X
Xi
Xi
Xi
Xi
X
X

X

X
X
Xk
Xk
X

X

End of
study
±14
days

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Study Flowchart

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Wk = week; QST = quantitative sensory testing; CASE IV = Computer Aided Sensory Evaluator, Version 4; TTR = transthyretin; HbsAg = hepatitis B surface antigen;
HCV = hepatitis C virus; HIV = human immunodeficiency virus; ECG = electrocardiogram; NIS = Neuropathy Impairment Score; HRDB = heart rate response to deep breathing;
NCS = nerve conduction studies; Norfolk QOL-DN = Norfolk QOL-Diabetic Neuropathy; AE = adverse eventa. Biopsy had to be performed within 5 years of enrollment. If greater than 5 years, biopsy was repeated at the investigative site.
b. Sampling 3 hours after dosing tafamidisc. 2 sampling point for each visit; first sample was as soon as when subject arrived at the site prior to tafamidis administration and the second sampling time was at 3 hour afteradministration of tafamidis.
d. Sampling prior to administration of tafamidis, 3 hours after, 4 hours after, 6 hours after and 10 hours after administration of tafamidis
e. Performed only at 45-60 year old females who had been amenorrhea for at least 2 years.
f. Baseline evaluations could have been performed during the screening period only in cases where scheduling did not permit the examinations at baseline.
g. Performed every 52 weeks after Week 52.
h. NIS testing was performed 2 times at least 24 hours apart within a 1-week period by the same neurologist before and/or at the baseline visit. Both evaluations were completed
prior to study medication administration at baseline visit.
i. For study completion or withdrawal after Week 26, these tests were not needed if last test was performed within 12 weeks of study completion or withdrawal or if study
completion or withdrawal occurred after Week 78.
j. After Week 12, every 6 weeks telephone contact (did not exceed 7 weeks since last confirmation) was conducted to monitor for AEs, study medication compliance andconcomitant medications. Reporting period of serious AE (SAE) was from obtaining the informed consent to 28 calendar days after the last administration. Should an
investigator be made aware of any SAE occurring any time after the active reporting period, it was required to be promptly reported.
k. Not performed for study completion or withdrawal after Week 78.

Table 1.

Public Disclosure Synopsis
Protocol B3461010 – 21 April 2015 – Final

Public Disclosure Synopsis
Protocol B3461010 – 21 April 2015 – Final

Number of Subjects (Planned and Analyzed): 10 subjects (planned and analyzed)
Diagnosis and Main Criteria for Inclusion: Subjects were male and female aged ≥20
through 75 years who had amyloid documented by biopsy and V30M or a TTR mutation
associated with peripheral neuropathy. Subjects had peripheral and/or autonomic neuropathy
with a Karnofsky Performance Status ≥50.
Study Treatment: All enrolled subjects were to receive oral tafamidis 20 mg soft gelatin
capsules once daily until available from market (up to 3 years). Study medication was to betaken at the same time each day throughout the treatment period.
Efficacy Endpoints: The primary endpoint was TTR stabilization at Week 8 compared withbaseline, as measured by a validated immunoturbidimetric assay.
The secondary endpoints included the following:

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

Change from baseline on the following scales:

Neuropathy Impairment Score (NIS) (total), Neuropathy Impairment Score-Lower
Limb (NIS-LL) and Neuropathy Impairment Score-Upper Limb (NIS-UL) Score

Total quality of life (TQOL) score and five domains as measured by the Norfolk
QOL-Diabetic Neuropathy (Norfolk QOL-DN)



Summated 7 Nerve Tests Normal Deviate Score (Σ7 NTs NDS) as measured by nerve
conduction studies (NCS), vibration detection threshold (VDT) and heart rate
response to deep breathing (HRDB)

Summated 3 Nerve Tests Small Fiber Normal Deviate Score (Σ3 NTSF NDS) as
measured by cooling and heat pain thresholds utilizing Computer Aided Sensory
Evaluator, Version 4 (CASE IV) and HRDBModified body mass index (mBMI), calculated by multiplying the body mass index(BMI) (kg/m2) by serum albumin level (g/L)

