Full Clinical Study Report
Protocol A4091057

CLINICAL STUDY REPORT SYNOPSIS
Sponsor: Pfizer Inc
Investigational Product: Tanezumab
Clinical Study Report Synopsis: Protocol A4091057
Protocol Title: A Phase 3 Randomized, Double-Blind, Placebo-Controlled, Multicenter
Study of the Analgesic Efficacy and Safety of the Subcutaneous Administration of
Tanezumab in 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 104 sites randomized patients in this study. The study was
conducted at sites in Austria, Bulgaria, Finland, France, Germany, Hungary, Italy, Japan,
Poland, Portugal, Romania, Slovakia, Spain, Sweden, and the United Kingdom.
Publications Based on the Study: None
Study Initiation and Completion Dates:
Study Initiation Date: 02 March 2016
Primary Completion Date: 08 June 2018
Study Completion Date: 14 November 2018
Report Date: 27 June 2019
Previous Report Date(s): 13 May 2019
Phase of Development: Phase 3
Study Objective(s)Primary ObjectiveDemonstrate superior efficacy of tanezumab 5 mg and tanezumab 2.5 mg administeredsubcutaneously (SC) every 8 weeks versus placebo at Week 24.

Secondary Objective

Evaluate the safety of tanezumab 2.5 mg SC and 5 mg SC.

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CLINICAL STUDY REPORT SYNOPSISMETHODS
Study Design
This was a randomized, double-blind, placebo-controlled, parallel-group, multicenter Phase 3
study of the efficacy and safety of tanezumab when administered by SC injection over
24 weeks, compared to placebo, in patients with osteoarthritis (OA) of the knee or hip. Eighthundred ten (810) patients were planned to be randomized to one of three treatment groups ina planned 1:1:1 ratio (ie, 270/group). Patients were to receive up to three 1 mL SC injectionsof study medication in the abdomen or anterior aspect of the thigh at 8-week intervals.


Tanezumab 2.5 mg;

Tanezumab 5 mg;

Placebo to match tanezumab.

The randomization was stratified by index joint (hip or knee), and most severe KellgrenLawrence (KL) grade (of any knee or hip joint) at study entry.
The study was designed with a total (post-Randomization) duration of 48 weeks andconsisted of three periods: Screening (up to 37 days), Double-Blind Treatment Period(24 weeks), and Safety Follow-up Period (24 weeks). The Screening Period (beginning up to
37 days prior to Randomization) included a Washout Period (lasting a minimum of two days
for all prohibited pain medications), if required, and an Initial Pain Assessment Period(IPAP) (7 days prior to Randomization/Baseline).
All patients signed an informed consent document and were assessed for eligibility prior to
randomization. In addition, the Screening Period included the discontinuation and washoutof all prohibited pain medications for at least five times the elimination half-life. The IPAP
began 7 days prior to the Baseline (Day 1) Randomization Visit, and patients must havecompleted at least three diary entries during the IPAP; all diary entries were used todetermine the Baseline value for the average pain score in the index joint. Patients
experiencing pain during the Washout Period could take acetaminophen as needed up to4000 mg per day, or as permitted by local or national labelling, but must have discontinued
rescue medication for at least 24 hours prior to the Baseline (Randomization) Visit.
Prior to the beginning of the IPAP, patients were provided with an electronic diary (eDiary)
to record, via Interactive Response Technology (IRT), index joint pain scores and rescue
medication use daily from the IPAP to the end of the Treatment Period (Week 24), and thenweekly to Week 48, index and non-index joint pain scores from IPAP to Week 48, andnon-steroidal anti-inflammatory drug (NSAID) use weekly from Baseline to Week 48.
On Day 1, eligible patients were randomized and received their first dose of blinded study
medication (tanezumab 2.5 mg, tanezumab 5 mg, or placebo) via SC injection, the second
dose was administered at Week 8 (Day 57±7 days), and the third dose at Week 16 (DayPFIZER CONFIDENTIAL
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113±7 days). Patients had additional in-clinic visits at Week 2 (Day 15±3 days), Week 4(Day 29±3 days), Week 12 (Day 85±7 days), and Week 24 (Day 169±7 days); they were
contacted by phone at Week 20 (Day 141±7 days). Patients could take rescue medication up
to five days per week during the Treatment Patients were to discontinue rescue medication
within 24 hours of any scheduled visit at which efficacy assessments were collected.
The Week 24 Visit marked both the end of the Treatment Period and the beginning of the
24-Week Safety Follow-up Period. After Week 24, patients could take rescue medication
daily but were required to abstain from taking rescue medication within 24 hours prior to the
Week 24 Visit. The Safety Follow-up Period included in-clinic visits at Week 32 (Day225±7 days, when last efficacy assessments were obtained; standard of care treatment could
be initiated following this visit), and Week 48 (Day 337±7 days, the End of Study Visit), andfour telephone contacts (Week 28 [Day 197±7 days], Week 36 [Day 253±7 days], Week 40[Day 281±7 days], and Week 44 [Day 309±7 days]) between site staff and enrolled patients.
The patients completed the Safety Follow-up and the Study at Week 48.
Patients who left the study prior to completing the Week 24 Visit were not considered tohave completed the Double-blind Treatment Period. Patients who discontinued fromtreatment prior to Week 24, either at their request or at the decision of the Investigator, wererequired to undergo 24 weeks of follow-up (referred to as Early Termination Follow-up).
The 24-week Early Termination Safety Follow-up was obtained through three clinic visits,
beginning eight weeks after the last dose was administered (Early Termination Visit 1).
Early Termination Visit 2 occurred 16 weeks after the last dose administered and Early
Termination Visit 3 took place 24 weeks after the last dose. Telephone contact was madewith the patient approximately 12 and 20 weeks after the last dose of study medication
Patients who completed 24 weeks of Early Termination Follow-up were considered to havecompleted the Safety Follow-up and the Study.
Diagnosis and Main Criteria for InclusionMale or female of any race, ≥18 years of age; willing and able to provide informed
consent.



A diagnosis of OA of the hip or knee in the index joint based on American College of
Rheumatology (ACR) criteria with X-ray confirmation (a Kellgren-Lawrence [KL]
X-ray grade of ≥2 as diagnosed by the Central Reader).



Documented history indicating that acetaminophen therapy had not provided
sufficient pain relief, that oral NSAID therapy had not provided adequate pain relief,or that the patient was unable to take NSAIDs due to contraindication or inability totolerate.

Documented history indicating that tramadol treatment had not provided adequate
pain relief or patient was unable to take tramadol due to contraindication or inability
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CLINICAL STUDY REPORT SYNOPSIS
to tolerate, 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 to tolerate.


Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain
Subscale numerical rating scale (NRS) ≥5 in the index joint at Screening.



Patients were willing to discontinue all pain medications for OA except rescue
medication (acetaminophen/paracetamol) 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 >39 kg/m2.



