Full Clinical Study Report
Protocol A4091058

CLINICAL STUDY REPORT SYNOPSIS
Sponsor: Pfizer, Inc.
Investigational Product: Tanezumab
Clinical Study Report Synopsis: Protocol A4091058
Protocol Title: A Phase 3 Randomized, Double-Blind, Active-Controlled, Multicenter
Study of the Long-Term Safety and Efficacy of Subcutaneous Administration of Tanezumabin Subjects With Osteoarthritis of the Hip or Knee
Investigators: Refer to Appendix 16.1.4.1 for a list of investigators involved in this study.
Study Center(s): A total of 307 sites randomized at least one patient in this study. The
study was conducted at sites in Australia, Brazil, Bulgaria, Colombia, Croatia, Japan,
Lithuania, Mexico, New Zealand, Peru, Philippines, Republic of Korea, Russian Federation,
Serbia, Slovakia, Taiwan, Ukraine, and the United States (US).
Publications Based on the Study: None
Study Initiation and Completion Dates:
Study Initiation Date: 21 July 2015
Primary Completion Date: 05 October 2018
Study Completion Date: 27 February 2019
Report Date: 06 November 2019
Previous Report Date(s): 05 September 2019
Phase of Development: Phase 3
Study Objective(s)Primary Objectives
Characterize the long-term risk of joint safety events in patients with osteoarthritis (OA)of the knee or hip who receive tanezumab 2.5 mg or tanezumab 5 mg subcutaneous (SC)versus non-steroidal anti-inflammatory drug (NSAID) treatment (naproxen 500 mg twice
daily [BID], celecoxib 100 mg BID, or diclofenac extended release [ER] 75 mg BID)
over the course of 56 weeks of treatment using a composite endpoint (includes
adjudication outcomes of rapidly progressive OA type 1 or type 2, subchondral
insufficiency fracture, primary osteonecrosis, or pathological fracture).

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CLINICAL STUDY REPORT SYNOPSIS

Demonstrate superior efficacy of tanezumab 2.5 mg and tanezumab 5 mg SC versus
NSAID treatment (naproxen 500 mg BID, celecoxib 100 mg BID, or diclofenac ER
75 mg BID) at Week 16.

Secondary Objectives
Characterize the long-term joint safety risk using a composite endpoint (includes
adjudication outcomes of rapidly progressive OA (type 2 only), subchondral
insufficiency fracture, primary osteonecrosis, or pathological fracture).

Characterize the long-term risk of the following individual adjudication outcomesoccurring: rapidly progressive OA (type 1 only), rapidly progressive OA (type 2 only),
rapidly progressive OA (type 1 or type 2 combined), subchondral insufficiency fracture,primary osteonecrosis, and pathological fracture.

Characterize the long-term risk of all cause total joint replacements (TJRs) (patients who
undergo TJR plus patients who have an adjudicated outcome of rapidly progressive OA
type 1 or type 2, subchondral insufficiency fracture, primary osteonecrosis, or
pathological fracture whether they undergo TJR or not) occurring.

Characterize joint space width changes in patients with Kellgren-Lawrence (KL) Grade 2
or 3 OA of the index knee or index hip.

Demonstrate superior efficacy of tanezumab 5 mg and tanezumab 2.5 mg SC versus eachseparate NSAID treatment group (naproxen 500 mg BID, celecoxib 100 mg BID anddiclofenac ER 75 mg BID) at Week 16.

Demonstrate the efficacy of tanezumab 2.5 mg and tanezumab 5 mg SC versus NSAID(combined) treatment at all time points to Week 56.

Evaluate the long-term safety of tanezumab 2.5 mg and tanezumab 5 mg SC.

Explore relationships between adjudicated outcomes of rapidly progressive OA (type 1 ortype 2), subchondral insufficiency fracture, primary osteonecrosis, or pathologicalfracture and variables that may be associated with these orthopedic risks.

Characterize changes in physical activity level.

METHODS
Study Design
This was a randomized, double-blind, active-controlled, multicenter, parallel-group
Phase 3 study of the safety and efficacy of tanezumab when administered by SC injection for
56 weeks compared to NSAIDs in patients with OA of the knee or hip.

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CLINICAL STUDY REPORT SYNOPSIS
Approximately 3000 patients were randomized to one of three treatment groups in a 1:1:1
ratio (N=1000/treatment group):
1. SC placebo (to match tanezumab) once every eight weeks (a total ofseven administrations) plus NSAID administered orally (PO) (naproxen 500 mg BID PO,
celecoxib 100 mg BID PO, or diclofenac ER 75 mg BID PO) through Week 56.
2. Tanezumab 2.5 mg SC once every eight weeks (a total of seven administrations) plus
placebo BID PO (to match naproxen, celecoxib or diclofenac ER) through Week 56.
3. Tanezumab 5 mg SC once every eight weeks (a total of seven administrations) plus
placebo BID PO (to match naproxen, celecoxib or diclofenac ER) through Week 56.
Note: Treatment groups specific to Japan were as follows:
1. SC placebo (to match tanezumab) once every eight weeks (a total ofseven administrations) plus celecoxib 100 mg BID administered PO through Week 56.
2. Tanezumab 2.5 mg SC once every eight weeks (a total of seven administrations) plus
placebo BID PO to match celecoxib through Week 56.
3. Tanezumab 5 mg SC once every eigh weeks (a total of seven administrations) plus
placebo BID PO to match celecoxib through Week 56.
Randomization was stratified by index joint, most severe KL grade of any knee or hip joint,
and NSAID treatment administered during Screening.
The total study duration (post-randomization) was approximately 80 weeks and consisted ofa Screening Period (maximum of 37 days), a Double-blind Treatment Period (56 Weeks),
and a Safety Follow-up Period (24 Weeks).
Eligible patients must have been receiving a stable dosing regimen of oral NSAID therapy,
be tolerating their NSAID regimen, and be taking their NSAID regularly (at least five days
per week) for 30 days prior to Screening.
The Screening Period was a minimum of two to three weeks (14 to 21 days) duration toensure patients were on a stable regimen of study-supplied NSAID for at least two to three
weeks prior to randomization. Patients taking celecoxib, naproxen, or diclofenac prior to
Screening were provided with the same NSAID for the remainder of the Screening Period.
Patients taking other NSAIDs prior to Screening were assigned to celecoxib, naproxen, or
diclofenac ER at the discretion of the Investigator for at least the final three weeks prior to
Baseline.
On Day 1, patients were administered an SC injection of tanezumab 2.5 mg, tanezumab 5
mg, or placebo. Patients took their first oral dose of NSAID or matching placebo in theevening on Day 1. Additional administrations of SC study medication occurred every eight
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CLINICAL STUDY REPORT SYNOPSIS
weeks through Week 48. Oral study medication (NSAID or placebo) was self-administeredby the patients BID through Week 56. During the Treatment Period, clinic visits occurred at
Weeks 2 and 4 and then every eight weeks from Week 8 to Week 56 and patients were
contacted by telephone every eight weeks between Weeks 12 and 60.
Up to Week 16, patients were allowed to use limited acetaminophen/paracetamol rescue
medication up to 3000 mg per day up to three days per week and abstained from using
analgesics for OA. After Week 16, rescue medication was permitted daily up to 3000 mg perday.
At Week 16, patients had to meet the following criteria in order to continue receiving SC
study medication:


A 30% or greater reduction in Western Ontario and McMaster Universities Osteoarthritis
Index (WOMAC) Pain subscale relative to Baseline in the index joint

A 15% or greater reduction in WOMAC Pain subscale from Baseline at either Week 2, 4,
or 8Patients who did not meet these response criteria were discontinued from the Treatment
Period and entered into the 24-week Early Termination Follow-up Period.
Patients who completed the Double-blind Treatment Period at Week 56 entered the 24-week
Safety Follow-up Period and returned for two additional study visits at Weeks 64 and Week
80 (End of Study). At Week 60 and between Weeks 64 and 80, patients were contacted bysite staff at approximately monthly intervals to collect adverse event, concomitant
medication, and concomitant non-drug data.
Concomitant medication and rescue medication restrictions were maintained during the
Safety Follow-up period until the last efficacy assessments were collected at the Week 64
visit.
Patients who were discontinued from treatment prior to Week 56 for any reason wererequired to participate in 24 weeks of follow-up, which included three clinic visits andmonthly phone calls. Patients also continued to use interactive response technology (IRT)
for weekly collection of pain scores for index joints (and non-index joints, when applicable),
rescue medication use, and concomitant medication use. Radiographs and magnetic
resonance imaging (MRI; when applicable) of all major joints imaged at Screening were
performed as soon as possible after withdrawal from study treatment.
Concomitant medication and rescue medication restrictions (daily up to 3000 mg per day)were maintained during the Early Termination Follow-up period until the last efficacy
assessments were collected at the Early Termination Visit 2.

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Patients who underwent or planned to undergo TJR or other arthroplasty procedure during
the study were discontinued from study treatment. In addition, patients who underwent totalknee, hip, or shoulder joint replacement surgery during the study (Treatment Period or
Follow-up Period) were followed for 24 weeks after the procedure as part of a separate
protocol (Study A4091064), provided the patient consented.
Diagnosis and Main Criteria for InclusionMale or female of any race, 18 years of age; who provided informed consent.



A diagnosis of OA of the index hip or knee based on American College of Rheumatology
criteria with X-ray confirmation (a KL X-ray Grade of 2 as diagnosed by the Central
Reader).

Documented history indicating that acetaminophen therapy had not provided sufficient
pain relief.



Was receiving a stable dose regimen of oral NSAID therapy, was tolerating this NSAID
and taking this medication regularly (defined as an average of at least 5 days per weekduring the 30 day period prior to the Screening visit):

Maintained a stabilized dose regimen of either naproxen 500 mg BID, celecoxib
100 mg BID or diclofenac ER 75 mg BID (provided at Screening) with a minimum
compliance of 70% (ie, 5 of 7 days per week) for the final 2 or 3 weeks of the Screening
period directly prior to the Baseline (Day 1) visit.

Documented history indicating that tramadol treatment had not provided adequate pain
relief or patient was unable to take tramadol due to contraindication or inability totolerate, or that opioid treatment had not provided adequate pain relief or patient was
unwilling to take opioids or unable to take opioids due to contraindication or inability totolerate.



WOMAC Pain Subscale numerical rating scale (NRS) ≥5 in the index knee or hip at
Screening.



Patients were willing to discontinue all non-study pain medications for OA and not use
prohibited pain medications throughout the duration of the study except as permitted per
protocol.

Diagnosis and Main Criteria for ExclusionBody Mass Index (BMI) of >39 kg/m2. For patients requiring dual energy X-ray
absorptiometry (DXA) scan body weight 300 lbs was exclusionary.

History of other disease that may have involved the index joint including inflammatory
joint disease such as rheumatoid arthritis, seronegative spondyloarthropathy
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CLINICAL STUDY REPORT SYNOPSIS(eg, ankylosing spondylitis, psoriatic arthritis, inflammatory bowel disease related
arthropathy), crystalline disease (eg, gout or pseudogout), endocrinopathies, metabolic
joint diseases, lupus erythematosus, joint infections, Paget’s disease, or tumors.
Radiographic evidence of any of the following conditions in any screening radiograph as
determined by the central radiology reviewer and as defined in the tanezumab program
imaging atlas: excessive malalignment of the knee, severe chondrocalcinosis; otherarthropathies (eg, rheumatoid arthritis), systemic metabolic bone disease (eg, pseudogout,
Paget’s disease, metastatic calcifications), large cystic lesions, primary or metastatic
tumor lesions, stress or traumatic fracture.