Ambulatory status (according to walking ability scale in polyneuropathy disability
score)

TTR stabilization at each follow-up visit after Week 8

Pharmacokinetic Evaluations: Blood samples for determination of plasma levels oftafamidis were collected at Week 2, Week 4, Week 8, Week 26, Week 52, Week 78 andstudy completion or withdrawal before Week 78. Each 5 mL whole blood sample wascollected into potassium edetic acid tubes. At least 1.5 mL plasma was collected from eachsample. Plasma was stored in polypropylene tubes at –70ºC until shipment to the analyticallab.

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Public Disclosure Synopsis
Protocol B3461010 – 21 April 2015 – Final

Safety Evaluations: Safety assessments to be performed during the study included physicalexaminations; measurement of vital signs; clinical laboratory evaluations, including
hematology, coagulation panel, and serum chemistry, electrocardiogram (ECG),
echocardiography and monitoring of adverse events (AEs).
Statistical Methods:
Efficacy
The full analysis set (FAS) included all subjects who received at least one dose of tafamidis.
All efficacy analyses were performed on the FAS.
The pharmacodynamic analysis set included all subjects treated who had at least 1 of TTR
stabilization assessment in treatment period. The TTR stabilization analyses were performedon the pharmacodynamic analysis set.

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Efficacy analyses were performed in a descriptive manner. The number and percentage of
responders and its 95% confidence interval (CI) were calculated for TTR stabilization (ie, thepercent stabilization was equal to or more than 32%) and for NIS-LL (ie, an increase frombaseline in the NIS-LL <2).
Pharmacokinetics
The pharmacokinetic analysis set included all subjects randomized and treated who had atleast 1 quantifiable plasma tafamidis concentration.
The pharmacokinetic parameters for tafamidis were obtained using population
pharmacokinetic approach. The analysis plan was prepared separately as population
pharmacokinetic modeling analysis plan.
SafetyThe safety analysis set included all subjects who received at least one dose of tafamidis soft
gelatin capsule 20 mg.
Safety analyses were performed in a descriptive manner in accordance with Pfizer Data
Standards (PDS).
RESULTS
Subject Disposition and Demography: A total of 10 subjects were enrolled (assigned totreatment) in the study. Of these subjects, 7 completed study treatment and 3 discontinued
from the study. All subjects were analyzed for pharmacokinetics, pharmacodynamics,
efficacy, and safety (Table 2).

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Public Disclosure Synopsis
Protocol B3461010 – 21 April 2015 – Final

Table 2.

Subject Disposition and Data Sets Analyzed

Number of Subjects
Assigned to study treatment
TreatedCompleted
Discontinued
Death
Other (unable to visit the site due to disease progression)
Data Sets Analyzed
Pharmacokinetic analysis set
Pharmacodynamic analysis set
Full analysis set
Safety analysis set

Tafamidis 20 mg
10
10
7
3
2
1
10
10
10
10
10

Demographic and baseline characteristics are presented in Table 3.
Table 3.

Demographic and Baseline Characteristics

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Number of Subjects

Tafamidis 20 mg
N=10

Sex
Male
FemaleAge (years)
<20
20-44
45-64
65
Mean (SD)
Range
Weight (kg)
Mean (SD)
Range
BMI (kg/m2)
Mean (SD)
Range
Height (cm)Mean (SD)Range
TTR genotype, n (%)
S77Y
V30M
BMI = Body mass index; SD = standard deviation

7
3
0
1
5
4
60.1 (13.0)
35-73
55.6 (10.8)
42.2-73.3
20.9 (3.1)
18.2-26.3
162.5 (6.3)
152.4-170.0
1 (10.0)9 (90.0)

Efficacy Results: The percentage of subjects achieving TTR stabilization is summarized inTable 4. All subjects achieved TTR stabilization (the percent stabilization was equal to or
more than 32%) at Week 8 and Week 26, and 9 of 10 subjects (90.0%) at Week 52 and 8 of
10 subjects (80.0%) at Week 78 achieved TTR stabilization.