History of other disease that involved the index joint, including inflammatory joint
disease, such as rheumatoid arthritis, seronegative spondyloarthropathy(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 radiographas determined by the Central Radiology Reviewer and as defined in the tanezumab
program imaging atlas: excessive malalignment of the knee, severechondrocalcinosis, other arthropathies (eg, rheumatoid arthritis), systemic metabolicbone 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 thecentral radiology reviewer and as defined in the tanezumab program imaging atlas at
Screening: 1) Rapidly progressive osteoarthritis, 2) Atrophic or Hypotrophic
osteoarthritis, 3) Subchondral insufficiency fractures, 4) Spontaneous osteonecrosis of
the knee, 5) Osteonecrosis, or 6) 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 theprevious 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 osteoarthritis. Patients with a present(current) history of sciatica were not eligible for participation. Patients with a past
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history of sciatica who were asymptomatic for at least one year and who had noevidence of radiculopathy or sciatic neuropathy on thorough neurologic examination
were eligible for participation.


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



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 acetaminophen was contraindicated (refer to product labeling).

Signs and symptoms of clinically significant cardiac disease.

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



History, diagnosis, or signs and symptoms of clinically significant neurologicaldisease.

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



WOMAC Pain subscale NRS ≥5 in the index knee or index hip at Baseline.



WOMAC Physical Function subscale NRS ≥5 in the index knee or index hip at Baseline.

1

Acetaminophen/paracetamol will be referred to as paracetamol going forward.
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CLINICAL STUDY REPORT SYNOPSIS

Patient’s Global Assessment of Osteoarthritis (PGA-OA) must have been “Fair”, “Poor,”or “Very Poor” 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.

Radiographic eligibility must have been confirmed by the Central Reader.

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). Eachtanezumab PFS contained a sufficient amount of tanezumab to provide the intended dose.
Each PFS was packed in an individual carton and had a unique container number.
Identity of Investigational Product
Table S1. Investigational Product Description
Investigational Product
Description
PF-04383119 solution for injection,
2.5 mg/mL
PF-04383119 solution for injection,
5 mg/mL
Placebo for PF-04383119 solution
for injection

Vendor Lot
Number
L47506

Pfizer Lot
Number15-002256

Strength/
Potency
2.5 mg/mL

Dosage Form

L5044715-002258

5.0 mg/mL

Prefilled syringe

L3916815-002262

0.0 mg/mL

Prefilled syringe

Prefilled syringe

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 (Day 1 and Weeks 8
and 16).
Primary Efficacy Evaluation
The three co-primary efficacy endpoints were the change from Baseline to Week 24 in the
WOMAC Pain Subscale (NRS 0-10, with a lower score indicating less pain), in the WOMAC
Physical Function Subscale (NRS 0-10, with a lower score indicating better physicalfunction), and in the PGA-OA (5-point Likert scale from Very Good [1] to Very Poor [5]).
Secondary Efficacy Evaluation
Patients with ≥50% reduction from Baseline in WOMAC Pain at Week 24, change fromBaseline to Week 2 in the WOMAC Pain subscale, and change from Baseline to Week 1 in
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average pain score in the index knee or hip were key secondary endpoints. Additional
secondary endpoints included the change from Baseline to Weeks 2, 4, 8, 12, 16, and 32 in
the WOMAC Pain Subscale, the WOMAC Physical Function Subscale, and the PGA-OA.
Time points for the evaluation of other secondary endpoints were Weeks 2, 4, 8, 12, 16, 24,
and 32, unless stated otherwise: Outcomes Measures in Arthritis Clinical TrialsOsteoarthritis Research Society International (OMERACT-OARSI) responder index;
treatment response defined as a reduction from Baseline in the WOMAC Pain Subscale of≥30%, ≥50%, ≥70%, or ≥90%; cumulative distribution of percent change in the WOMAC
Pain Subscale score to Weeks 16 and 24 (endpoint for summary only); treatment response
defined as a reduction from Baseline in the WOMAC Physical Function Subscale of ≥30%,≥50%, ≥70%, or ≥90%; cumulative distribution of percent change in the WOMAC Physical
Function Subscale score to Weeks 16 and 24 (endpoint for summary only); treatment
response defined as an improvement of ≥2 points in PGA-OA; WOMAC Stiffness Subscalechange from Baseline (0-10 NRS with a lower score indicating less stiffness); WOMAC
Average Score (the mean of the three WOMAC subscale scores of Pain, Physical Functionand Stiffness) change from Baseline; WOMAC Pain Subscale item: pain when walking on aflat surface, WOMAC Pain Subscale item: pain when going up or down stairs; and incidence
and time to discontinuation due to lack of efficacy; average pain score in the index jointchange from Baseline (Weeks 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 28, and 32).
Secondary patient-reported outcome endpoints included Work Productivity and Activity
Impairment Questionnaire for Osteoarthritis (WPAI:OA) impairment scores change fromBaseline to Weeks 8, 16, and 24; EuroQol-5 Dimension-5 Level™ dimensions and overall
health utility score at Baseline, Weeks 8, 16, and 24; Patient Reported Treatment Impact
Assessment-Modified (mPRTI) at Weeks 16 and 24; and Health Care Resource Utilization at
Baseline, and Weeks 32 and 48.
Rescue medication was measured by the incidence and number of days of patients using
rescue medication (Weeks 2, 4, 8, 12, 16, 24, and 32) and the amount (mg) of rescue
medication taken (Weeks 2, 4, 8, 12, 16, and 24) during the study.
Pharmacokinetic and Pharmacodynamic Evaluations
Pharmacokinetic Evaluations
Tanezumab concentrations were measured to support the development of an updated SC
population pharmacokinetic (PK) model to allow the prediction of the tanezumab
concentration over time in individuals. In addition, tanezumab concentrations were
measured to inform the immunogenicity profile of tanezumab.