Radiographic evidence of any of the following conditions as determined by the central
radiology reviewer and as defined in the tanezumab program imaging atlas at Screening:1) rapidly progressive OA, 2) atrophic or hypotrophic OA, 3) subchondral insufficiency
fractures, 4) spontaneous osteonecrosis of the knee (SPONK), 5) osteonecrosis, or6) pathologic fracture.

A history of osteonecrosis or osteoporotic fracture (ie, a patient with a history ofosteoporosis and a minimally traumatic or atraumatic fracture).

History of significant trauma or surgery to a knee, hip or shoulder within the previous
year.



Fibromyalgia, regional pain caused by lumbar or cervical compression withradiculopathy, or other moderate to severe pain that may confound assessments or
self-evaluation of the pain associated with OA. Patients with a present (current) historyof sciatica were not eligible for participation. Patients with a past history of sciatica who
had been asymptomatic for at least one year and who had no evidence of radiculopathy or
sciatic neuropathy on thorough neurologic examination were eligible for participation.



A past history of carpal tunnel syndrome (CTS) with signs or symptoms of CTS in the
one year prior to Screening.



History of intolerance or hypersensitivity to the relevant oral NSAID (naproxen,celecoxib or diclofenac) the patient could have been randomized to receive or any of its
excipients or existence of a medical condition or use of concomitant medication forwhich the use of this NSAID was contraindicated (refer to product labeling).



History of intolerance or hypersensitivity to acetaminophen (paracetamol1) or any of its
excipients or existence of a medical condition or use of concomitant medication forwhich the use of paracetamol was contraindicated (refer to product labeling).

1

Acetaminophen/paracetamol will be referred to as paracetamol going forward.
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Signs and symptoms of clinically significant cardiac disease.

Diagnosis of a transient ischemic attack in the 6 months prior to Screening, diagnosis ofstroke with residual deficits (eg, aphasia, substantial motor or sensory deficits), thatwould have precluded completion of required study activities.



History, diagnosis, or signs and symptoms of clinically significant neurological disease.

Previous exposure to exogenous nerve growth factor (NGF) or to an anti-NGF antibody.

History of allergic or anaphylactic reaction to a therapeutic or diagnostic monoclonal
antibody or immunoglobulin G (IgG)-fusion protein.



Patients who had evidence of orthostatic hypotension based upon replicate orthostatic
blood pressure measurements.

Randomization Criteria

Patient must have completed appropriate washout of analgesics.

Patient must have made at least three pain diary entries in the seven days prior to theBaseline (Day 1) visit.

Patient must have maintained a stabilized dose regimen of either naproxen 500 mg BID,
celecoxib 100 mg BID or diclofenac ER 75 mg BID (depending on the patient’s
pre-study NSAID) with a minimum compliance of 70% (ie, 5 of 7 days per week) for atleast the final 2 or 3 weeks of the Screening period directly prior to the Baseline (Day 1)
visit.
NOTE: In Japan, all patients maintained a stabilized dose regimen of celecoxib as
defined above.

Patient must have abstained from taking rescue medication (paracetamol) within the
24 hours that preceded dosing.



WOMAC Pain and Physical Function subscales NRS 5 in the index knee or index hip at
Baseline.



Patient’s Global Assessment of OA (PGA-OA) must have been “fair,” “poor,” or “verypoor” at Baseline.



Review of the electrocardiogram (ECG) and laboratory results and confirmation that
there were no clinically significant or exclusionary findings.



Patient must have had required Baseline X-rays, MRI and DXA (if appropriate) scan(s)obtained.
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CLINICAL STUDY REPORT SYNOPSIS

The index joint should have been the most painful joint with a qualifying WOMAC Painscore and KL grade as confirmed by the Central Reader.



In Japan, confirmation that female patients were not of childbearing potential.

STUDY TREATMENT
Tanezumab 2.5 mg, tanezumab 5 mg, and placebo for tanezumab were presented as a sterile
solution for SC administration, in a glass pre-filled syringe (PFS) (Table S1). Each PFS
contained a sufficient amount of sterile solution to provide the intended dose. Each PFS waspackaged in an individual carton and had a unique container number.
Celecoxib was provided as oral capsules containing 100 mg of active celecoxib. Placebo forcelecoxib was provided as oral capsules matching those used for celecoxib 100 mg capsules.
Celecoxib 100 mg and matching placebo were packaged in high-density polyethylene(HDPE) bottles with child resistant closures.
Naproxen was provided as oral tablets containing 500 mg of active naproxen. Placebo fornaproxen was provided as oral tablets matching those used for naproxen 500 mg tablets.
Naproxen 500 mg and matching placebo were packaged in HDPE bottles with child resistantclosures.
Diclofenac was provided as oral extended release capsules containing 75 mg of active
diclofenac sodium. Placebo to match diclofenac was provided as oral capsules matching
those used for diclofenac 75 mg ER active. Diclofenac 75 mg ER and matching placebo
were packaged in HDPE bottles with child resistant closures.

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CLINICAL STUDY REPORT SYNOPSIS
Table S1. Investigational Product Description
Investigational Product
Description

Vendor Lot
Number

Pfizer Lot Number

Strength/Potency

Dosage Form

PF-04383119 Solution
for Injection, 2.5 mg/mL

L47506
M76804
S73087
L50447
M76807
S73916
L39168
S6426915-002256, 15-002257
16-000830
17-001777
15-002258, 15-002259
16-000831
17-001780
15-002262, 15-002263
17-001779

2.5 mg/mL

Pre-filled Syringe

5 mg/mL

Pre-filled Syringe

0 mg/ml

Pre-filled Syringe

H04083
T0173V
T0942VA

100 mgCapsule0 mg

Capsule

500 mgTablet0 mg

TabletDiclofenac Sodium
75mg Extended Release
Size AA
Gray Capsule

H04007
H04009
T0992V
HA00414
HF26915
B12222B14010B151188234.148234.178234.228234.25

13-111559
12-004951
12-004950
13-111563
13-111564
12-004954
14-001172
15-005106
12-004534
14-001197
15-004765
14-005994
15-005386
16-004894
16-004895

75 mg

CapsuleSize AA Gray Placebo
Capsule8234.198234.215-006769
12-005114

0 mg

CapsulePF-04383119 Solution
for Injection, 5 mg/mL
Placebo for PF04383119 Solution for
Injection
Celecoxib 100 mg Hard
Gel Capsule
Placebo for 100/200 mg
Celecoxib Capsule
Naproxen 500 mg Tablet
Placebo for Naproxen
500 mg Tablet

EFFICACY EVALUATIONSQuestionnaires for primary and secondary efficacy parameters were completed by thepatients at the site via IRT (electronic tablets), or at home via electronic diaries.
Questionnaires at the site were completed prior to dosing on dosing days.
Primary Efficacy Evaluation
The three co-primary efficacy endpoints were change from Baseline to Week 16 in the
WOMAC Pain subscale, change from Baseline to Week 16 in the WOMAC Physical
Function subscale, and change from Baseline to Week 16 in the PGA-OA. The Japanesespecific co-primary efficacy endpoints were change from Baseline to Week 16 in the
WOMAC Pain subscale and change from Baseline to Week 16 in the WOMAC Physical
Function subscale.

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Secondary Efficacy Evaluation
The key secondary endpoint was patients with 50% reduction from Baseline in the
WOMAC Pain at Week 16. Additional secondary endpoints included change from Baseline
to Weeks 2, 4, 8, 16 (PGA-OA, Japan only), 24, 32, 40, 48, 56 and 64 in the WOMAC Pain
subscale, WOMAC Physical Function subscale, and PGA-OA. Time points for theevaluation of other secondary endpoints were Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56, and 64
unless stated otherwise: Outcome Measures in Rheumatology – Osteoarthritis ResearchSociety Initiative (OMERACT-OARSI) responder index; treatment response defined as a
reduction in the WOMAC Pain subscale of 30%, 50%, 70% or 90%; cumulative
distribution of percent change from Baseline in the WOMAC Pain subscale score to
Week 16, 24, and 56 (endpoint for summary only); treatment Response defined as reductionin the WOMAC Physical Function subscale of 30%, 50%, 70% or 90%; cumulative
distribution of percent change from Baseline in the WOMAC Physical Function subscalescore to Week 16, 24, and 56 (endpoint for summary only); treatment response defined as
improvement of 2 points in the PGA-OA; change from Baseline in average pain score in theindex joint (Weeks 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 32, 40, 48, 56 and 64); change fromBaseline in the WOMAC Stiffness Subscale; change from Baseline in the WOMAC
Average; change from Baseline in the WOMAC Pain Subscale item: Pain When Walking on
a Flat Surface; change from Baseline in the WOMAC Pain Subscale item: Pain When Going
Up or Down Stairs; and incidence and time to discontinuation due to lack of efficacy.
Secondary patient-reported outcome endpoints included Work Productivity and Activity
Impairment Questionnaire for Osteoarthritis (WPAI:OA) impairment scores change fromBaseline to Weeks 16, 24, 56, and 64; EuroQol-5 Dimension-5 Level (EQ-5D-5L™)
dimensions and overall health utility score at Baseline and Weeks 8, 16, 24, 40, 56, and 64;
Treatment Satisfaction Questionnaire Medicine v.II (TSQM v.II) satisfaction witheffectiveness, side effects and convenience, and overall satisfaction at Weeks 16 and 56;
Patient Reported Treatment Impact Assessment-Modified (mPRTI) at Weeks 16 and 56; andHealth Care Resource Utilization at Baseline and Weeks 64 and 80.
Rescue medication was measured by the incidence and number of days patients used rescue
medication (Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56, and 64) and the amount taken (Weeks 2, 4,
8, and 16) during the study.
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and/or Other Evaluations:Pharmacokinetic Evaluations
Tanezumab concentrations were measured to support the development of an SC
administration population PK model that allows for the prediction of the tanezumab
concentration over time in individuals. In addition, tanezumab concentrations were
measured to inform the immunogenicity profile of tanezumab.
Pharmacodynamic Evaluations
Blood samples were collected for the assessment of NGF for PD analyses.
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Synovial fluid samples for the assessment of tanezumab and NGF could be collected when an
Investigator performed arthrocentesis for a patient and the appropriate informed consent was
obtained.
Biomarkers
Blood and urine samples for the assessment of biomarkers were collected for all patients.
For patients that had activity level monitoring via accelerometry, additional biomarker
samples were collected. Serum and urine biomarker assessments will be presented in a
supplementary report. Additional exploratory analyses of biomarker concentrations insynovial fluid may be conducted for patients who had arthrocentesis performed during thestudy and who provided consent for analysis of synovial fluid samples.
SAFETY EVALUATIONS
Primary Safety Evaluation
The primary safety endpoint was the incidence of a predefined composite endpoint consistingof adjudication outcomes of rapidly progressive OA (type 1 or type 2), subchondral
insufficiency fracture, primary osteonecrosis, or pathological fracture (primary composite
endpoint).
Bone and Joint Safety
Bone and joint safety endpoints included the incidence of a predefined composite endpointconsisting of adjudication outcomes of rapidly progressive OA (type 2 only), subchondral
insufficiency fracture, primary osteonecrosis, or pathological fracture; the incidence ofindividual adjudication outcomes of rapidly progressive OA (type 1 only), rapidly
progressive OA (type 2 only), rapidly progressive OA (type 1 or type 2 combined),
subchondral insufficiency fracture, primary osteonecrosis, and pathological fracture; and theincidence of all cause TJRs (patients who underwent TJR plus patients who had an
adjudicated outcome of rapidly progressive OA type 1 or type 2, subchondral insufficiency
fracture, primary osteonecrosis, or pathological fracture whether or not they underwent TJR).
Radiographic
Radiographic endpoints included the change from Baseline to Week 56 and Week 80 inMedial or Lateral Minimum Joint Space Width of the index knee (for patients with KL Grade2 or 3 medial or lateral OA of the index knee); change from Baseline to Week 56 and Week
80 in Minimum Joint Space Width of the index hip (for patients with KL Grade 2 or 3 OA of
the index hip); the incidence of patients with progression of OA in the index knee according
to Bland and Altman method at Week 56 and Week 80 (separately) (for patients with KL
Grade 2 or 3 medial or lateral OA of the index knee); and the incidence of patients with
progression of OA in the index hip according to Bland and Altman method, at Week 56 andWeek 80 (separately) (for patients with KL Grade 2 or 3 OA of the index hip).