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Public Disclosure Synopsis
Protocol B3461010 – 21 April 2015 – Final

Table 4.

TTR Stabilization Status
Tafamidis 20 mg
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Week 8
Stabilizeda/number of evaluable subjects
10/10
Percent stabilized (95% CI)
100.0% (69.2, 100.0)
Week 26
Stabilizeda/number of evaluable subjects
10/10
Percent stabilized (95% CI)
100.0% (69.2, 100.0)
Week 52
Stabilizeda/number of evaluable subjects
9/10
Percent stabilized (95% CI)
90.0% (55.5, 99.7)
Week 78
Stabilizeda/number of evaluable subjects
8/10
Percent stabilized (95% CI)
80.0% (44.4, 97.5)
CI = confidence interval; TTR = transthyretin
Missing data in TTR stabilization were dealt as non-TTR stabilization. Two subjects had missing
data at Week 78 (Table 5).
a. The percent stabilization is equal to or more than 32%.

Changes from baseline in NIS, NIS-LL, and NIS-UL scores are summarized in Table 5.
Higher scores on each item of NIS indicate worse impairment. Thus, increases from baselinereflect a worsening in impairment.

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Sex

Age

Genotype

BL

Change From Baseline in NIS, NIS-LL, and NIS-UL Scores

Page 9NIS Total
NIS-LLNIS-UL
Change from BL
BL
Change from BL
BL
Change from BL
W 26
W 52
W 78
W 26
W 52
W 78
W 26 W 52 W 78
1
M
73
V30M
1.0
0.0
0.0
0.0
0.0
0.0
0.0
1.0
1.0
0.0
0.0
−1.0
2
F
46
V30M
18.0
−0.6
0.5
ND
14.8
0.7
0.8
ND
3.3
−1.3
−0.3
ND
3
F
35
V30M
3.5
0.0
−1.0
−0.3
3.5
−1.3
−1.0
−0.3
0.0
1.3
0.0
0.0
4
M
48
V30M
15.8
1.8
0.0
2.5
11.3
0.8
1.8
1.8
4.5
1.0
−1.8
0.8
5
F
69
V30M
50.9
0.3
13.3
22.6
30.3
−1.1
1.7
3.2
20.6
1.4
11.6
19.4
6
M
63
V30M
0.5
1.5
15.0
7.0
0.5
1.0
6.0
4.0
0.0
0.5
9.0
3.0
7
M
60
S77Y
39.1
29.3
22.5
35.4
19.0
16.3
10.4
14.5
20.1
13.0
12.1
20.9
8
M
71
V30M
63.7
9.3
15.7
ND
28.4
6.4
10.6
ND
35.3
2.9
5.1
ND
9
M
73
V30M
67.0
−3.3
6.0
7.5
36.8
−3.3
−0.3
0.3
30.3
0.0
6.3
7.3
10
M
63
V30M
50.8
5.4
11.0
4.5
25.5
1.1
6.3
2.0
25.3
4.3
4.8
2.5
Mean
31.03
4.37
8.30
9.90
16.99
2.06
3.62
3.30
14.03
2.31
4.68
6.59
(SD)
(26.260)(9.408) (8.326) (12.584)(13.143)(5.565) (4.374) (4.739)(13.716)(4.066) (5.103) (8.724)
BL = baseline; NIS = Neuropathy Impairment Score; NIS-LL = Neuropathy Impairment Score-Lower Limb; NIS-UL = Neuropathy Impairment Score-Upper Limb; SD = standard
deviation; ND = not done
Two subjects had missing data at Week 78. One subject discontinued due to death on Day 431, and the other subject could not visit the site at Week 78 due to disease progression.

NumberTable 5.