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CLINICAL STUDY REPORT SYNOPSIS
Pharmacokinetic SamplingBlood samples for the assessment of the PK of tanezumab were collected pre-dose at
Baseline (Day 1, predose), Weeks 8 (predose), 16 (predose), 24, 32 and 48, or at Early
Termination Visits 1 and 2.
Pharmacodynamic Evaluations
Blood samples were collected for the assessment of biomarkers, soluble p75, total NGF, andproNGF. In addition, urine samples were collected for the assessment of biomarkers.
Pharmacodynamic SamplingBlood and urine samples for the assessment of biomarkers were collected at Baseline (Day 1;
predose) and Week 8 (predose). Blood samples for the assessment of soluble p75
concentrations were collected at Baseline (Day 1; predose) and Week 8 (predose), Week 24,
and Week 32, or at Early Termination. Blood samples for the assessment of NGF (total NGF
and proNGF) were collected at Baseline (Day 1; predose) and Week 8 (predose), Week 24,
Week 32, and Week 48, or at Early Termination.
SAFETY EVALUATIONS
Safety was evaluated in all patients who received at least one dose of investigational product,
through the patient’s last visit. Tanezumab safety was reviewed at two levels; blinded data
reviews by the Sponsor and unblinded reviews by the External Safety Monitoring Committee(E-SMC). The E-SMC reviewed unblinded safety data including adverse events, serious
adverse events (SAEs), joint safety adjudication outcomes, total joint replacements (TJRs),
neurologic examination, vital signs data, and clinical laboratory data on a regular basis
throughout the course of this study.
Safety Assessments
Except for adverse events which were collected at any time, all assessments were collectedprior to dosing at dosing visits.
Adverse events, including serious adverse events and deaths, were collected throughout the
study. A general physical examination was performed at Screening and at Week 24 or at
Early Termination. Blood and urine samples for clinical laboratory testing were collected at
Screening, Baseline, Week 16, and Week 32, or at Early Termination Visit 2. For women ofchild-bearing potential, serum pregnancy tests were conducted at Screening, Week 24 andWeek 32, or at Early Termination Visits 1 and 2. Urine pregnancy tests were conducted prior
to dosing at the Day 1 and Week 8 and Week 16 visits, prior to dosing. Sitting vital signs
were obtained at all study visits; at each visit, vital signs were collected after the patient had
been in a sitting position for at least five minutes.

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NeurologicalSupine/Standing blood pressure (BP) measurements were done at all study visits to assess thepatient for possible Orthostatic hypotension. An adverse event of Orthostatic hypotension
was reported for all patients meeting criteria for Orthostatic hypotension at a visit. If thepatient was symptomatic but with no apparent medical cause, a neurological consult was
obtained. If the patient was asymptomatic or there was an apparent cause that could be
addressed (eg, dehydration), a repeat assessment was done one to four weeks later. If
Orthostatic hypotension was still present at time of the repeat assessment, a consult was
obtained. Dosing could not resume until presence of sympathetic autonomic neuropathy was
ruled out by the consulting cardiologist or neurologist.
Twelve-lead ECGs were performed at Screening, Week 24, and Week 48, or at Early
Termination. An adverse event was reported for patients meeting protocol-defined criteria
for bradycardia on a post-Baseline ECG (heart rate of ≤45 beats per minute [BPM]), or heart
rate decrease from Screening of ≥25% with resulting heart rate <60 BPM, and patients werereferred for consult with a cardiologist or neurologist to evaluate the patients for the possible
presence of sympathetic autonomic neuropathy.
Consults were also obtained to rule out sympathetic autonomic neuropathy for patients withadverse event reports of Syncope, Anhidrosis, or Hypohydrosis.
Neurological examinations were performed at all study visits and the investigator completed
the Neuropathy Impairment Score (NIS) at these time points based on the neurologicalexamination. Neurologic examination assessed strength of groups of muscles of the head andneck, upper limbs and lower limbs, deep tendon reflexes, and sensation (tactile, vibration,
joint position sense, and pinprick) of index fingers and great toes to complete the NIS. The
neurological examinations were performed in a controlled and consistent manner by the same
trained examiner when possible. The examiner was an MD or DO. The Survey ofAutonomic Symptoms (SAS) was completed by the patient at Screening, Week 24, and at
Week 48, or at Early Termination.
A neurological consultation was obtained if an adverse event suggestive of new or worsening
peripheral neuropathy or an adverse event of abnormal peripheral sensation (eg, Allodynia,
Burning sensation, Carpal tunnel syndrome, Dysesthesia, Hyperesthesia, Hyperpathia,
Hypoesthesia, Neuralgia, Neuritis, Neuropathy peripheral, Pallanesthesia, Paresthesia,
Peripheral sensory neuropathy, Sensory disturbance, Sensory loss, Sciatica, Tarsal tunnel
syndrome) was reported as an SAE, resulted in the patient being withdrawn from the study,
was ongoing at the end of the patient’s participation in the study, or was of severe intensity.
Consults were also obtained if new or worsened clinically significant abnormalities on theneurologic exam were reported as adverse events met criteria listed above, or if a reported
non-neuropathic neurological event (eg, stroke, seizure) was considered medically importantby the investigator.

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CLINICAL STUDY REPORT SYNOPSIS
Musculoskeletal and Joint-Related
The investigator conducted a thorough musculoskeletal physical examination of all major
joints at all study visits (Screening, Baseline [Day 1] and at Weeks 2, 4, 8, 12, 16, 24, 32, and48; or at Early Termination if the patient discontinued early). The musculoskeletal physicalexam evaluated the joints for swelling, redness, tenderness, deformity, osteophytes or nodes,
crepitus and pain on motion, and was documented on the case report form. The investigatorcollected patient-reported information on any current joint symptoms including pain,
stiffness, and swelling. Any clinically significant change in symptoms or the examination
was reported as an adverse event.
X-rays of shoulders, hips and knees (and other major joints considered at risk) were collectedat Screening, Week 24, and Week 48, or if patient discontinued, at Early Termination Visit 1
and Early Termination Visit 3. Screening X-rays were reviewed by a Central Reader for
determination of eligibility. After randomization, the Central Reader reviewed radiology
images for diagnosis of joint conditions that would warrant further evaluation by the
Adjudication Committee. For patients who were identified with a possible or probable joint
event (ie, Rapidly progressive OA, Subchondral insufficiency fractures, Primaryosteonecrosis, or Pathological fracture) and patients undergoing TJR for any reason, allimages and other source documentation were provided to the blinded Tanezumab
Adjudication Committee for review and adjudication of the event. The Adjudication
Committee’s assessment of the event represented the final classification of the event.
Immunogenicity
Blood samples for the assessment of anti-drug antibodies (ADA [anti-tanezumab antibodies])
were collected at Baseline (Day 1; pre-dose) and Weeks 8 (predose), 16 (predose), 24, 32,
and 48, or at Early Termination.
Adverse Event Reporting
For SAEs, the active reporting period to the Sponsor or its designated representative beganfrom the time that the patient provided informed consent, which was obtained prior to thepatient’s participation in the study (ie, prior to undergoing any study-related procedure and/or
receiving study medication) through the end of the Safety Follow-up Period or through andincluding 112 calendar days after the patient’s last administration of the SC study
medication, if the patient refused the protocol-defined Follow-up Period.
Statistical Methods
A sample size of 270 patients per treatment group was needed to provide approximately 80%
power to achieve statistical significance (at the 5% two-sided level) for the two comparisonsof tanezumab 2.5 and tanezumab 5 mg SC versus placebo, over all three co-primary
endpoints. The total sample size was planned to be approximately 810 patients.