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Activity Level Monitoring
Activity level monitoring endpoints were change from Baseline to Weeks 4, 8, 16, 24, 56
and 80 in the Lower Extremity Activity Scale (all patients); change from Baseline to
Weeks 16 and 56 in average daily minutes of physical activity (a subset of patients); change
from Baseline to Weeks 16 and 56 in average daily physical activity counts (a subset ofpatients); change from Baseline to Weeks 16 and 56 in average daily minutes of moderate tovigorous physical activity (a subset of patients); change from Baseline to Weeks 16 and 56 inaverage daily minutes of bouted (sustained) moderate to vigorous physical activity (a subsetof patients); and change from Baseline to Weeks 16 and 56 in average daily step count (asubset of patients).
General Safety
Safety evaluations included adverse events, standard safety assessments (safety laboratory
testing [chemistry, hematology], sitting vital signs, ECG [12-lead]), orthostatic(supine/standing) blood pressure assessments, Survey of Autonomic Symptom scores,
neurologic exam (Neuropathy Impairment Score [NIS]), Anti-drug antibody (ADA)
assessments, general physical examination, and musculoskeletal history and physicalexamination.
STATISTICAL METHODS
A sample size of approximately 1000 patients for each of the treatment groups of NSAID,
tanezumab 2.5 mg, and tanezumab 5 mg were used in this study. This sample size allowed
for a high probability of observing patients with any component of the composite endpoint
where the event rate over this study was very small. If the event rate were 0.25%, then there
would be a >90% probability of observing at least one patient with an event in any single
treatment group. In addition, the sample size allowed for good precision to estimate theincidence rate for each treatment group in order to estimate an upper bound for the true
incidence rate.
Analysis of Co-Primary Efficacy Endpoints
The primary efficacy population was the Intent-to-Treat (ITT) population, defined as all
randomized patients who received SC investigational product (either tanezumab or matchingplacebo). The primary efficacy analysis used multiple imputation methods for missing data
at Week 16. All treatment comparisons used the two-sided 5% significance level.
The co-primary efficacy endpoints were analyzed using an analysis of covariance(ANCOVA) model, with terms of Baseline score, Baseline diary average pain, index joint(knee or hip), highest KL grade (2, 3 or 4), NSAID cohort, treatment group, and study site asa random effect. The assessment of significance for SC tanezumab versus NSAID treatment
contrasts of the primary and key secondary efficacy parameters used a graphical multiple
testing (gate-keeping) approach to control the family-wise type I error rate at 5% (two-sided).

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Efficacy data collected during the post-treatment Safety Follow-up Period were generally
considered off-treatment and excluded from analysis.
Analysis of Secondary Efficacy Endpoints
The secondary endpoint of patients with 50% reduction from Baseline in the WOMAC Painat Week 16 was identified as a key secondary endpoint and was included in the graphicalmultiple testing strategy.
All secondary efficacy analyses used the ITT analysis set. Unless otherwise stated, efficacy
data was summarized up to Week 64, and analyzed up to Week 56. Only observed data were
presented at Week 64, ie, no imputation was used past Week 56.
The ANCOVA model for the co-primary endpoints was used in the analysis of WOMAC
Pain, WOMAC Physical Function, PGA-OA, WOMAC Stiffness subscale, WOMAC
Average score, WOMAC Pain item “Pain When Walking on a Flat Surface,” WOMAC Pain
item “Pain When Going Up or Down Stairs,” and the Average Pain in the index joint fromthe diary.
The response endpoints of OMERACT, improvement in PGA ≥2 and WOMAC Pain andPhysical Function ≥30%, ≥50%, ≥70% and ≥90% improvements as well as the incidence of
rescue medication use and incidence of treatment discontinuation due to lack of efficacy
were analyzed using logistic regression.
The time to treatment discontinuation due to lack of efficacy used the log-rank test.
The number of days and amount of rescue medication endpoints were analyzed using thenegative binomial model.
Analysis of Pharmacokinetic and Pharmacodynamic Parameters
PK analyses included a listing of all plasma tanezumab concentrations sorted by patient,active treatment group, and actual and nominal time post-dose, a descriptive summary of theplasma tanezumab concentrations based on nominal time post-dose for each treatment group,
boxplots of plasma tanezumab concentrations at the nominal times for the tanezumab
treatment groups, and a listing of available synovial fluid tanezumab concentrations at thetime of the arthrocentesis only sorted by patient, treatment group, and actual collection date
and time. Samples were analyzed using a validated analytical method in compliance withSponsor standard operating procedures.
Analysis of Joint Safety Endpoints
The primary joint safety endpoint is shown by number of patients treated and patient years of
exposure (treatment plus follow-up periods) for individual treatment groups and differences
between tanezumab treatment groups and the NSAID treatment group. The risk ratio andrisk difference with 95% confidence interval (CI) was calculated for the comparisons of eachtanezumab treatment group versus NSAID, as well as significance tests for each comparison.
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The time to each event was summarized and Kaplan-Meier estimates of the time to event
were produced, together with an analysis of each tanezumab treatment group versus NSAID
using the log-rank test.
The primary analysis of the primary joint safety endpoint was the analysis of the
exposure-adjusted risk difference. The analyses of the exposure-adjusted risk ratio and risk
difference and ratio based on percentage of patients with the event were secondary analyses.
The summary and analysis of the secondary joint safety endpoints followed the same method
described above for the primary joint safety endpoint.
RESULTS
Subject Disposition and Demography
A total of 17,730 patients were screened for the study, of which 14,496 failed Screening and
213 were screened but not randomized (Table S2). In total, 3021 patients were randomized:
1008 in the tanezumab 2.5 mg treatment group, 1005 in the tanezumab 5 mg treatment group,and 1008 in the NSAID treatment group. The ITT population was comprised of 2996
patients that were randomized and treated with SC study medication. The Safety Populationin this study is the same as the ITT population. Six patients in the tanezumab 2.5 mg
treatment group, seven patients in the tanezumab 5 mg treatment group, and 12 patients in
the NSAID treatment group were randomized and not treated.
Overall, 2227 (74.3%) patients completed the study. A total of 1312 (43.8%) patientscompleted the Treatment Period, and of those, 1222 (93.1%) patients completed the Safety
Follow-up period. Of the 1684 (56.2%) patients who discontinued from the Treatment
Period, 1005 (59.7%) completed the Safety Follow-up Period.
Table S2. Subject Evaluation Groups
Tanezumab
2.5 mg(N=1008)n (%)

Tanezumab
5 mg(N=1005)
n (%)

NSAID
(N=1008)

Total(N=3021)

n (%)

n (%)

Randomized
TreatedNot Treated1008 (100.0)
1002 (99.4)
6 (0.6)1005 (100.0)
998 (99.3)
7 (0.7)1008 (100.0)
996 (98.8)
12 (1.2)

3021 (100.0)
2996 (99.2)
25 (0.8)

Safety Population
ITT Population
Per-Protocol Population

1002 (99.4)
1002 (99.4)
896 (88.9)

998 (99.3)
998 (99.3)
876 (87.2)

996 (98.8)
996 (98.8)
885 (87.8)

2996 (99.2)
2996 (99.2)
2657 (88.0)

Screened: 17730
Screen Failure: 14496
Other Screened but not Randomized: 213

Number of subjects[1]PFIZER CONFIDENTIAL
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Table S2. Subject Evaluation Groups
Tanezumab
2.5 mg(N=1008)n (%)

Tanezumab
5 mg(N=1005)
n (%)

NSAID
(N=1008)

Total(N=3021)

n (%)

n (%)

Completed Treatment Phase
Completed Safety Follow-Up
Discontinued Safety Follow-Up
Did not enter Safety Follow-Up
Discontinued Treatment Phase
Completed Safety Follow-Up
Discontinued Safety Follow-Up
Did not enter Safety Follow-Up

447 (44.6)
422 (42.1)
24 (2.4)
1 (0.1)555 (55.4)
319 (31.8)
115 (11.5)
121 (12.1)

419 (42.0)
386 (38.7)
28 (2.8)
5 (0.5)579 (58.0)
343 (34.4)
128 (12.8)
108 (10.8)

446 (44.8)
414 (41.6)
28 (2.8)
4 (0.4)550 (55.2)
343 (34.4)
102 (10.2)
105 (10.5)

1312 (43.8)
1222 (40.8)
80 (2.7)
10 (0.3)
1684 (56.2)
1005 (33.5)
345 (11.5)
334 (11.1)

Completed study
Discontinued study

741 (74.0)
261 (26.0)

729 (73.0)
269 (27.0)757 (76.0)
239 (24.0)

2227 (74.3)
769 (25.7)

Rollover to Study A4091064

30 (3.0)42 (4.2)

17 (1.7)

89 (3.0)

N is Number of Subjects Randomized. Percentages are based on the number of subjects Randomized.
[1]Subjects in Safety Population. Percentages are based on the number of subjects in Safety Population.
Treatment Period is planned for 56 weeks and Safety Follow-Up period is planned for 24 weeks.
Safety population consists of all subjects treated with SC study medication. ITT population consists of all randomized
subjects who received at least one SC dose.
"Other Screened but not Randomized" displays subjects who were screened but not randomized for a reason not related toa specific eligibility criterion.
Rollover to Study A4091064 includes the subjects who intended to rollover at the time of discontinuation from 1058.
PFIZER CONFIDENTIAL SDTM Creation: 03APR2019 (02:27) Source Data: Listing 16.2.1.1 Output File:./nda1/A4091058_IM_Safety/adsl_s002i Date of Generation: 09MAY2019 (16:44)
Table 14.1.1.1.i is for Pfizer internal use.