Public Disclosure Synopsis
Protocol B3461010 – 21 April 2015 – Final

Public Disclosure Synopsis
Protocol B3461010 – 21 April 2015 – Final

Changes from baseline in TQOL and each domain are summarized in Table 6 and Table 7,
respectively. Higher scores on each item of the Norfolk QOL-DN TQOL indicate worse
QOL. Thus, increases from baseline reflect a worsening in QOL.
Table 6.

Change From Baseline in TQOL by Norfolk QOL-DN

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Tafamidis 20 mg
N=101052.9 (32.76)
54.5
4, 105Baseline, nMean (SD)MedianRange
Change from baseline
Week 26, n
10
Mean (SD)11.8 (20.01)
Median5.5
Range−6, 54
Week 52, n
10
Mean (SD)
9.1 (12.49)
Median10.0
Range−14, 26
Week 78, n
8Mean (SD)
10.8 (13.69)
Median12.5
Range−7, 34
SD = standard deviation; Norfolk QOL-DN = Norfolk QOL-Diabetic Neuropathy; TQOL = total quality of life

Table 7.

Change From Baseline in Each Domain by Norfolk QOL-DN

Physical functioning/large fiber
10
25.6 (15.28)
24.5
3, 48

Tafamidis 20 mg
N=10Activities ofSymptoms
daily living
1010
8.5 (7.63)
8.5 (5.34)
7.5
8.5
0, 20
0, 18

Small fiber

Autonomic

Baseline, n
10
Mean (SD)
6.3 (5.31)
Median
5.5
Range
0, 13
Change from baseline
Week 26, n
10
10
10
10
Mean (SD)
4.8 (10.02)
1.2 (3.61)
2.6 (3.47)
1.9 (4.25)
Median
0.0
0.5
3.0
0.5
Range
−5, 27−5, 8−2, 7−2, 11
Week 52, n
10
10
10
10
Mean (SD)
2.2 (8.87)
0.8 (3.52)
4.0 (5.73)
1.6 (2.32)
Median
3.5
1.0
4.0
0.5
Range
−12, 16−7, 5−3, 16−1, 6
Week 78, n
88
8
8Mean (SD)
4.1 (7.83)
0.6 (2.33)
3.1 (3.94)
2.1 (3.76)
Median
4.0
0.5
3.0
0.5
Range
−6, 18−4, 4−2, 10−3, 8
SD = standard deviation; Norfolk QOL-DN = Norfolk QOL-Diabetic Neuropathy

10
4.0 (3.06)
4.0
0, 9

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1.3 (1.42)
1.0
0, 4
10
0.5 (1.43)
0.0
−1, 3
8
0.8 (1.91)
0.5
−2, 4

Public Disclosure Synopsis
Protocol B3461010 – 21 April 2015 – Final

Changes from baseline in Σ7 NTs NDS and Σ3 NTSF NDS are summarized in Table 8. A
higher score indicates worse nerve function. Thus, increases from baseline reflect aworsening in nerve function.
Table 8.

Change From Baseline in Σ7 NTs NDS and Σ3 NTSF NDS

090177e18662d55f\Approved\Approved On: 29-Apr-2015 01:23

Tafamidis 20 mg
N=10Σ7 NTs NDS
Σ3 NTSF NDS
Baseline, n
10
10
Mean (SD)8.33 (5.574)
6.39 (3.160)
Median
8.02
5.75
Range
−0.6, 16.6
1.4, 11.2
Change from baseline
Week 26, n
10
10Mean (SD)0.55 (2.657)
0.16 (1.619)
Median
1.10
0.31
Range
−6.3, 3.3
−3.4, 2.2
Week 52, n
10
10Mean (SD)1.04 (2.992)−0.13 (1.334)
Median
1.26
−0.04
Range
−4.8, 5.0
−2.0, 2.6
Week 78, n
8
8Mean (SD)1.92 (5.129)
0.40 (1.985)
Median
0.56
−0.33
Range
−3.1, 12.8
−1.6, 4.4
SD = standard deviation; Σ7 NTs NDS = Summated 7 Nerve Tests Normal Deviate Score;Σ3 NTSF NDS = Summated 3 Nerve Tests Small Fiber Normal Deviate Score

Changes from baseline in mBMI are summarized in Table 9. Decreases from baseline reflect
a worsening.