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CLINICAL STUDY REPORT SYNOPSIS
Analysis of the Co-Primary Endpoints
The primary efficacy population was the Intent-to-Treat (ITT) population, defined as all
randomized patients who received SC study medication (either tanezumab or placebo). The
primary analysis used multiple imputation methods for missing data at Week 24. Details of
the multiple imputation procedure are given below. All treatment comparisons used the twosided 5% significance level.
The co-primary efficacy endpoints were analyzed using an analysis of covariance(ANCOVA) model, with model terms for Baseline score, Baseline diary average pain, index
joint (knee or hip), highest KL grade, treatment group, and study site as a random effect. The
assessment of significance for the tanezumab SC versus placebo treatment contrasts used a
step-down testing strategy within each of the co-primary efficacy endpoints defined as firsttesting tanezumab 5 mg versus placebo, and if significant (p≤0.05), then testing tanezumab
2.5 mg versus placebo. Finally, a tanezumab treatment group was declared as superior toplacebo if the corresponding treatment contrast was significant over all three co-primary
endpoints. This testing procedure maintained the Type I error to ≤5% within each of the
co-primary efficacy endpoints, and to <5% for all three co-primary efficacy endpoints.
Analysis of Secondary Endpoints
The secondary endpoints of patients with ≥50% reduction from Baseline in WOMAC Pain at
Week 24, change from Baseline to Week 2 in the WOMAC Pain Subscale, and average painscore in the index knee or hip change from Baseline to Week 1 were identified as key
secondary endpoints.
All endpoints up to Week 32 were summarized (where available) and endpoints up to
Week 24 were analyzed. Efficacy data at Week 32 was planned to be off-treatment; allavailable data in the Week 32 window was used in summaries.
The analysis of secondary endpoints used the same ANCOVA analysis described for the
co-primary endpoints, with multiple imputation for missing data.
Patient response endpoints were analyzed using logistic regression for binary data, withmodel terms for Baseline scores, Baseline diary average pain, index joint, KL grade, andtreatment group. Imputation for missing data used both last observation carried forward(LOCF) and Baseline observation carried forward (BOCF), where imputation with BOCF led
to the patient being assessed as a non-responder for the response endpoint at a particular time
point. In addition, to closely match the primary imputation analysis, a mixed BOCF/LOCF
imputation for response endpoints was used. In this analysis, BOCF imputation (ie, a patient
was a non-responder) was used for missing data due to discontinuation for reasons of lack ofefficacy, adverse event, or death up to the time point of interest, and LOCF imputation wasused for missing data for any other reason.
Analysis of Pharmacokinetic Data
The following reporting of PK data was done:
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A listing of all plasma tanezumab concentrations sorted by patient, active treatmentgroup and nominal time post-dose. The listing of concentrations also includes theactual times post dose.



A descriptive summary of the plasma tanezumab concentrations based on nominal
time post-dose for each treatment group.



Creation of boxplots of tanezumab plasma trough concentrations at the nominal times
for the tanezumab treatment groups.

Samples were analyzed using a validated analytical method in compliance with Sponsor
standard operating procedures.
RESULTS
Subject Disposition and Demography
A total of 2145 patients were screened for the study, of which 1248 failed Screening, and 48
were screened but not randomized; these patients were not randomized primarily because
enrollment for the study had closed. Eight hundred and forty-nine (849) patients wereenrolled into the study and randomized, 282 in the placebo treatment group, 283 in thetanezumab 2.5 mg treatment group and 284 in the tanezumab 5 mg treatment group (Table
S2). All randomized patients received at least one dose of study medication. By definition,these 849 patients comprise the ITT population; in this study, the Safety Population is thesame as the ITT population because there were no patients taking study medication otherthan as randomized.
A total of 750 (88.3%) patients completed the Treatment Period of the study: 257 (90.8%)
patients in the tanezumab 2.5 mg treatment group, 255 (89.8%) patients in the tanezumab
5 mg treatment group and 238 (84.4%) patients in the placebo treatment group, and 726(85.5%) patients completed the study per protocol, 249 (88.0%) patients in the tanezumab
2.5 mg treatment group, 239 (84.2%) patients in the tanezumab 5 mg treatment group and
238 (84.4%) patients in the placebo treatment group.
Table S2. Subject Evaluation Groups
Placebo(N=282)

Tanezumab
2.5 mg(N=283)

Tanezumab
5 mg(N=284)

Total(N=849)

n (%)

n (%)

n (%)

n (%)

282 (100.0)

283 (100.0)

284 (100.0)

849 (100.0)

Screened: 2145
Screen Failure: 1248
Other screened but not randomized: 48
Randomized

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Table S2. Subject Evaluation Groups
Placebo(N=282)

Tanezumab
2.5 mg(N=283)

Tanezumab
5 mg(N=284)

Total(N=849)

n (%)

n (%)

n (%)

n (%)

282 (100.0)

283 (100.0)

284 (100.0)

849 (100.0)

0

0

0

0

Safety population

282 (100.0)

283 (100.0)

284 (100.0)

849 (100.0)

ITT population

282 (100.0)

283 (100.0)

284 (100.0)

849 (100.0)

Per-Protocol population

200 (70.9)

209 (73.9)

210 (73.9)

619 (72.9)

TreatedNot treated

Number of subjects[1]Completed Treatment Phase238 (84.4)

257 (90.8)

255 (89.8)

750 (88.3)

Completed Safety Follow-up

222 (78.7)

243 (85.9)

231 (81.3)

696 (82.0)

Discontinued Safety Follow-up

15 (5.3)

14 (4.9)22 (7.7)

51 (6.0)

Did not enter Safety Follow-up

1 (0.4)0

2 (0.7)3 (0.4)

Discontinued Treatment Phase

44 (15.6)

26 (9.2)

29 (10.2)

99 (11.7)

Completed Safety Follow-up

16 (5.7)

6 (2.1)8 (2.8)30 (3.5)

Discontinued Safety Follow-up

12 (4.3)

5 (1.8)5 (1.8)22 (2.6)

Did not enter Safety Follow-up

16 (5.7)

15 (5.3)

16 (5.6)

47 (5.5)

Completed study

238 (84.4)

249 (88.0)

239 (84.2)

726 (85.5)

Discontinued study

44 (15.6)

34 (12.0)

45 (15.8)

123 (14.5)

Rollover to Study A4091064

17 (6.0)

17 (6.0)

14 (4.9)48 (5.7)

N is Number of Subjects Randomized. Percentages were based on the number of subjects Randomized.
[1]Subjects in Safety Population. Percentages were based on the number of subjects in Safety Population.
Treatment Period was planned for 24 weeks and Safety Follow-Up period was planned for 24 weeks.
Safety population consisted of all subjects treated with SC study medication. ITT population consisted of all randomized
subjects who received at least one dose.
'Other Screened but not Randomized displays subjects who were screened but not randomized for a reason not related to a
specific eligibility criterion.
PFIZER CONFIDENTIAL SDTM Creation: 26DEC2018 (05:14) Source Data: Listing 16.2.1.1 Output File:./nda1/A4091057/adsl_s002i Date of Generation: 22JAN2019 (20:27)
Table 14.1.1.1.i is for Pfizer internal use.