The incidence of discontinuation from treatment was higher in the tanezumab 5 mg treatmentgroup (58.0%) compared with the tanezumab 2.5 mg and NSAID treatment groups (55.4%
and 55.2%, respectively). The most frequent reasons for discontinuation from treatment
across treatment groups were “Patient meets protocol-specified pain criteria for
discontinuation” (21.7%), “Other” (9.5%), “Adverse event” (7.9%), and “Insufficient clinicalresponse” (7.1%). The incidence of treatment discontinuation due to “Patient meets
protocol-specified pain criteria for discontinuation” was similar across treatment groups. The
incidence of treatment discontinuation due to “Insufficient clinical response” was higher inpatients who received NSAID (9.1%) compared with patients who received tanezumab (6.0%
and 6.3% in the tanezumab 2.5 mg and 5 mg treatment groups, respectively). The proportionof patients who discontinued treatment due to adverse events was highest in the tanezumab 5
mg treatment group (10.4%).
The most frequent reasons for discontinuation from study were “Withdrawal by subject”(10%) and “Other” (8.5%). The proportion of patients who discontinued from study due toadverse events was higher in patients receiving tanezumab (2.3% and 2.2% in the tanezumab

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2.5 mg and 5 mg treatment groups, respectively) compared with patients receiving NSAID(0.8%).
A total of 89 of the 164 patients (54.3%) who had at least one TJR during the study intended
to roll over into Study A4091064 at the time of discontinuation from Study A4091058(Table S2).
Demographic characteristics were similar across treatment groups. More patients werefemale (63.6% to 66.5%) than male (33.5% to 36.4%) and most patients were white (68.3%
to 71.3%). The mean age of patients was 60.3 to 61.2 years (range 28 to 90 years), and mostpatients were in the 45-64 years age range. Across treatment groups, patients 65 years orolder represented 32.1% to 36.2% of the study population and those 75 years or older
represented 5.5% to 8.0% of the study population.
Insufficient pain relief to paracetamol was an entry requirement and was reported by all
patients with the exception of one patient in the NSAID treatment group. Inadequate pain
relief was the primary reason for treatment failure with paracetamol and tramadol, andunwilling to take was the primary reason for treatment failure with opioids.
The mean time from the first diagnosis of OA was similar across treatment groups, ranging
from 8.5 years for patients in the tanezumab 5 mg treatment group to 9.1 years for patients in
the NSAID treatment group. The mean time from the index joint OA diagnosis ranged from
7.9 years for patients in the tanezumab 5 mg treatment group to 8.1 years for patients in the
NSAID treatment group.
The majority of patients (84.9% to 85.5%) had the knee as the index joint. The overall
radiographic severity of OA was similar across treatment groups, with KL grade 3 reported
most frequently for the index joint (47.4% to 47.8%). Across treatment groups, thepercentage of patients with a KL grade of 4 for the index joint was 21.5% to 22.7%. Most
patients (53.7% to 56.2) reported two joints with KL grade ≥2. The WOMAC Pain subscalescores at Screening and the WOMAC Pain subscale, WOMAC Physical Function subscale,and PGA-OA scores at Baseline were similar across treatment groups.
Most patients were enrolled in the naproxen NSAID cohort (48.3% to 48.4%), followed bycelecoxib (32.2% to 32.6%), then diclofenac (19.1% to 19.4%).
Efficacy Results
For tanezumab 5 mg treatment, two co-primary endpoints achieved significant2 improvement
over NSAID at Week 16 (WOMAC Pain, WOMAC Physical Function) while the third
co-primary endpoint (PGA-OA) did not achieve significant improvement over NSAID at

2“Significant” is used here and following to mean statistically significant (p≤0.05).
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Week 16. Treatment with tanezumab 2.5 mg did not meet any of the co-primary efficacy
endpoints at Week 16.
Outside of the framework of the gate-keeping procedure, focusing on nominal(unadjusted) p-values, both tanezumab treatment groups showed significant
improvement from Baseline in the WOMAC Pain subscale, WOMAC Physical
Function subscale, and the PGA-OA compared with NSAID treatment at Week 4, andtanezumab 5 mg treatment showed significant improvement compared with NSAID at
Week 8. The tanezumab 2.5 mg treatment group showed significant improvementcompared with NSAID in the WOMAC Physical Function subscale at Week 2.
Due to the non-significant results of tanezumab 5 mg treatment compared with NSAID
treatment for PGA-OA at Week 16, further hypothesis testing of the key secondary endpoint(patients with 50% reduction from Baseline in WOMAC Pain at Week 16) could not be
performed, and tanezumab treatment was concluded to be not significantly better than
NSAID treatment due to the testing strategy.
The results of the co-primary efficacy endpoints and key secondary efficacy endpoint were
evaluated considering the gate-keeping approach. All other efficacy endpoints were
evaluated without considering multiplicity, focusing on unadjusted p-values.
Primary Efficacy Analysis
For the WOMAC Pain subscale and the WOMAC Physical Function subscale, thegate-keeping procedure showed significant improvement in efficacy for treatment withtanezumab 5 mg versus NSAID at Week 16 (p=0.0.0148 for WOMAC Pain and p=0.0030 for
WOMAC Physical Function; Table S3). Treatment with 2.5 mg tanezumab did not result insignificant improvement versus NSAID in the WOMAC Pain and Physical function
subscales (p=0.1597 and p=0.0691, respectively). The PGA-OA did not achieve significant
improvement versus NSAID (p=0.6332 and p=0.3431 for the tanezumab 2.5 and 5 mg
treatment groups, respectively).
Table S3. Summary of Co-Primary Efficacy Endpoints - Analysis of Change fromBaseline to Week 16 (ITT, Multiple Imputation)
Tanezumab
2.5 mg(N=1002)

WOMAC Pain Subscale

Tanezumab
5 mg(N=998)NSAID(N=996)LS Mean (SE)-3.22 (0.11)-3.33 (0.11)-3.07 (0.11)

95% CI for LS Mean(-3.43, -3.01)(-3.54, -3.12)(-3.29, -2.86)

LS Mean Difference (SE)

-0.15 (0.11)-0.26 (0.11)

95% CI for LS Mean
Difference(-0.36, 0.06)(-0.46, -0.05)

Versus NSAIDPFIZER CONFIDENTIAL
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Table S3. Summary of Co-Primary Efficacy Endpoints - Analysis of Change fromBaseline to Week 16 (ITT, Multiple Imputation)
Tanezumab
2.5 mg(N=1002)

Tanezumab
5 mg(N=998)0.15970.0148LS Mean (SE)-3.27 (0.11)-3.39 (0.11)-3.08 (0.11)

95% CI for LS Mean(-3.48, -3.05)(-3.60, -3.17)(-3.29, -2.86)

LS Mean Difference (SE)

-0.19 (0.11)-0.31 (0.10)

95% CI for LS Mean
Difference(-0.40, 0.02)(-0.52, -0.11)

0.06910.0030p-value
WOMAC Physical Funcation
Subscale

NSAID(N=996)

Versus NSAID

p-value
Patient Global Assessment of
Osteoarthritis

LS Mean (SE)-0.96 (0.04)-0.97 (0.04)-0.94 (0.04)

95% CI for LS Mean(-1.03, -0.88)(-1.05, -0.90)(-1.01, -0.86)

Versus NSAIDLS Mean Difference (SE)-0.02 (0.04)-0.04 (0.04)

95% CI for LS Mean
Difference(-0.09, 0.06)(-0.11, 0.04)

0.6332

0.3431p-value

A change from Baseline < 0 is an improvement.
Multiple imputation method was applied for missing data, with imputation dependent on reason for missing data.
ANCOVA model for imputed datasets included treatment, randomization stratification variables (index joint, highest
Kellgren-Lawrence grade, and NSAID) as fixed effects, Baseline value and Baseline diary average pain as covariates, andstudy site as a random effect.
Results were taken from a combined analysis of the individual imputed dataset ANCOVA results.
PFIZER CONFIDENTIAL SDTM Creation: 07APR2019 (22:38) Source Data: Listing 16.2.6.1 Output File:./nda1/A4091058_IM_Efficacy/adwn_sg_infr_chg_ancova_mi Date of Generation: 08JUL2019 (11:32)
Table 14.2.1.3.1.i is for Pfizer internal use.

Secondary Efficacy Analysis
Key Secondary Efficacy Endpoint
Patients with 50% reduction from Baseline in WOMAC Pain at Week 16: Due tothe non-significant results of tanezumab 5 mg versus NSAID treatment for the
PGA-OA, under the specified testing procedure, further hypothesis testing of the key
secondary endpoint could not be performed and tanezumab treatment was concluded to
be not significantly better than NSAID treatment. However, both tanezumab treatmentgroups had numerically higher percentages of 50% responders than the NSAID
treatment group at Week 16: tanezumab 2.5 mg treatment group, 54.9%; tanezumab 5
mg treatment group, 56.5% (unadjusted p≤0.05); NSAID treatment group, 51.5%.
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There was a consistent improvement from Baseline in WOMAC Pain subscale scores
across treatment groups beginning at Week 2 and persisting through Week 16. The
reduction from Baseline was significantly greater with tanezumab 2.5 mg and tanezumab
5 mg treatment compared with NSAID treatment at Week 4 and was significantly greaterwith tanezumab 5 mg treatment compared with NSAID at Weeks 8 and 16.

Across treatment groups, there was an improvement from Baseline in WOMAC Physical
Function subscale scores from Week 2 to Week 16. Compared with NSAID, there wasa significantly greater reduction from Baseline at Week 2 with tanezumab 2.5 mg
treatment. At Week 4, both tanezumab treatment groups showed a significantly greater
reduction from Baseline compared with the NSAID treatment group. There was asignificantly greater reduction from Baseline with tanezumab 5 mg treatment comparedwith NSAID at Weeks 8 and 16.

An improvement in PGA-OA score was observed across treatment groups beginning at
Week 2 through Week 16. At Week 4, the reduction from Baseline was significantly
greater in both tanezumab treatment groups compared with the NSAID treatment group.
At Week 8, the tanezumab 5 mg treatment group showed a significantly greater reduction
from Baseline compared with the NSAID treatment group.

The proportion of responders on the OMERACT-OARSI responder index was
significantly greater for patients in both tanezumab treatment groups compared with the
NSAID treatment group at Week 4. At Week 8, the proportion of responders was
significantly greater for patients in the tanezumab 5 mg treatment group compared with
the NSAID treatment group.



Reduction in the WOMAC Pain subscale of 30%, ≥50%, ≥70%, and ≥90%: A
significantly greater proportion of patients in both tanezumab treatment groups than in
the NSAID treatment group responded at the 30% and 50% levels at Week 4.
Additionally, a significantly greater proportion of patients in the tanezumab 5 mg
treatment group compared with the NSAID treatment group responded at the 70% and
90% levels at Weeks 4 and 16, at the 30%, 50%, 70%, and 90% level at Week 8, and at
the 70% level at Week 24. The unadjusted p-value for tanezumab 5 mg treatmentcompared with NSAID treatment was ≤0.05 at Week 16 at the 50% response level,although this (the key secondary endpoint) could not be concluded as significantly
different, due to the testing procedure.