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Protocol B3461010 – 21 April 2015 – Final

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Table 9.

Change From Baseline in mBMI

Baseline, nMean (SD)MedianRange
Change from baseline
Week 8, n
Mean (SD)MedianRange
Week 26, n
Mean (SD)MedianRange
Week 52, n
Mean (SD)MedianRange
End of study, nMean (SD)MedianRange
SD = standard deviation; mBMI = modified body mass index

Tafamidis 20 mg
N=1010805.70 (193.378)
728.60577.3, 1095.0
1074.86 (88.706)
79.98−92.0, 182.7
1026.61 (61.862)
33.47−77.1, 148.8
1064.86 (80.016)
61.80−82.3, 207.8
753.65 (81.386)
82.77−97.5, 150.1

The shift from baseline in ambulatory status is summarized in Table 10. The ambulatory
status at Week 26 improved in 1 subject, worsened in 2 subjects, and was unchanged in 7
subjects, at Week 52 improved in 1 subject, worsened in 3 subjects, and was unchanged in 6
subjects, and at Week 78 improved in 1 subject, worsened in 4 subjects, and was unchangedin 3 subjects.

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Public Disclosure Synopsis
Protocol B3461010 – 21 April 2015 – Final

Table 10. Shift From Baseline in Ambulatory Status
Visitn
Week 26

Week 52090177e18662d55f\Approved\Approved On: 29-Apr-2015 01:23

Week 7810108Baselinestatus
0
1
2
3a
3b
4
0
1
2
3a
3b
4
0
1
2
3a
3b
4

0

Tafamidis 20 mg (N=10)
Ambulatory status
1
2
3a

1

3b

4

2
3

1

1

1

1
3

1
2

1
1

1
1

1
1

1
1

1
1
2

0: Good
1: Sensory disturbances in the feet but able to walk without difficulty
2: Some difficulties with walking but can walk without aid
3a: Able to walk with 1 stick or crutch
3b: Able to walk with 2 sticks or crutches
4: Not ambulatory, confined to a wheelchair or bedridden

Pharmacokinetic and Pharmacodynamic Results: The mean tafamidis concentration at 3
hours after administration of tafamidis 20 mg achieved steady state after Week 8. At Week 8,
Week 26, Week 52 and Week 78, the mean tafamidis concentrations were 2773.0, 2739.0,
2829.0 and 3655.0 ng/mL, respectively. The mean percent stabilization of subjects with
V30M or non-V30M TTR-FAP at 3 hours after administration of tafamidis 20 mg at Week 8,
Week 26, Week 52 and Week 78 were 167.8%, 196.1%, 144.3% and 258.8%, respectively(Table 11). The TTR stabilization of all subjects except 1 subject at Week 52 achieved morethan 32%, which was the prior definition of TTR stabilization, at 3 hours after administration
at Week 8, Week 26, Week 52. At Week 78, 8 subjects achieved the TTR stabilization, and 2
subjects had missing data. Results of population pharmacokinetic analysis were reported
separately in the planned population modeling analysis report.
The relationship between tetramer stabilization and tafamidis: TTR stoichiometry observedin this study is consistent with Study Fx-002.

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M
F
F
M
F
M
M
M
M
M

1
2
3
4
5
6
7
8
9
10
Mean (SD)

73
46
35
48
69
63
60
71
73
63

V30M
V30M
V30M
V30M
V30M
V30M
S77Y
V30M
V30M
V30M

Age Genotype

Week 8
Tafamidis
TTR
concentration stabilization(ng/mL)
(%)
7260
131.5
1730
44.4
3000
178
1910
99.8
1780
196.4
2450
165.3
1790
352.5
1530
195
2010
166.9
4270
148.5
2773.0167.8 (79.81)(1777.71)