The most frequent reasons for discontinuation from the Treatment Period across treatmentgroups were “Withdrawal by subject”, followed by “Insufficient clinical response” and“Adverse event”. The incidence of patients discontinuing from treatment due to insufficient
clinical response was lower in tanezumab-treated patients compared to those receiving
placebo: placebo (18 [6.4%]), tanezumab 2.5 mg (2 [0.7%]), and tanezumab 5 mg (3 [1.1%]).
A similar trend for discontinuation due to Insufficient clinical response was observed indiscontinuations from the Study overall: 3 (1.1%) in both tanezumab treatment groups and
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7 (2.5%) in the placebo treatment group; in the Safety Follow-up period, “Insufficient
clinical response” applied to the response to any analgesic being taken for OA pain. Few
patients discontinued from treatment or study due to adverse events and no dose-response
was observed.
Forty-eight (48 [5.7%]) patients, 17 (6.0%) in the placebo, 17 (6.0%) in the tanezumab
2.5 mg, and 14 (4.9%) in the tanezumab 5 mg treatment groups who had joint replacements
during the course of the study planned to roll over into Study A4091064 (Table S2) at time of
discontinuation from Study A4091057.
Across the 3 treatment groups, the mean age of patients was 64.2 to 65.2 years (range 26 to
89 years); 68.0% to 70.0% of the patients were female; and 86.6% to 87.6% were white(3.5% to 6.7% Hispanic or Latino). The tanezumab 5 mg treatment group had fewer patientsin the 45-64 age range (103 [36.3%]) versus the tanezumab 2.5 mg (136 [48.1%]) treatmentgroup and placebo (132 [46.8%]) treatment group, and a higher proportion of patients over
65: tanezumab 5 mg treatment group (169 [59.5%]), tanezumab 2.5 mg treatment group(145 [51.2%]), placebo treatment group (144 [51.1%]). Patients 75 years or older
represented 12.7%-16.5% of the study population across treatment groups.
Insufficient pain relief to paracetamol was an entry requirement for the study and wasreported by 100% of patients. Inadequate pain relief was the primary reason for treatment
failure with paracetamol, NSAIDs, opioids, and tramadol. Approximately 16% of patients
across treatment groups were unwilling to take opioids.
The mean time from the first diagnosis of OA was similar across treatment groups, ranging
from 6.7 years for patients in the tanezumab 2.5 mg treatment group to 8.2 years in theplacebo treatment group. The mean time from the index joint OA diagnosis ranged from
6.0 years for patients in the tanezumab 2.5 mg treatment group to 7.4 years in the placebo
treatment group.
The majority of patients (82.7%-83.3% across treatment groups) had the knee as the index
joint. The overall radiographic severity of OA was similar across treatment groups, withsimilar proportions of patients reporting KL grades of 2, 3, or 4 for the index joint; KL grade
3 was reported most frequently for the index joint (42.6%-46.3% across treatment groups).
The percentage of patients with a KL grade of 4 for the index joint was 35.5%-37.0% acrosstreatment groups; KL grade 4 was reported by 19.1-27.1% of patients with the hip and
38.5%-39.0% of patients with the knee as the index joint. A majority of patients (56.7%59.0% across treatment groups) reported two joints with KL grade ≥2.
The mean WOMAC Pain scores at Screening and Baseline were consistent across treatmentgroups, ranging from 6.49 to 6.54 at Screening and from 6.59 to 6.70 at Baseline. The mean
WOMAC Physical Function score at Baseline ranged from 6.67 to 6.77 across treatmentgroups. All patients had a PGA-OA at Baseline of Fair, Poor, or Very poor, with the
majority of patients (46.8% to 51.6%) reporting PGA-OA scores of Fair at Baseline. The

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percentage of patients who reported a PGA-OA of Very poor ranged from 6.0% in thetanezumab 5 mg treatment group to 7.4% in the tanezumab 2.5 mg treatment group.
Efficacy Results
The primary objective of the study was met for the 5 mg dose of tanezumab, but not for the
2.5 mg dose, applying the gate-keeping strategy.
For patients in the tanezumab 5 mg treatment group, significant2 changes from Baseline wereobserved for all three co-primary endpoints (WOMAC Pain and Physical Function Subscales
and PGA-OA) at Week 24 compared to those in the placebo treatment group. For patients inthe tanezumab 2.5 mg treatment group, significant changes from Baseline were observed for
two of three co-primary endpoints (WOMAC Pain and Physical Function Subscales) at
Week 24, compared to those in the placebo treatment group. However, the changes in the
PGA-OA were not significant, and no further testing was performed.
Outside of the framework of the gate-keeping strategy, focusing on nominal(unadjusted) p-values, the tanezumab 5 mg treatment group showed improvementfrom Baseline in each co-primary efficacy endpoint (WOMAC Pain and Physical
Function Subscales and PGA-OA) compared to the placebo treatment group from thefirst measurement obtained at Week 2 through Week 16 (unadjusted p-values ≤0.05),
and including Week 24. Compared to the placebo treatment group, the tanezumab
2.5 mg treatment group showed improvement from Baseline in the WOMAC Pain
and Physical Function Subscales from the first measurement obtained at Week 2
through Week 16 (unadjusted p-values ≤0.05) and including Week 24. Improvementfrom Baseline in the PGA-OA was also observed at Weeks 2 through 16.
The results for all key secondary efficacy endpoints (Patients with 50% reduction fromBaseline in WOMAC Pain at Week 24; Change from Baseline to Week 2 in the WOMAC
Pain Subscale; Change from Baseline to Week 1 in the average pain in the index joint) weredeemed not significant due to the testing strategy, although both the tanezumab 5 mg
treatment group and the tanezumab 2.5 mg treatment group had favorable observed
percentages of patients compared to placebo for all key secondary efficacy endpoints(unadjusted p-values ≤0.05).
The results of the co-primary efficacy endpoints and key secondary efficacy endpoints were
evaluated considering the graphical approach. All other efficacy endpoints were evaluated
without considering multiplicity, focusing on unadjusted p-values.
Table S3 summarizes the change from Baseline to Week 24 in the three co-primary
endpoints. For the WOMAC Pain Subscale and the WOMAC Physical Function Subscale,the step-down testing procedure showed significant improvement in efficacy for treatment

2“Significant” is used here and following to mean statistically significant (p≤0.05).
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with tanezumab 5 mg and tanezumab 2.5 mg versus placebo at Week 24. In the PGA-OA,
the tanezumab 5 mg treatment group was superior to placebo treatment (p≤0.05) but thetanezumab 2.5 mg treatment group was not (p=0.1092).
Table S3. Summary of Co-Primary Efficacy Endpoints - Analysis of Change fromBaseline to Week 24 (ITT, Multiple Imputation)
Placebo(N=282)WOMAC Pain Subscale

Tanezumab
2.5 mg(N=283)

Tanezumab
5 mg(N=284)LS Mean (SE)-2.24 (0.17)-2.70 (0.17)-2.85 (0.17)

95% CI for LS Mean(-2.58,-1.90)(-3.03,-2.37)(-3.19,-2.52)