Reduction in the WOMAC Physical Function Subscale of ≥30%, ≥50%, ≥70%, and≥90%: A significantly greater proportion of patients in both tanezumab treatment groups
than in the NSAID treatment group responded at the 70% level at Week 2, at the 30%,
50%, 70%, and 90% levels at Week 4, and at the 50% and 70% levels at Week 8. A
significantly greater proportion of patients in the tanezumab 2.5 mg treatment groupresponded at the 50% level at Week 2; in the tanezumab 5 mg treatment group there wasa significantly greater proportion of responders compared with the NSAID treatment
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group at the 50% level at Week 16, at the 70% level at Weeks 16 and 24, and at the 90%
level at Weeks 2, 8, 16, 24, 32, and 40.
From Weeks 2 to 16, a greater proportion of tanezumab-treated patients tended to have a≥2 point reduction in the PGA-OA compared with NSAID-treated patients. The
difference was significant for both tanezumab treatment groups at Week 4 and for thetanezumab 5 mg treatment group at Weeks 2 and 8.

Patients in the study reported pain in the index joint using an eDiary daily from Day 1 to
Week 16 and then weekly from Week 16 to End of Study. Pain scores in the index joint
were significantly improved in both tanezumab treatment groups compared with the
NSAID treatment group from Week 4 to 20. A significantly greater reduction fromBaseline compared with NSAID treatment was also observed for the tanezumab 2.5 mg
treatment group at Week 3 and the tanezumab 5 mg treatment group at Week 24.

Treatment with tanezumab 2.5 mg resulted in significant improvement compared with
NSAID at Week 16 in the WOMAC Stiffness subscale. Treatment with tanezumab
5 mg resulted in significant improvement compared with NSAID at Week 16 in reductionin the WOMAC Stiffness subscale, WOMAC Average Score (the mean of the
WOMAC Subscale Scores of Pain, Physical Function, and Stiffness), and WOMAC
Pain subscale item: Pain When Going Up or Down Stairs.



Patients in the NSAID treatment group showed a significantly greater improvement in the
WPAI:OA item of reported percent activity impairment score compared withtanezumab-treated patients at Week 56. No additional significant differences wereobserved with tanezumab treatment compared to NSAID treatment for percent work time
missed, percent impairment while working, or percent overall work impairment at Weeks
16, 24, or 56.



The mean EuroQol-5 Dimension-5 Level index values were similar across treatmentgroups at all time points evaluated.

A significant improvement in TSQM satisfaction with effectiveness score was observedwith tanezumab 2.5 mg and tanezumab 5 mg treatments at Week 16 compared with
NSAID treatment. A significant improvement in TSQM satisfaction with convenience
score was observed with tanezumab 2.5 mg and tanezumab 5 mg treatments at Week 16
compared with NSAID treatment. A significant improvement in TSQM global
satisfaction score was observed with tanezumab 2.5 mg and tanezumab 5 mg treatments
at Week 16 compared with NSAID treatment.

In the mPRTI assessment, at Week 16, significantly more patients in the tanezumab
treatment groups than in the NSAID treatment group reported that they would be willingto use the same drug that they received in the study for their OA pain in the future.
Additionally, significantly more patients in the tanezumab 5 mg treatment group than in
the NSAID treatment group reported that they preferred the drug that they received in the
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study to their most recent treatment before entering the study. At Week 56, significantly
more patients in the tanezumab 2.5 mg treatment group than in the NSAID treatmentgroup reported that they would be willing to use the same drug that they received in the
study for their OA pain in the future.
The proportion of patients that discontinued due to insufficient clinical response wassignificantly higher in the NSAID treatment group compared with both tanezumab
treatment groups. NSAID-treated patients tended to discontinue sooner due toinsufficient clinical response than tanezumab-treated patients, and there was a significant
difference in time to discontinuation due to insufficient clinical response between bothtanezumab treatment groups and the NSAID treatment group.



There was no significant difference in the incidence of rescue medication use for either
tanezumab treatment group compared with the NSAID treatment group at any time point.
From Week 4 to Week 32, the proportion of patients that did not take rescue medication
tended to be higher in the tanezumab 5 mg treatment group compared with the tanezumab
2.5 mg and NSAID treatment groups.



From Week 1 to Week 9, the mean amount of rescue medication used on a weekly
basis was lower in the tanezumab 5 mg treatment group compared with the tanezumab
2.5 mg and NSAID treatment groups. The mean amount of rescue medication used was
lower in both tanezumab treatment groups compared with the NSAID treatment groupfrom Week 10 to Week 16. The amount of rescue medication used was significantly
lower in the tanezumab 5 mg treatment group compared with the NSAID treatment groupat Weeks 4 and 8.

Pharmacokinetic Results
At Weeks 8, 16, 32, 48, and 56, the mean tanezumab plasma concentrations were higher forthe 5 mg dose group relative to the 2.5 mg dose group by a proportion approximately similar
to the increase in dose. By Week 64, at 16 weeks after the last dose, the mean tanezumab
plasma concentrations were low, consistent with complete elimination from the body over
five half-lives post seventh injection and were similar for the two tanezumab treatmentgroups.
Pharmacodynamic Results
Mean serum total NGF concentrations were comparable at Baseline across treatment groups.
From Weeks 8 through 56, mean serum total NGF concentrations were higher in thetanezumab 5 mg treatment group than in the tanezumab 2.5 mg treatment group by aproportion approximately similar to the increase in dose. Beginning at Week 64, mean serum
total NGF concentrations began to decline in both the tanezumab 2.5 mg and tanezumab 5
mg treatment groups. Mean serum proNGF concentrations were comparable acrosstreatment groups at all nominal sampling times. Mean and median serum soluble p75
concentrations were comparable at all time points for all treatment groups.

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Safety Results
Adverse Events
During the Treatment Period, adverse events were reported for a greater proportion ofpatients in the tanezumab 5 mg treatment group (67.1%) than in the tanezumab 2.5 mg
treatment group (62.8%) (Table S4). The proportion of patients with adverse events waslowest in the NSAID treatment group (60.3%). Serious adverse events (SAEs) were reported
for the greatest proportion of patients in the tanezumab 5 mg treatment group (8.0%)
followed by the tanezumab 2.5 mg treatment group (5.1%) and the NSAID treatment group(4.6%). The incidence of treatment discontinuation due to an adverse event was highest in
the tanezumab 5 mg treatment group (8.8%).
Table S4. Treatment-Emergent Adverse Events During the Treatment Period (All
Causalities) - Safety Population

Number (%) of subjects
Subjects evaluable for adverse events
Number of adverse events
Subjects with adverse events
Subjects with serious adverse events
Subjects with severe adverse events
Subjects discontinued from study due to adverse events (a)Subjects discontinued study drug due to AE and continued Study (b)Subjects with dose reduced or temporary discontinuation due to adverse
eventsTanezumab
2.5 mgn (%)

Tanezumab
5 mg
n (%)

NSAID

1002

998

996

1723
629 (62.8)
51 (5.1)
45 (4.5)
23 (2.3)
53 (5.3)
17 (1.7)2031
670 (67.1)
80 (8.0)
68 (6.8)
20 (2.0)
88 (8.8)
22 (2.2)

1498
601 (60.3)
46 (4.6)
45 (4.5)
7 (0.7)52 (5.2)
22 (2.2)

n (%)

Includes treatment-emergent events that begin up to the week 56 (end of treatment) visit date for subjects who completed
the treatment period or up to the withdrawal
from treatment date for subjects who withdrew early from the treatment period.
Except for the Number of Adverse Events subjects are counted only once per treatment in each row.
Serious Adverse Events - according to the investigator's assessment.
(a) Subjects who have an AE record that indicates that the AE caused the subject to be discontinued from the study.
(b) Subjects who have an AE record that indicates that action taken with study treatment was drug withdrawn but AE did
not cause the subject to be discontinued from
Study.
MedDRA v21.1 coding dictionary applied.
PFIZER CONFIDENTIAL SDTM Creation: 04APR2019 (07:24) Source Data: Listing 16.2.7.1 Output File:./nda1/A4091058_IM_Safety/adae_s020_i Date of Generation: 09MAY2019 (19:17)
Table 14.3.1.2.1.1.i is for Pfizer internal use.

The incidence of adverse events reported during the Safety Follow-up Period was higher inthe tanezumab 5 mg treatment group (41.5%) than in the tanezumab 2.5 mg (33.5%) and
NSAID (30.9%) treatment groups (Table S5). SAEs were reported for a greater proportionof patients in the tanezumab treatment groups (tanezumab 2.5 mg, 3.8%; tanezumab 5 mg,
3.6%) than in the NSAID treatment group (2.1%). One patient in the tanezumab 5 mg
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treatment group and one patient in the NSAID treatment group discontinued the study due toan adverse event during the Safety Follow-up Period.
Table S5. Treatment-Emergent Adverse Events During the Safety Follow-up Period(All Causalities) - Safety Population

Number (%) of Subjects

Tanezumab
2.5 mgn (%)

Tanezumab
5 mg
n (%)

NSAID

880

885

887

580
295 (33.5)
33 (3.8)
26 (3.0)000688367 (41.5)
32 (3.6)
27 (3.1)
1 (0.1)00501274 (30.9)
19 (2.1)
23 (2.6)
1 (0.1)0
3 (0.3)

Subjects evaluable for adverse events
Number of adverse events
Subjects with adverse events
Subjects with serious adverse events
Subjects with severe adverse events
Subjects discontinued from study due to adverse events (a)Subjects discontinued study drug due to AE and continued Study (b)Subjects with dose reduced or temporary discontinuation due toadverse eventsn (%)

Includes treatment-emergent events that began after the Week 56 (End of Treatment) visit date for subjects who completed
the Treatment Period or after the withdrawal from treatment date for subjects who withdrew early from the Treatment
Period.
Except for the number of adverse events subjects were counted only once per treatment in each row.
Serious Adverse Events - according to the investigator's assessment.
(a) Subjects who had an AE record that indicates that the AE caused the subject to be discontinued from the study.
(b) Subjects who had an AE record that indicates that action taken with study treatment was drug withdrawn but AE did
not cause the Subject to be discontinued from Study.
MedDRA v21.1 coding dictionary applied.
PFIZER CONFIDENTIAL SDTM Creation: 04APR2019 (07:24) Source Data: Listing 16.2.7.1 Output File:./nda1/A4091058_IM_Safety/adae_s020_fup_i Date of Generation: 23MAY2019 (10:59)
Table 14.3.1.2.1.2.i is for Pfizer internal use.