Week 26
Tafamidis
TTR
concentration stabilization(ng/mL)
(%)
7690
129.3
1550
101.6
1860
89.2
1980
126.4
2630
246.3
1570
129.7
2030
401.1
2000
247.3
1950
204.5
4130
285.5
2739.0196.1 (99.62)(1893.25)

Week 52
Tafamidis
TTR
concentration stabilization(ng/mL)
(%)
8270
141.6
1660
28.4
2480
102.7
1870
81.4
1330
152.6
2120
123.6
1690
328.4
1640
126.9
1430
98
5800
259.1
2829.0144.3 (87.65)(2315.58)

Week 78
Tafamidis
TTR
concentration stabilization(ng/mL)
(%)
7930
210.9
ND
ND
3430
171.9
3350
173.9
1880
245.6
3010
175.2
1550
426.6
ND
ND
1890
246.2
6200
419.7
3655.0258.8 (105.85)(2268.08)

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TTR = transthyretin; SD = standard deviation; ND = not done
Two subjects had missing data at Week 78. One subject discontinued due to death on Day 431, and the other subject could not visit the site at Week 78 due todisease progression.

Sex

NumberTable 11. Summary of Tafamidis Concentration and TTR Stabilization

Public Disclosure Synopsis
Protocol B3461010 – 21 April 2015 – Final

Public Disclosure Synopsis
Protocol B3461010 – 21 April 2015 – Final

Safety Results: Treatment-emergent AEs are summarized in Table 12.
Table 12. Summary of Treatment-Emergent Adverse Events
Number of Subjects, n (%)
Subjects evaluable for AEs
Number of AEs
Subjects with AEs
Subjects with SAEs
Subjects with severe AEs
Subjects discontinued due to AEs
Subjects with dose reduced or temporary discontinuation
due to AEs
AE = adverse event; SAE = serious adverse event

Tafamidis 20 mg
All
Treatment
causalities
related101085
2
10 (100.0)
2 (20.0)
7 (70.0)
1 (10.0)
3 (30.0)
1 (10.0)00
1 (10.0)0090177e18662d55f\Approved\Approved On: 29-Apr-2015 01:23

Incidence of treatment-emergent non-serious AEs is summarized by causality in Table 13.
The most common AEs (all causalities) (2 subjects) were nasopharyngitis and muscular
weakness (5 subjects each), thermal burn (3 subjects), and cataract, vitreous opacities, nausea,
vomiting, muscle spasms, myalgia, and insomnia (2 subjects each).

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Public Disclosure Synopsis
Protocol B3461010 – 21 April 2015 – Final

Table 13. Incidence of Treatment-Emergent Non-Serious Adverse Events

090177e18662d55f\Approved\Approved On: 29-Apr-2015 01:23

System Organ ClassMedDRA Preferred Term
Number of Subjects, n (%)
Blood and lymphatic system disorders
Iron deficiency anaemia
Cardiac disorders
Atrioventricular block second degree
Palpitations
Ear and labyrinth disorders
Ear discomfort
Meniere’s disease
Eye disorders
Cataract
Conjunctivitis
Dry eyeEye discharge
Vitreous opacities
Gastrointestinal disorders
Diarrhoea
Gingival swelling
NauseaParaesthesia oral
Stomatitis
Vomiting
General disorders and administration site conditions
OedemaPyrexia
Infections and infestations
Bronchitis
Hordeolum
Influenza
Nasopharyngitis
Oral herpes
Tinea capitis
Tinea pedis
Injury, poisoning and procedural complications
Laceration
Limb injury
Muscle strain
Thermal burnMetabolism and nutrition disorders
Hyperlipidaemia
Musculoskeletal and connective tissue disorders
Back pain
Flank pain
Muscle spasms
Muscular weakness
Myalgia
Pain in extremity
Trigger finger
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
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Tafamidis 20 mg
N=10All
Treatment
causalities
related
1 (10.0)0
1 (10.0)02 (20.0)0
1 (10.0)0
1 (10.0)02 (20.0)0
1 (10.0)0
1 (10.0)03 (30.0)02 (20.0)0
1 (10.0)0
1 (10.0)0
1 (10.0)02 (20.0)03 (30.0)
1 (10.0)
1 (10.0)0
1 (10.0)
1 (10.0)
2 (20.0)0
1 (10.0)0
1 (10.0)02 (20.0)02 (20.0)0
1 (10.0)0
1 (10.0)07 (70.0)0
1 (10.0)0
1 (10.0)0
1 (10.0)05 (50.0)0
1 (10.0)0
1 (10.0)0
1 (10.0)04 (40.0)0
1 (10.0)0
1 (10.0)0
1 (10.0)03 (30.0)0
1 (10.0)0
1 (10.0)09 (90.0)0
1 (10.0)0
1 (10.0)02 (20.0)05 (50.0)02 (20.0)0
1 (10.0)0
1 (10.0)0
1 (10.0)0
1 (10.0)0Public Disclosure Synopsis
Protocol B3461010 – 21 April 2015 – Final