LS Mean Difference (SE)-0.46 (0.18)-0.62 (0.18)

95% CI for LS Mean
Difference(-0.81,-0.12)(-0.97,-0.26)

0.00880.0006-2.11 (0.17)-2.70 (0.17)-2.82 (0.17)(-2.45,-1.77)(-3.03,-2.37)(-3.15,-2.49)

Versus Placebo

p-value
WOMAC Physical Function Subscale LS Mean (SE)
95% CI for LS Mean
Versus Placebo
LS Mean Difference (SE)-0.59 (0.18)-0.71 (0.17)

95% CI for LS Mean
Difference(-0.93,-0.24)(-1.05,-0.36)

0.0008<.0001p-value
Patient Global Assessment of
Osteoarthritis

LS Mean (SE)-0.72 (0.06)-0.82 (0.06)-0.90 (0.06)

95% CI for LS Mean(-0.84,-0.59)(-0.94,-0.70)(-1.02,-0.78)

LS Mean Difference (SE)

-0.11 (0.07)-0.19 (0.07)

95% CI for LS Mean
Difference(-0.24,0.02)(-0.32,-0.06)

0.10920.0051

Versus Placebo

p-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 and highest
Kellgren-Lawrence grade) as fixed effects, Baseline Patient Global Assessment of Osteoarthritis and Baseline diary averagepain as covariates, and study site as a random effect.
Results were taken from a combined analysis of the individual imputed dataset ANCOVA results.
PFIZER CONFIDENTIAL SDTM Creation: 02JAN2019 (14:20) Source Data: Listing 16.2.6.1 Output File:./nda1/A4091057/adwn_sg_infr_chg_ancova_mi Date of Generation: 06JUN2019 (10:41)
Table 14.2.1.3.1.i is for Pfizer internal use.

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Secondary Efficacy Analysis
Key Secondary Efficacy Endpoints
Patients with ≥50% reduction from Baseline in WOMAC Pain at Week 24: Bothtanezumab treatment groups had higher percentages of ≥50% responders at Week 24
than the placebo treatment group: placebo treatment group, 95 (33.8%); tanezumab
2.5 mg treatment group, 128 (45.4%), (unadjusted p=0.0022 versus placebo);tanezumab 5 mg treatment group 136 (47.9%), (unadjusted p=0.0004 versus placebo).
Change from Baseline to Week 2 in the WOMAC Pain Subscale: At Week 2, thechange from Baseline for both tanezumab treatment groups compared to the placebo
treatment group was favorable: tanezumab 2.5 mg treatment group (unadjusted
p<0.0001), tanezumab 5 mg treatment group (unadjusted p=0.0149).
Change from Baseline to Week 1 in the Average Pain in the Index Joint: At
Week 1, the change from Baseline for both tanezumab treatment groups compared tothe placebo treatment group was favorable: tanezumab 2.5 mg treatment group(unadjusted p<0.0001), tanezumab 5 mg treatment group (unadjusted p=0.0009).


There was a consistent pattern of increased efficacy on the change from Baseline in the
WOMAC Pain Subscale for patients in both tanezumab treatment groups compared tothose in the placebo treatment group starting at Week 2. The improvement in patients ineach of the tanezumab treatment groups versus placebo was similar in magnitude
between the tanezumab treatment groups and remained significant through Week 24.

There was a consistent pattern of increased efficacy on the change from Baseline in the
WOMAC Physical Function Subscale for patients in the tanezumab treatment groups
compared to those in the placebo treatment group starting at Week 2. Comparisons toplacebo were significant at all time points analyzed. The improvement in patients in eachof the tanezumab treatment groups versus placebo was similar in magnitude between thetanezumab treatment groups and remained significant through Week 24.

The change from Baseline on the PGA-OA was significantly different from placebo
starting at Week 2, through Week 16 for patients in the tanezumab 2.5 mg treatmentgroup, and through Week 24 for patients in the tanezumab 5 mg treatment group.

The proportion of responders on the OMERACT-OARSI responder index was
significantly greater for patients in both tanezumab treatment groups compared to theplacebo treatment group at all weeks reported.



Reduction in the WOMAC Pain Subscale of 30%, ≥50%, ≥70%, and ≥90%: A
significantly greater proportion of patients in the tanezumab 2.5 mg treatment group thanin the placebo treatment group responded at the 30% level and 50% level at all weeks
from Week 2 through Week 24. A significantly greater proportion of patients in thetanezumab 5 mg treatment group than in the placebo treatment group responded at the
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30% from Week 2 to Week 24, at the 50% level at all weeks from Week 4 to 24, at the
70% and 90% levels at all weeks from Week 4 through Week 12, and at the 70% level at
Week 16.


Reduction in the WOMAC Physical Function Subscale of ≥30%, ≥50%, ≥70%, and≥90%: A significantly greater proportion of patients in the tanezumab 2.5 mg treatmentgroup than in the placebo treatment group responded at the 30% level at all weeks from
Week 2 through Week 24, at the 50% level from Weeks 4 through 24, at the 70% levelfrom Weeks 2 through 16, and at the 90% level from Weeks 8 through 24. A
significantly greater proportion of patients in the tanezumab 5 mg treatment group than in
the placebo treatment group responded at the 30% level at all weeks from Week 2
through Week 24, at the 50% level from Weeks 4 through 24, at the 70% level from
Weeks 4 through 12, and at the 90% level from Weeks 4 through 24.

A significantly greater proportion of patients in the tanezumab 2.5 mg treatment group
showed a 2-point reduction in the PGA-OA at Week 2 through Week 16 compared topatients in the placebo treatment group; for patients in the tanezumab 5 mg treatmentgroup, the difference from patients in the placebo treatment group was significant at
Week 4 through Week 24.

Patients in the tanezumab treatment groups showed a statistically significant decrease inpain in the index joint, based on patient-reported eDiary data, starting one week after the
first dose of study drug (starting on Day 2 for patients in the tanezumab 2.5 mg treatmentgroup and on Day 4 in the tanezumab 5 mg treatment group) that was maintained throughto Week 20 in the tanezumab 2.5 mg treatment group and through Week 24 in thetanezumab 5 mg treatment group.

Starting at Week 2 and continuing through the Week 24 Visit, patients in the tanezumab
treatment groups showed a significant improvement compared to placebo-treated patientsin the WOMAC Stiffness Subscale, WOMAC Average Score, WOMAC Pain
Subscale Items: Pain when walking on a flat surface, and Pain when going up or
down stairs.

In the components of the WPAI:OA, patients in the tanezumab 2.5 mg treatment group
showed significant improvement over placebo-treated patients in reported percent
impairment while working and overall work impairment at Week 16, and in percent
activity impairment at Weeks 8 and 16. Patients in the tanezumab 5 mg treatment group
showed significant improvement over placebo-treated patients in reported percent
impairment while working and in reported percent overall work impairment at Weeks 8
and 16, and in reported percent activity impairment at Weeks 8, 16, and 24.