Adverse events occurring at a greater frequency (≥1% difference between treatment groups)
in the tanezumab treatment groups versus the NSAID treatment group included Arthralgia,
Nasopharyngitis, Osteoarthritis, Joint swelling, Headache, Rapidly progressive osteoarthritis,
and Carpal tunnel syndrome (Table S6). Adverse events occurring at a greater frequency(≥1% difference between treatment groups) in the tanezumab 5 mg treatment group versus
the tanezumab 2.5 mg and NSAID treatment groups included Arthralgia, Nasopharyngitis,
Back pain, Osteoarthritis, Oedema peripheral, Rapidly progressive osteoarthritis,
Paraesthesia, Carpal tunnel syndrome, Cough, and Joint effusion. Adverse events of Fall
were reported at a higher frequency (≥1% difference between treatment groups) in thetanezumab 2.5 mg treatment group than in the tanezumab 5 mg and NSAID treatmentgroups. Bronchitis and Hypoaesthesia were reported at a higher frequency (≥1% difference
between treatment groups) in the tanezumab 5 mg treatment group than in the NSAID
treatment group. Upper respiratory tract infection was reported at a higher frequency (≥1%

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difference between treatment groups) in the NSAID and tanezumab 2.5 mg treatment groups
than in the tanezumab 5 mg treatment group.
Table S6. Incidence of Treatment-Emergent Adverse Events During the Treatment
Period in >=2% of Subjects in Any Treatment Group (All Causalities) –Safety Population
Number of subjects evaluable for adverse events

Tanezumab
2.5 mg(N=1002)n (%)

Tanezumab
5 mg(N=998)
n (%)

NSAID
(N=996)

With any adverse event

629 (62.8)

670 (67.1)

601 (60.3)

Arthralgia

133 (13.3)

165 (16.5)

117 (11.7)

Nasopharyngitis

57 (5.7)

67 (6.7)

40 (4.0)

Back pain

34 (3.4)

55 (5.5)

35 (3.5)

Osteoarthritis

39 (3.9)54 (5.4)

23 (2.3)

Fall

65 (6.5)

53 (5.3)

46 (4.6)

Joint swelling

43 (4.3)

48 (4.8)

10 (1.0)

Headache56 (5.6)

45 (4.5)

25 (2.5)

Upper respiratory tract infection

57 (5.7)

45 (4.5)

59 (5.9)

Oedema peripheral

19 (1.9)43 (4.3)

17 (1.7)

Musculoskeletal pain

43 (4.3)

41 (4.1)

37 (3.7)

Rapidly progressive osteoarthritis

18 (1.8)

41 (4.1)

4 (0.4)

Pain in extremity31 (3.1)

37 (3.7)

28 (2.8)

Paraesthesia

18 (1.8)30 (3.0)

13 (1.3)

Bronchitis

22 (2.2)

28 (2.8)

13 (1.3)

Hypoaesthesia

27 (2.7)

28 (2.8)

18 (1.8)

Carpal tunnel syndrome

16 (1.6)

27 (2.7)

6 (0.6)Cough

13 (1.3)

26 (2.6)

7 (0.7)

Influenza

20 (2.0)

21 (2.1)

26 (2.6)

Joint effusion

8 (0.8)21 (2.1)

5 (0.5)

Muscle spasms

15 (1.5)

20 (2.0)19 (1.9)

Urinary tract infection

12 (1.2)

20 (2.0)

15 (1.5)

Hypertension

16 (1.6)

11 (1.1)

25 (2.5)

Nausea14 (1.4)

11 (1.1)

21 (2.1)

Number (%) of subjects:
by Preferred Term

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Table S6. Incidence of Treatment-Emergent Adverse Events During the Treatment
Period in >=2% of Subjects in Any Treatment Group (All Causalities) –Safety Population
Number of subjects evaluable for adverse events

Number (%) of subjects:
by Preferred Term

Tanezumab
2.5 mg(N=1002)n (%)

Tanezumab
5 mg(N=998)
n (%)

NSAID
(N=996)n (%)

Subjects are only counted once per treatment per event.
Adverse events are shown by descending frequency by the highest Tanezumab dose.
Includes treatment-emergent events that begin up to the Week 56 (end of treatment) visit date for subjects who completed
the treatment period or up to the withdrawal from treatment date for subjects who withdrew early from the Treatment
Period.
MedDRA v21.1 coding dictionary applied.
PFIZER CONFIDENTIAL SDTM Creation: 04APR2019 (07:24) Source Data: Listing 16.2.7.1 Output File:./nda1/A4091058_IM_Safety/adae_s030_i Date of Generation: 05JUN2019 (16:57)
Table 14.3.1.2.3.i is for Pfizer internal use.



Treatment-Related Adverse Events: Adverse events considered by the Investigator to
be treatment-related were reported for a higher proportion of patients in the tanezumab
5 mg treatment group (20.8%) than in the tanezumab 2.5 mg treatment group (16.5%)
and the NSAID treatment group (15.9%). Adverse events most frequently consideredtreatment-related by the Investigator (≥1% of patients) in the tanezumab 2.5 mg treatmentgroup were Arthralgia, Hypoaesthesia, Paraesthesia, Rapidly progressive osteoarthritis,
Headache, and Osteoarthritis. Adverse events most frequently considered treatmentrelated by the Investigator (≥1% of patients) in the tanezumab 5 mg treatment group were
Arthralgia, Rapidly progressive osteoarthritis, Osteoarthritis, Paraesthesia,
Hypoaesthesia, Oedema peripheral, and Carpal tunnel syndrome. Arthralgia was the only
treatment-related adverse event reported in ≥1% of patients in the NSAID treatmentgroup. Treatment-related Arthralgia was reported more frequently (≥1% difference
between treatment groups) in the tanezumab 5 mg treatment group than in the tanezumab
2.5 mg and NSAID treatment groups. Treatment-related Osteoarthritis, Rapidly
progressive osteoarthritis, and Carpal tunnel syndrome were reported more frequently(≥1% difference between treatment groups) in the tanezumab 5 mg treatment group thanin the NSAID treatment group, and treatment-related Rapidly progressive osteoarthritis
was reported more frequently reported (≥1% difference between treatment groups) in thetanezumab 5 mg treatment group than in the tanezumab 2.5 mg treatment group.



Severe Adverse Events: During the Treatment Period, severe adverse events werereported for more patients in the tanezumab 5 mg treatment group (6.8%) than in thetanezumab 2.5 mg treatment group (4.5%) and the NSAID treatment group (4.5%). The
most commonly reported (≥0.5% of patients in any treatment group) severe adverse
events were Arthralgia, Osteoarthritis, and Rapidly progressive osteoarthritis.
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Osteoarthritis that was considered severe occurred more frequently (≥0.5% difference
between treatment groups) in the tanezumab 5 mg treatment group than in the tanezumab
2.5 mg treatment group and the NSAID treatment group. Severe Rapidly progressive
osteoarthritis was reported more frequently (≥0.5% difference between treatment groups)
in the tanezumab 5 mg treatment group than in the NSAID treatment group.
Injection Site Reactions: Injection site reactions were infrequently reported (0.5%
across treatment groups) during the Treatment Period. All Injection site reactions weremild in severity, and none were serious.



Potential Hypersensitivity Adverse Events: Few hypersensitivity adverse events werereported during the Treatment Period. The incidence of potential hypersensitivity
adverse events was slightly greater in both tanezumab treatment groups (tanezumab 2.5
mg, 3.0%; tanezumab 5 mg, 3.1%) than in the NSAID treatment group (2.1%). These
adverse events were mild or moderate in severity, except for one adverse event ofHypersensitivity in a patient in the tanezumab 5 mg treatment group that was serious andconsidered severe; this SAE was considered related to a concomitant drug treatment andhad resolved within 24 hours.



Tier 1 Adverse Events: Pre-specified adverse events of potential sympathetic
dysfunction (Syncope, Bradycardia, orthostatic hypotension [OH], Anhidrosis, andHypohidrosis) were considered clinically important and the overall pooled incidence ofthe events was classified as a Tier 1 adverse event in the Product's Safety Review Plan.
The overall incidence of these events during the Treatment Period was low (tanezumab
2.5 mg, 1.8%; tanezumab 5 mg, 2.3%; NSAID, 2.9%). There was no significant
difference between the frequencies of occurrence when comparing either of thetanezumab treatment groups to the NSAID treatment group.



Tier 2 Adverse Events: Tier 2 adverse events were defined as adverse events occurringat ≥3% in any treatment group. The frequency of occurrence in each tanezumab
treatment group is compared to the NSAID group with 95% confidence intervals
provided to help gauge the precision of the estimates for risk difference. Joint swelling,
Osteoarthritis, and Headache occurred more frequently (CI did not include zero) in thetanezumab 2.5 mg treatment group than in the NSAID treatment group. Oedema
peripheral, Nasopharyngitis, Arthralgia, Joint swelling, Rapidly progressive
osteoarthritis, Osteoarthritis, Back pain, Headache, and Paraesthesia occurred more
frequently (CI did not include zero) in the tanezumab 5 mg treatment group than in the
NSAID treatment group.



Deaths: A total of 10 patients died during the study. Five deaths occurred during theTreatment Period (two patients in the tanezumab 2.5 mg treatment group [Myocardial
infarction and Cardiac arrest] and three patients in the tanezumab 5 mg treatment group[Acute myocardial infarction and Myocardial rupture, Pulmonary embolism, andMyocardial infarction]) and three deaths occurred during the Safety Follow-up Period
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CLINICAL STUDY REPORT SYNOPSIS(two patients in the tanezumab 2.5 mg treatment group [Toxicity to various agents andAcute respiratory failure secondary to Lung adenocarcinoma] and one patient in thetanezumab 5 mg treatment group [Acute respiratory failure]). Two deaths occurred inpatients who had discontinued from the study: one patient in the tanezumab 5 mg
treatment group (Sudden death) and one patient in the NSAID treatment group(Cardio-respiratory arrest).


Serious Adverse Events: During the Treatment Period, SAEs were reported for a greater
proportion of patients in the tanezumab 5 mg treatment group (8.0%) than in thetanezumab 2.5 mg treatment group (5.1%) and the NSAID treatment group (4.6%). In
the Musculoskeletal and connective tissue disorders system organ class, more (≥1%difference between treatment groups) SAEs were reported for patients in the tanezumab 5
mg treatment group (4.5%) than for patients in the tanezumab 2.5 mg treatment group(1.8%) and the NSAID treatment group (1.0%). SAEs of Osteoarthritis, Rapidly
progressive osteoarthritis, and Arthralgia were reported more frequently (≥0.5%
difference between treatment groups) in the tanezumab 5 mg treatment group than in thetanezumab 2.5 mg and NSAID treatment groups. All other individual preferred terms
occurred in one or two patients per treatment group, with the exception of Acutemyocardial infarction (three patients in the NSAID treatment group), Meniscus injury(three patients in the tanezumab 5 mg treatment group) and Subchondral insufficiency
fracture (four patients in the tanezumab 5 mg treatment group).