Table 13. Incidence of Treatment-Emergent Non-Serious Adverse Events

090177e18662d55f\Approved\Approved On: 29-Apr-2015 01:23

System Organ ClassMedDRA Preferred Term
Number of Subjects, n (%)
Nervous system disorders
AtaxiaDementia
HeadacheHypoaesthesia
Loss of consciousness
Psychiatric disorders
Anxiety
Insomnia
Reproductive system and breast disorders
Gynaecomastia
Respiratory, thoracic and mediastinal disorders
Cough
Rhinitis allergic
Sleep apnoea syndrome
Skin and subcutaneous tissue disorders
BlisterDecubitus ulcer
Dermatitis
Hyperhidrosis
Rash
Skin ulcer
Solar dermatitis
Urticaria
MedDRA = Medical Dictionary for Regulatory Activities (version 16.1)

Tafamidis 20 mg
N=10All
Treatment
causalities
related2 (20.0)0
1 (10.0)0
1 (10.0)0
1 (10.0)0
1 (10.0)0
1 (10.0)03 (30.0)0
1 (10.0)02 (20.0)0
1 (10.0)0
1 (10.0)02 (20.0)0
1 (10.0)0
1 (10.0)0
1 (10.0)05 (50.0)0
1 (10.0)0
1 (10.0)0
1 (10.0)0
1 (10.0)0
1 (10.0)0
1 (10.0)0
1 (10.0)0
1 (10.0)
0

SAEs are summarized in Table 14. A total of 13 SAEs were reported in 7 subjects. Of these
13 events, sudden death was assessed by the investigator as related to the study drug.

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Public Disclosure Synopsis
Protocol B3461010 – 21 April 2015 – Final

Table 14. SAEs
Number

Sex

Agea

MedDRA
Preferred Term

Severity

Event
Onset
Day

Event Study Drug Relationship
Stop
Actionto Treatment
Day

1

Female47

Completed suicide

Severe431

NA2Female37

Moderate

619

686

3

Male

48

Sick sinus
syndrome
Pyelonephritis

Moderate

31

40

AtrioventricularModerate
block second
degreeBurns third degree Moderate

364

433

258

288

Pneumonia
bacterial
Ileus bModerate

4

20

Severe644

736

Decreased
appetite
Urinary retention

Moderate

390

431

NA

578

NA

49
49
4

Male

60
61

5

Male

72
73

090177e18662d55f\Approved\Approved On: 29-Apr-2015 01:23

73

Outcome

Dose notchanged
Dose notchanged
Dose notchangedTemporarily
withdrawn

Unrelated

Fatal

Unrelated

Recovered

Unrelated

Recovered

Unrelated

Recovered

Dose notchanged
Dose notchangedTemporarily
withdrawn
Dose notchangedPost-therapy

Unrelated

Recovered

Unrelated

Recovered

Unrelated

Recovered

Unrelated

Recovered

Unrelated

Not
recovered
Recovering

Benign prostaticNA578
NA Post-therapy
Unrelated
hyperplasia
6
Male
74
Pneumonia
Moderate
301
351
Dose notUnrelatedbacterialchanged75
Sudden death
Severe651
NA
NA
Related7
Male63
Pneumonia
Moderate
29
57
Dose notUnrelatedbacterialchangedSAE = serious adverse event, MedDRA = Medical Dictionary for Regulatory Activities (version 16.1)
a. Age at date of serious adverse event onset.
b. This event was coded as ‘intestinal obstruction’ in the corporate safety database.