For each of the dimensions of the EuroQol-5 Dimension-5 Level analyzed (Mobility,
Self-care, Usual activities, Pain/Discomfort, Anxiety/Depression), as well as the Index

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Value, the mean values reported for patients in the placebo, tanezumab 2.5, andtanezumab 5 mg treatment groups were the same or similar at all time points evaluated.
In the mPTRI assessment, patients in both tanezumab treatment groups reported
significantly more frequently than those in the placebo treatment group that they weresatisfied with the drug that they received in the study, that they preferred the drug thatthey received in the study to previous treatment, and that they would be willing to use thesame drug that they received in the study for their OA pain.

In general, the Health Care Resource Utilization was relatively low and the proportionof patients who visited a health care provider within the three months that preceded theBaseline Visit was higher than in the three months that preceded the Week 48 visit, ie,during the Safety Follow-up. Across treatment groups, primary care physician visitswere the most frequently used resource within the three months that preceded theBaseline Visit (39-41% of patients). Rheumatologists (29-35% of patients), orthopedists(29-30% of patients), radiologists (12-16%), physical therapists (7-11%), pain specialists(4-8%) and other practitioners (5-7%) were other healthcare providers commonly
consulted during that period.

A small percentage of patients in any group discontinued treatment due to lack ofefficacy (placebo, 18 [6.4%]; tanezumab 2.5 mg, 2 [<1.0%]; tanezumab 5 mg, 3 [1.1%]).
Placebo-treated patients discontinued treatment sooner due to lack of efficacy thantanezumab-treated patients. There was a significant difference in the number of patientsthat discontinued and the time to discontinuation between the tanezumab treatmentgroups and the placebo treatment group.

Overall up to Week 24, the incidence of rescue medication use by week was slightly
larger in the placebo treatment group than the 2 active treatment groups (placebo[86.2%], tanezumab 2.5 mg [80.6%], tanezumab 5 mg [83.1%]); the frequency of use
reported in tanezumab-treated patients was consistently lower than that reported byplacebo-treated patients from Week 1 to Week 23. Significant differences from patientsin the placebo treatment group were seen in patients in the tanezumab 2.5 mg treatmentgroup at Weeks 2 to 16, and in the tanezumab 5 mg treatment group at Weeks 2, 4, 12,
and 16.

Only at Week 2 in the tanezumab 2.5 mg treatment group was the amount of rescue
medication used by patients in either tanezumab treatment group significantly less thanthat used by those in the placebo treatment group. At all other weeks the differences
between tanezumab and placebo-treated patients in the amount of rescues medication
used per week failed to reach significance .

Pharmacokinetic Results
At Weeks 8, 16, and 24, the mean tanezumab plasma concentrations were higher in thetanezumab 5 mg treatment group than the tanezumab 2.5 mg treatment group by a proportion
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similar to the larger dose. By Week 32, 16 weeks after the third dose of study medication,
the mean tanezumab plasma concentrations were low, consistent with complete eliminationof tanezumab from the body over five half-lives post-injection and were similar for the twotreatment groups.
Pharmacodynamic Results
Mean total NGF concentrations were comparable at Baseline across treatment groups. From
Weeks 8 through 24, mean total NGF concentrations were higher in the tanezumab 5 mg
treatment group than in the tanezumab 2.5 mg treatment group by a proportion approximately
similar to the increase in dose. Beginning at Week 32, mean total NGF concentrations began
to decline in both the tanezumab 2.5 mg and tanezumab 5 mg treatment groups and wereapproaching the Baseline values by Week 48. Mean proNGF was comparable acrosstreatment groups at all nominal sampling times. Mean and median soluble p75 serum troughconcentrations were comparable at all time points for all treatment groups.
Safety Results
The incidence of adverse events during the Treatment Period and Safety Follow-up aresummarized in Table S4 and Table S5, respectively. The incidence of adverse events in theTreatment Period and the Safety Follow-up do not add up to the total incidence to End of
Study, as some patients had events that occurred in both time periods.
The overall incidence of adverse events was similar across treatment groups both during theTreatment Period (55.0%, 53.0%, and 57.0% of patients in the placebo, tanezumab 2.5 mg,
and tanezumab 5 mg treatment groups, respectively); during the Safety Follow-up fewer
patients in the placebo treatment group (35.1%) reported adverse events than those in thetanezumab 2.5 mg (44.4%), and tanezumab 5 mg treatment groups (43.6%).
Table S4. Treatment-Emergent Adverse Events During the Treatment Period (All
Causalities) - Safety Population
PlaceboTanezumab
2.5 mgTanezumab
5 mg

Number (%) of subjects

n (%)

n (%)

n (%)

Subjects evaluable for adverse events

282

283

284

Number of adverse events

349

354

424

Subjects with adverse events

155 (55.0)

150 (53.0)

162 (57.0)

Subjects with medication error events

0

0

0

Subjects with serious adverse events

3 (1.1)8 (2.8)9 (3.2)

Subjects with severe adverse events

4 (1.4)9 (3.2)

11 (3.9)

Subjects discontinued from study due to adverse events (a)2 (0.7)5 (1.8)1 (0.4)

Subjects discontinued study drug due to AE and continued Study (b)7 (2.5)3 (1.1)4 (1.4)PFIZER CONFIDENTIAL
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Table S4. Treatment-Emergent Adverse Events During the Treatment Period (All
Causalities) - Safety Population

Number (%) of subjects

PlaceboTanezumab
2.5 mgTanezumab
5 mg

n (%)

n (%)

n (%)

0

0

0

Subjects with dose reduced or temporary discontinuation due to adverse
eventsIncludes treatment-emergent events that began up to the Week 24 (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 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 notcause the subject to be discontinued from Study.
MedDRA v21.1 coding dictionary applied.
PFIZER CONFIDENTIAL SDTM Creation: 02JAN2019 (05:35) Source Data: Listing 16.2.7.1 Output File:./nda1/A4091057/adae_s020_i Date of Generation: 22JAN2019 (20:51)
Table 14.3.1.2.1.1.i is for Pfizer internal use.

Table S5. Treatment-Emergent Adverse Events During the Safety Follow-up Period(All Causalities) - Safety Population
PlaceboTanezumab
2.5 mgTanezumab
5 mg

Number (%) of Subjects

n (%)

n (%)

n (%)

Subjects evaluable for adverse events

265

268

266

Number of adverse events

197

243

213

Subjects with adverse events

93 (35.1)

119 (44.4)

116 (43.6)

Subjects with medication error events

0

0

0

Subjects with serious adverse events

8 (3.0)16 (6.0)

16 (6.0)

Subjects with severe adverse events

6 (2.3)

11 (4.1)

14 (5.3)

Subjects discontinued from study due to adverse events (a)0

1 (0.4)1 (0.4)

Subjects discontinued study drug due to AE and continued Study (b)1 (0.4)00Subjects with dose reduced or temporary discontinuation due to adverse
events0

0

0

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Table S5. Treatment-Emergent Adverse Events During the Safety Follow-up Period(All Causalities) - Safety Population

Number (%) of Subjects

PlaceboTanezumab
2.5 mgTanezumab
5 mg

n (%)

n (%)

n (%)

Includes treatment-emergent events that began after the Week 24 (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 notcause the Subject to be discontinued from Study.
MedDRA v21.1 coding dictionary applied.
PFIZER CONFIDENTIAL SDTM Creation: 02JAN2019 (05:35) Source Data: Listing 16.2.7.1 Output File:./nda1/A4091057/adae_s020_fup_i Date of Generation: 25JAN2019 (14:21)
Table 14.3.1.2.1.2.i is for Pfizer internal use.