Joint Safety Events of Special Interest
Primary Composite Joint Safety Outcome
Across treatment groups, 335 patients had joint safety events that met criteria for
adjudication (Table S7). The highest number of patients with events requiring adjudication
was in the tanezumab 5 mg treatment group, followed by the tanezumab 2.5 mg treatmentgroup and the NSAID treatment group.
The incidence of the primary composite joint safety outcome was highest in the tanezumab
5 mg treatment group (7.1%), followed by the tanezumab 2.5 mg treatment group (3.8%) andthe NSAID treatment group (1.5%). The risk difference versus NSAID was significantly
greater for both tanezumab treatment groups (tanezumab 2.5 mg, p=0.0156; tanezumab 5 mg,
p<0.0001).
The primary analysis of the primary composite joint safety outcome, observation
time-adjusted rate of the primary composite joint safety outcome, was highest in thetanezumab 5 mg treatment group (71.5 events/1000 patient-years), followed by thetanezumab 2.5 mg treatment group (37.4 events/1000 patient-years) and the NSAID
treatment group (14.8 events/1000 patient-years). The observation time-adjusted rate wassignificantly greater for both tanezumab treatment groups compared with the NSAID
treatment group (rate difference versus NSAID: tanezumab 2.5 mg, p=0.0017; tanezumab
5 mg, p<0.0001).
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There were 124 patients across treatment groups who had adjudication results included in the
primary composite joint safety outcome; the most frequently observed outcome was Rapidly
progressive OA type 1 (88 patients [71.0%]), followed by Rapidly progressive OA type 2 (18patients [14.5%]) and Subchondral insufficiency fracture (17 patients [13.7%]). One patientin the tanezumab 5 mg treatment group had an outcome of Primary osteonecrosis. There
were no events of Pathologic fracture observed in any treatment group.
One patient in the tanezumab 2.5 mg group had an Investigator-reported adverse event ofsuspected Osteonecrosis of the right hip that was not evaluated by the Adjudication
Committee until after the study database had been locked. The Adjudication Committee’s
final evaluation of the event was “Osteonecrosis”. This adjudicated event is not included inanalyses of the primary or secondary composite joint safety outcomes or in the analysis ofindividual adjudication outcomes of primary osteonecrosis. No other joint safety analyses
are affected by this case and the overall conclusions regarding joint safety are not impacted.
Table S7. Summary of Adjudicated Joint Safety Outcomes - Subject-Level, Primary
Outcome - Safety Population
Tanezumab 2.5 mg(N=1002)

Tanezumab 5 mg
(N=998)NSAID(N=996)

Subjects analyzed by the Adjudication Committee [n (%)]

115 ( 11.5%)

171 ( 17.1%)

49 ( 4.9%)

Primary Composite Joint Safety Endpoint (1) [n (%), {95%CI}]

38 ( 3.8%)

71 ( 7.1%)

15 ( 1.5%)[ 2.7%, 5.2%][ 5.6%, 8.9%][ 0.8%, 2.5%]

9 ( 0.9%)22 ( 2.2%)

5 ( 0.5%)[ 0.4%, 1.7%][ 1.4%, 3.3%][ 0.2%, 1.2%]

32 ( 3.2%)[ 2.2%, 4.5%]

63 ( 6.3%)[ 4.9%, 8.0%]

11 ( 1.1%)[ 0.6%, 2.0%]

Rapidly Progressive OA type 1 [n (%), {95% CI}]

29 ( 2.9%)[ 1.9%, 4.1%]

49 ( 4.9%)[ 3.7%, 6.4%]

10 ( 1.0%)[ 0.5%, 1.8%]

Rapidly Progressive OA type 2 [n (%), {95% CI}]

3 ( 0.3%)[ 0.1%, 0.9%]14 ( 1.4%)[ 0.8%, 2.3%]

1 ( 0.1%)[ 0.0%, 0.6%]

Primary Osteonecrosis [n (%), {95% CI}]0
[ 0.0%, 0.4%]

1 ( 0.1%)[ 0.0%, 0.6%]

0[ 0.0%, 0.4%]

Pathological Fracture [n (%), {95% CI}]0
[ 0.0%, 0.4%]

0[ 0.0%, 0.4%]

0[ 0.0%, 0.4%]

Subchondral Insufficiency Fracture [n (%), {95% CI}]

6 ( 0.6%)[ 0.2%, 1.3%]

7 ( 0.7%)[ 0.3%, 1.4%]

4 ( 0.4%)[ 0.1%, 1.0%]

2 ( 0.2%)0066 ( 6.6%)
9 ( 0.9%)79 ( 7.9%)
21 ( 2.1%)

27 ( 2.7%)7 ( 0.7%)

Secondary Composite Joint Safety Endpoint (2) [n (%),
{95% CI}]
Rapidly Progressive OA [n (%), {95% CI}]

Not Enough Info to Determine Rapid vs. Normal
Progression of OA [n (%)]
Normal Progression of OA [n (%)]
Other Joint Outcome [n (%)]

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Table S7. Summary of Adjudicated Joint Safety Outcomes - Subject-Level, Primary
Outcome - Safety Population
Tanezumab 2.5 mg(N=1002)

Tanezumab 5 mg
(N=998)NSAID(N=996)(1) The primary composite joint safety endpoint includes any subject with an adjudicated outcome of primaryosteonecrosis, rapidly progressive OA type 1 or type 2,subchondral insufficiency fracture, or pathological fracture.
(2) The secondary composite joint safety endpoint includes any subject with an adjudicated outcome of primaryosteonecrosis, rapidly progressive OA type 2,subchondral insufficiency fracture, or pathological fracture.
Primary outcome for each subject is shown, according to the following hierarchy: primary osteonecrosis, rapidly
progressive OA type 2, subchondral insufficiency fracture, pathological fracture, rapidly progressive OA type 1, notenough info to determine rapid vs. normal progression of OA, other, normal progression of OA.
Includes TJR or adjudicated event up to the end of the safety follow-up period or 26 weeks after the end of the treatment
period, whichever is later.
PFIZER CONFIDENTIAL SDTM Creation: 15APR2019 (18:25) Source Data: Table 16.2.8.7 Output File:./nda1/A4091058_IM_Efficacy/adadj_s0032_i Date of Generation: 05JUN2019 (17:40)
Table 14.5.1.2.2.1.i is for Pfizer internal use.

Secondary Joint Safety Analysis
The secondary composite joint safety outcome, reported for 36 patients total, was more
frequently observed in the tanezumab 5 mg treatment group (22 patients [2.2%])
compared with the tanezumab 2.5 mg and NSAID treatment groups (nine patients [0.9%]
and five patients [0.5%], respectively). The risk difference was significantly greater forthe tanezumab 5 mg treatment group compared with the NSAID treatment group(p=0.0238); there was no significant difference with tanezumab 2.5 mg treatmentcompared with NSAID treatment. The observation time-adjusted rate of the secondary
composite joint safety outcome was highest in the tanezumab 5 mg treatment group (21.8
events/1000 patient-years), followed by the tanezumab 2.5 mg treatment group (8.8
events/1000 patient-years) and the NSAID treatment group (4.9 events/1000 patientyears). The observation time-adjusted rate was significantly greater in the tanezumab 5
mg treatment group compared with the NSAID treatment group (rate difference versus
NSAID: p=0.0010); there was no significant difference with tanezumab 2.5 mg treatmentcompared with NSAID treatment.



Rapidly progressive OA was the most common individual adjudication outcome, with
114 events observed in 107 patients. Of these, the majority of events were Rapidly
progressive OA type 1, with 94 events reported for 89 patients across treatment groups.
The incidence of the Rapidly progressive OA type 1 was highest in the tanezumab 5 mg
treatment group (49 patients [4.9%]) followed by the tanezumab 2.5 mg treatment group(29 patients [2.9%]) and the NSAID treatment group (11 patients [1.1%]); the incidence
was significantly greater for both tanezumab treatment groups compared with the NSAID
treatment group. A total of seventeen events adjudicated to Subchondral insufficiency
fracture (six in the tanezumab 2.5 mg treatment group, seven in the tanezumab 5 mg
treatment group, and four in the NSAID treatment group) and one event for a patient in
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the tanezumab 5 mg treatment group adjudicated to Primary osteonecrosis. No events
adjudicated to Pathological fracture.
In total, 172 patients had joint safety events adjudicated to Normal progression of OA
and did not also have an event in the primary composite joint safety outcome. The
incidence of these events was higher in the tanezumab treatment groups (66 patients[6.6%] and 79 patients [7.9%] in the tanezumab 2.5 and 5 mg treatment groups,
respectively) than in the NSAID treatment group (27 patients [2.7%]). A total of 37
patients across treatment groups had 42 joint safety events adjudicated to Other joint
outcome and did not also have an event included in the primary composite joint safety
outcome, with a higher incidence in the tanezumab 5 mg treatment group (21 patients[2.1%]) compared with the tanezumab 2.5 mg and NSAID treatment groups (ninepatients [0.9%] and seven patients [0.7%], respectively).
Total Joint Replacements: A total of 159 patients across treatment groups had at least
one TJR. The incidence of TJR was highest in the tanezumab 5 mg treatment group(8.0%), followed by the tanezumab 2.5 mg treatment group (5.3%) and the NSAID
treatment group (2.6%); the incidence was significantly higher for both tanezumab
treatment groups compared with NSAID. More patients had an adjudicated outcome that
was a component of the primary composite joint safety outcome in the tanezumab 5 mg
treatment group (20 patients [25.0%]) compared with the tanezumab 2.5 mg treatmentgroup (four patients [7.5%]) and NSAID treatment group (four patients [15.4%]). The
secondary composite joint safety outcome was also more frequently associated with a
TJR for patients in the tanezumab 5 mg treatment group (13 patients [16.3%]) comparedwith the tanezumab 2.5 mg (one patient [1.9%]) and the NSAID (two patients [7.7%])
treatment groups. Rapidly progressive OA types 1 and 2 were both most frequently
associated with a TJR in the tanezumab 5 mg treatment group. Three patients in thetanezumab 5 mg treatment group and one patient in the NSAID treatment group with a
TJR had an adjudication outcome of Subchondral insufficiency fracture, and one patientin the tanezumab 5 mg treatment group with a TJR had an adjudication outcome ofPrimary osteonecrosis. Five patients had an adjudicated outcome of Other joint outcome.

Radiography: In patients with Baseline KL grade 2 or 3, a significantly greater decreasein minimum joint space width (JSW) of the medial compartment of the index knee wasobserved in the tanezumab 5 mg treatment group compared with the NSAID treatmentgroup at Weeks 56 and 80. There were no significant differences in JSW decrease of theindex hip for either tanezumab treatment group compared with NSAID at Week 56 or
Week 80, although the sample size evaluated was relatively small (approximately 5% of
the total population).
Using the Bland and Altman method, the proportion of patients with progression of OA
in the index knee (medial compartment, KL Grade 2 or 3) was significantly greater in thetanezumab 5 mg treatment group compared with the NSAID treatment group at Weeks
56 and 80. There was no significant difference in the proportion of patients withPFIZER CONFIDENTIAL
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progression of OA in the index hip when comparing tanezumab-treated patients with
NSAID-treated patients at Weeks 56 and 80, although the proportion of patients in bothtanezumab treatment groups who were considered to have progression of OA wasnumerically higher than in the NSAID treatment group at Week 80 and the sample size
evaluated was relatively small (approximately 5% of the total population).
Other Safety Analysis
Adverse Events of Abnormal Peripheral Sensation: The incidence of adverse events ofabnormal peripheral sensation was highest in the tanezumab 5 mg treatment group(9.0%), followed by the tanezumab 2.5 mg treatment group (6.2%) and the NSAID
treatment group (4.6%). Carpal tunnel syndrome occurred at a greater frequency (≥1%difference between treatment groups) in the tanezumab 5 mg treatment group than in thetanezumab 2.5 mg treatment group and the NSAID treatment group, and also occurred ata greater frequency in the tanezumab 2.5 mg treatment group than in the NSAID
treatment group. Hypoaesthesia occurred at a greater frequency (≥1% difference between
treatment groups) in the tanezumab 5 mg treatment group than in the NSAID treatmentgroup, and Paraesthesia occurred at a greater frequency in the tanezumab 5 mg treatmentgroup than in the tanezumab 2.5 mg and NSAID treatment groups. An SAE of Carpal
tunnel syndrome was reported for one patient in the tanezumab 2.5 mg treatment group.
Carpal tunnel syndrome was considered severe for one patient in the tanezumab 2.5 mg
treatment group, two patients in the tanezumab 5 mg treatment group, and one patient in
the NSAID treatment group. Across treatment groups, 12 patients had a total of 14 carpal
tunnel release surgeries. Seven (four in the tanezumab 2.5 mg treatment group, two in
the tanezumab 5 mg treatment group, and one in the NSAID treatment group) of thesesurgeries occurred within 16 weeks of the last dose of SC study medication. Sensory loss
was considered severe for one patient in the tanezumab 5 mg treatment group. All otheradverse events of abnormal peripheral sensation were mild or moderate in severity.