Recovered
Fatal
Recovered

Two deaths (completed suicide and sudden death) were reported in this study (Table 14).
A 47-year-old female subject committed suicide after receiving tafamidis meglumine for a
total of 430 days. The investigator considered that the subject committed suicide because of
disease and that it was not related to the study drug.
A 75-year-old male subject died after receiving tafamidis meglumine for a total of 650 days.
The investigator commented that although the subject suddenly went into cardiopulmonaryarrest and the possibility of cardiac disease and heavy bleeding were considered, it wasdifficult to identify the immediate cause of death because autopsy and diagnostic imaging
were not performed. Thus, the investigator considered that the causal relationship withtafamidis meglumine could not be ruled out.
No permanent discontinuations or dose reductions due to AEs were reported in this study.
One subject temporarily discontinued the treatment due to ileus. This event was severe inseverity and confirmed to have resolved.

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Public Disclosure Synopsis
Protocol B3461010 – 21 April 2015 – Final

The laboratory test abnormalities in retinol-binding protein, N-terminal pro-B-type natriuretic
peptide, and transthyretin (pre-albumin) were reported in all subjects at baseline and during
the study. The incidences of other laboratory test abnormalities were generally infrequent
except decreased red blood cell count (50.0%). There was a laboratory test abnormality
reported as an AE (iron deficiency anaemia) in 1 subject. There were no vital signabnormalities reported as AEs during the study. There was an ECG abnormality reported as
an AE (atrioventricular block second degree) in 1 subject. This AE was moderate in severity
and was not considered by the investigator to be related to the study drug. No significant
change of echocardiography compared to baseline was observed until end of study. The
most commonly reported abnormalities of physical examination were neurological andmusculoskeletal findings that appeared to be related to the underlying TTR-FAP disease.
CONCLUSION(S):Study B3461010 was a single-arm, open-label, multicenter study designed to determine TTR
stabilization as well as tafamidis safety and tolerability, efficacy and population
pharmacokinetics in patients with V30M and non-V30M TTR-FAP.

090177e18662d55f\Approved\Approved On: 29-Apr-2015 01:23

The TTR genotypes were V30M in 9 subjects and non-V30M in 1 subject out of 10 subjects
who enrolled this study.
All enrolled patients were to receive oral tafamidis 20 mg soft gelatin capsules once daily
until available from market. After marketing approval of tafamidis, the subjects were toreceive continued study treatment within the framework of a post-marketing study until the
product became available at medical institutions. The median duration of treatment was
713.5 days (range: 380 to 796 days).
Key outcomes included:All subjects achieved TTR stabilization (the percent stabilization was equal to or morethan 32%) at Week 8 and Week 26. Nine of 10 subjects (90.0%) achieved TTR
stabilization at Week 52, and 8 of 10 subjects (80.0%) achieved TTR stabilization at
Week 78.

The percentage (95% CI) of responders in NIS-LL score (the change in NIS-LL score
was less than 2) was 80.0% (44.4, 97.5) at Week 26, 60.0% (26.2, 87.8) at Week 52, and40.0% (12.2, 73.8) at Week 78.

The treatment with tafamidis 20 mg was generally safe and well-tolerated. Most of AEs
were mild or moderate in severity. No permanent discontinuations due to AEs werereported in this study. A total of 13 SAEs were reported in 7 subjects. Of these events,
sudden death was assessed by the investigator as related to the study drug. Two deaths(completed suicide and sudden death) were reported in this study.

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