Peripheral Neurological Consultations: More patients in the tanezumab 2.5 mg and 5
mg treatment groups had adverse events of abnormal peripheral sensation that met
criteria for requiring a neurologic consult than in the NSAID treatment group. The mostfrequent expert primary diagnosis across treatment groups was Mononeuropathy, which
occurred at a greater frequency in the tanezumab 5 mg treatment group than in thetanezumab 2.5 mg and NSAID treatment groups. Radiculopathy was diagnosed in morepatients in the tanezumab 2.5 mg treatment group than in the tanezumab 5 mg treatmentgroup and the NSAID treatment group. Polyneuropathy was diagnosed intanezumab-treated patients only.



Adverse Events Potentially Indicative of Decreased Sympathetic Function: The
incidence of treatment emergent adverse events of interest that could be indicative ofdecreased sympathetic function during the Treatment Period was highest in the NSAID
treatment group (7.3%), followed by the tanezumab 5 mg treatment group (6.8%) and thetanezumab 2.5 mg treatment group (6.1%). Nausea occurred at a greater frequency (≥1%difference between treatment groups) in the NSAID treatment group than in the
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tanezumab 5 mg treatment group. One patient in both the tanezumab 2.5 mg and NSAID
treatment groups had an adverse event of syncope that was considered severe. Diarrhoea
was considered severe for one patient in the tanezumab 5 mg treatment group and one
patient in the NSAID treatment group. In the tanezumab 5 mg treatment group, severe
adverse events of Nausea and Vomiting were reported for one patient each. All otheradverse events potentially indicative of decreased sympathetic function were mild or
moderate in severity.
A subset of these adverse events (Bradycardia, OH, Syncope, Anhidrosis, andHypohidrosis) were considered signs or symptoms suggestive of sympathetic
dysfunction. The incidence of these events was low across treatment groups.
Bradycardia was reported at a higher incidence in the NSAID treatment group (1.6%)
than in the tanezumab 2.5 mg and 5 mg treatment groups (0.7% and 0.9%, respectively).
OH and Syncope occurred at similar, low frequencies across treatment groups.
Hypohidrosis occurred in one patient in the tanezumab 5 mg treatment group and was
mild in severity. No events of Anhidrosis were reported.


Consultations for Adverse Events Potentially Indicative of Decreased Sympathetic
Function: Patients with adverse events of Bradycardia and Syncope met criteria for
consultation in all treatment groups. Patients with adverse events of OH met criteria for
consultation in the tanezumab 5 mg and NSAID treatment groups. One patient in thetanezumab 5 mg treatment group had an adverse event of Hypohidrosis that met criteria
for consult. No events of Anhidrosis were reported. Consults were obtained in the
majority of patients who met criteria for a consult. Sympathetic neuropathy was notconfirmed for any of the patients who had a consultation, as determined by theInvestigator after a review of clinical data, including available consultation material.



Neuropathy Impairment Score: For over 93% of patients across treatment groups, theconclusion from the neurological examinations at the last assessment was no new orworsened neurological examination abnormality. Less than 1% of patients in any
treatment group had a new or worsened neurological examination abnormality that wasconsidered by the Investigator to be clinically significant.

Laboratory Parameters: The incidence of patients with normal Baseline who had postBaseline laboratory test abnormalities that met the pre-specified threshold for change
from Baseline was low, affected no more than 25 (approximately 3%) patients within atreatment group, and was generally evenly distributed across treatment groups.
Laboratory abnormalities considered clinically significant by the Investigator postBaseline were to be reported as adverse events. The incidence of adverse events
associated with laboratory abnormalities during the Treatment Period was low andsimilar across treatment groups. All laboratory abnormalities reported as adverse eventsin the Treatment Period were reported in one or two patients each in any treatment group,with the exception of Blood creatinine phosphokinase increased (six patients and threepatients in the tanezumab 2.5 mg and 5 mg treatment groups, respectively) and
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Gamma-glutamyltransferase increased (three patients in the NSAID treatment group).
One patient in the tanezumab 2.5 mg treatment group had an adverse event of Bloodcreatinine increased, considered mild, that resulted in discontinuation. No laboratory
abnormalities were considered severe.


Vital Signs: Categorical changes from Baseline to the last post-Baseline value during theTreatment period in sitting systolic and diastolic blood pressure (BP) were generally
similar across treatment groups. The proportion of patients with a maximum increase
from Baseline of greater than zero and less than 10 mmHg in sitting systolic and diastolic
BP was lower in the tanezumab 5 mg treatment group than in the tanezumab 2.5 mg and
NSAID treatment groups. The proportion of patients with only a decrease or no change
from Baseline in sitting systolic and diastolic BP was greater in the tanezumab treatmentgroups than in the NSAID treatment group. The proportion of patients with only an
increase or no change from Baseline in sitting systolic and diastolic BP was lower in thetanezumab 5 mg treatment group than in the tanezumab 2.5 mg and NSAID treatmentgroup.
During the Treatment Period, the incidence of adverse events associated with vital signs
was higher in the NSAID treatment group (5.3%) compared with the tanezumab 2.5 mg(3.9%) and tanezumab 5 mg (3.8%) treatment groups. Hypertension was the mostfrequently reported adverse event associated with vital signs and occurred mostfrequently in the NSAID treatment group (2.5%), followed by the tanezumab 2.5 mg
treatment group (1.6%) and the tanezumab 5 mg treatment group (1.1%). Adverse eventsof Bradycardia occurred at a higher frequency in the NSAID treatment group (1.6%) thanin the tanezumab 2.5 mg (0.7%) and tanezumab 5 mg (0.9%) treatment groups.



ECG: One patient in the tanezumab 5 mg treatment group and one patient in the NSAID
treatment group had a QTcB (QTc corrected using Bazett's formula) interval 500 msec.
The maximum changes in all ECG parameters were similar across treatment groups.
ECG abnormalities considered clinically significant by the Investigator and any episodeof a decrease in heart rate that met protocol criteria for Bradycardia on ECG were to bereported as adverse events. Across treatment groups, few ECG-related adverse eventswere observed during the Treatment Period. The most frequently reported adverse event
associated with ECG was Bradycardia, which was reported at a higher frequency in the
NSAID treatment group (1.6%) than in the tanezumab 2.5 mg (0.7%) and tanezumab
5 mg (0.9%) treatment groups.



Immunogenicity: Treatment-emergent (TE) ADA status (ie, TE ADA+ or TE ADA-) did
not appear to influence the proportion of patients identified as responders (ie, patientswith a change from Baseline in WOMAC Pain Subscale reduction of 30% at Week 16)
in the tanezumab treatment groups. The overall percent incidence of adverse events andinjection site reactions in the combined TE ADA+ tanezumab treatment group was

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CLINICAL STUDY REPORT SYNOPSIS
comparable to the corresponding TE ADA- combined tanezumab treatment group andthere was no association between TE ADA+ and potential hypersensitivity reactions.
CONCLUSIONS

The incidence of the primary composite joint safety outcome was significantly higher inboth tanezumab treatment groups compared with the NSAID treatment group, primarily
due to a higher rate of Rapidly progressive OA with tanezumab treatment. The
observation time-adjusted rate of the primary composite joint safety outcome wassignificantly greater for both the tanezumab 2.5 mg (37.4 events/1000 patient-years;
p=0.0017) and tanezumab 5 mg (71.5 events/1000 patient-years; p<0.0001) treatmentgroups compared with the NSAID treatment group (14.8 events/1000 patient-years).



There were 124 patients total who had adjudication results included in the primary
composite joint safety outcome; the most frequently observed individual outcome was
Rapidly progressive OA type 1 (89 patients [71.8%]).

The incidence and observation time-adjusted rate of TJR were significantly higher forboth tanezumab treatment groups compared with the NSAID treatment group.

In patients with Baseline KL grade 2 or 3, treatment with tanezumab 5 mg resulted in asignificantly greater decrease in JSW of the medial compartment of the index knee and asignificantly greater proportion of patients with progression of OA in the medialcompartment of the index knee at Weeks 56 and 80; there were no significant differences
when comparing tanezumab 2.5 mg treatment with NSAID treatment.

Treatment with tanezumab was associated with an increased incidence of adjudicatedjoint safety events. Tanezumab 2.5 mg treatment had a more favorable joint safety
profile than tanezumab 5 mg treatment based on the frequency and severity of joint safety
events observed.



The adverse event data were generally consistent with previous tanezumab studies and no
new safety signals were identified.



The adverse event data related to abnormal peripheral sensation were consistent withprevious studies and the incidence of these events was more frequent in the tanezumab
treatment groups. As in previous studies, Paraesthesia and Hypoaesthesia were the mostcommonly reported adverse events of abnormal peripheral sensation.



There was no evidence of an effect of tanezumab on sympathetic nervous system
function.



The immunogenicity results do not provide any evidence that the presence oftreatment-emergent ADA affects the safety or efficacy profile of tanezumab.

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CLINICAL STUDY REPORT SYNOPSIS

Treatment with tanezumab 5 mg met two co-primary efficacy endpoints (WOMAC Pain andPhysical Function subscales) but not the third co-primary endpoint (PGA-OA) at Week 16,
and so did not meet the overall primary objective. Further hypothesis testing of the key
secondary endpoint could not be performed because the PGA-OA endpoint for
tanezumab 5 mg was not met.

Treatment with tanezumab 2.5 mg did not meet any of the co-primary efficacy endpoints at
Week 16.



The results for the key secondary efficacy endpoint were deemed not significant due tothe testing strategy. Both tanezumab treatment groups had numerically higher
percentages of 50% responders than the NSAID treatment group at Week 16 and theunadjusted p-value for tanezumab 5 mg compared with NSAID was ≤0.05.

Both tanezumab treatment groups tended to have numerically higher percentages of
responders than the NSAID treatment group at the 30%, 50%, 70%, and 90% levels in
WOMAC Pain and Physical Function scores at Weeks 2, 4, 8, and 16. Most of thesecomparisons were significant (unadjusted p≤0.05) for the tanezumab 5 mg treatmentgroup compared with the NSAID treatment group, while fewer were significant for thetanezumab 2.5 mg treatment group compared with the NSAID treatment group.

Treatment with tanezumab 2.5 mg resulted in significant (unadjusted p≤0.05)
improvement compared with NSAID at Week 16 in average pain score in the index joint
and the WOMAC Stiffness subscale. Treatment with tanezumab 5 mg resulted insignificant improvement (unadjusted p≤0.05) compared with NSAID at Week 16 inaverage pain score in the index joint, WOMAC Stiffness subscale, WOMAC Average
Score, and WOMAC Pain subscale item: Pain When Going Up or Down Stairs.

For all endpoints evaluated across the 56-week treatment duration, tanezumab treatment
resulted in improved or similar efficacy compared with NSAID treatment.

This study was primarily a long-term safety study and was not powered nor designed
optimally to assess long-term efficacy (eg, large amount of imputed data due to planned
discontinuation of non-responding subjects from treatment) for treatment groupcomparisons of efficacy after Week 16. Given these limitations, improvement in pain
was maintained long-term across all treatment groups.

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