Arthralgia was the most frequently observed adverse event during the Treatment Period witha reported frequency of 8.1% (tanezumab 5 mg treatment group) to 12.1% (placebo treatmentgroup) (Table S6). Other adverse events reported in ≥2% of subjects in any treatment group
included Nasopharyngitis (placebo [8.9%], tanezumab 2.5 mg [11.0%], tanezumab 5 mg
[7.7%]) and Back pain (placebo [5.3%], tanezumab 2.5 mg [5.7%], tanezumab 5 mg [6.0%]),the frequency of which was comparable across treatment groups.
Although the number of reported events was small, the adverse events for which a doserelated increase in frequency was observed were OA, Joint swelling, and Hypoesthesia.
Dizziness was observed more frequently in the tanezumab treatment groups than in theplacebo treatment group; however, there was no dose-dependence.
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

Placebo(N=282)

Tanezumab
2.5 mg(N=283)

Tanezumab
5 mg(N=284)

n (%)

n (%)

n (%)

With any adverse event

155 (55.0)

150 (53.0)

162 (57.0)

INFECTIONS AND INFESTATIONS

53 (18.8)

58 (20.5)

57 (20.1)

Number (%) of subjects:
by SYSTEM ORGAN CLASS
and 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 SYSTEM ORGAN CLASS
and by Preferred Term

Placebo(N=282)

Tanezumab
2.5 mg(N=283)

Tanezumab
5 mg(N=284)

n (%)

n (%)

n (%)

Influenza

5 (1.8)5 (1.8)9 (3.2)

Nasopharyngitis

25 (8.9)31 (11.0)

22 (7.7)

Upper respiratory tract infection

3 (1.1)5 (1.8)6 (2.1)

Urinary tract infection

4 (1.4)6 (2.1)2 (0.7)21 (7.4)

17 (6.0)

19 (6.7)

8 (2.8)12 (4.2)

7 (2.5)INJURY, POISONING AND PROCEDURAL COMPLICATIONS
FallMUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS

67 (23.8)

69 (24.4)

74 (26.1)

Arthralgia

34 (12.1)

27 (9.5)

23 (8.1)

Back pain

15 (5.3)

16 (5.7)

17 (6.0)

Joint swelling

3 (1.1)6 (2.1)8 (2.8)

Musculoskeletal pain

7 (2.5)6 (2.1)7 (2.5)

Osteoarthritis

5 (1.8)9 (3.2)13 (4.6)

Pain in extremity

7 (2.5)9 (3.2)5 (1.8)28 (9.9)37 (13.1)

35 (12.3)

NERVOUS SYSTEM DISORDERS
Dizziness

2 (0.7)7 (2.5)6 (2.1)Headache18 (6.4)

15 (5.3)

14 (4.9)

Hypoaesthesia

2 (0.7)4 (1.4)6 (2.1)Paraesthesia

5 (1.8)5 (1.8)12 (4.2)

9 (3.2)5 (1.8)21 (7.4)

6 (2.1)2 (0.7)6 (2.1)VASCULAR DISORDERS
Hypertension

Subjects were only counted once per treatment per event.
Adverse events are shown by descending frequency by the highest tanezumab dose.
Includes treatment-emergent events that began up to the Week 24 (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: 02JAN2019 (06:35) Source Data: Listing 16.2.7.1 Output File:./nda1/A4091057/adae_s030_i Date of Generation: 15MAR2019 (09:16)
Table 14.3.1.2.2.1.i is for Pfizer internal use.

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Treatment-Related Adverse Events: During the Treatment Period, 130 patients
experienced 201 adverse events considered by the Investigator to be treatment-related.
More treatment-related adverse events were reported in the tanezumab 5 mg treatmentgroup (84 adverse events in 48 [16.9%] patients) than in the tanezumab 2.5 mg treatmentgroup (59 adverse events in 42 [14.8%] patients) or placebo treatment group (58 adverse
events in 40 [14.2%] patients). Most of the adverse events during the Treatment Period
assessed as treatment-related were mild or moderate in severity; two patients experienced
severe adverse events that were considered treatment-related during the treatment period.

Severe Adverse Events: A total of 24 patients experienced severe adverse events during
the Treatment Period: 4 (1.4%) in the placebo treatment group, 9 (3.2%) in thetanezumab 2.5 mg treatment group, and 11 (3.9%) in the tanezumab 5 mg treatmentgroup. Nasopharyngitis and Cardio-respiratory arrest in the tanezumab 5 mg treatmentgroup were fatal.



Injection Site Reactions: Seven (7) injection site reactions were reported by six patientsin total: one patient each in the placebo treatment group and the tanezumab 2.5 mg
treatment group and four in the tanezumab 5 mg treatment group. Injection site reactions
reported were Injection site erythema, Administration site pain, Injection site warmth,and Injection site reaction. All were mild in severity and resolved.



Potential Hypersensitivity Adverse Events: Overall few hypersensitivity adverse
events were reported during the study: 10 adverse events in 10 patients (3.5%) in theplacebo treatment group, 3 adverse events in 3 patients (1.1%) in the tanezumab 2.5 mg
treatment group, and 10 adverse events in 9 patients (3.2%) in the tanezumab 5 mg
treatment group. Hypersensitivity adverse events reported were Rash, Rhinitis allergic,
Eczema, Rash macular, Dermatitis allergic, Bronchospasm, Conjunctivitis allergic,
Hypersensitivity, and Urticaria. These adverse events were mild or moderate in severity,and most had resolved prior to the end of the study.

Tier 1 Adverse Events: The overall incidence of Tier 1 adverse events (pre-specified
adverse events of potential sympathetic dysfunction [Syncope, Bradycardia, Orthostatic
hypotension, Anhidrosis, and Hypohidrosis] considered clinically important) was low:
2 (0.7%) in the placebo treatment group, 3 (1.1%) in the tanezumab 2.5 mg treatmentgroup, and 8 (2.8%) in the tanezumab 5 mg treatment group. There was no significant
difference between the frequencies of occurrence when comparing placebo to either of
the tanezumab treatment group.



Tier 2 Adverse Events: Tier 2 adverse events are defined as non-Tier 1 adverse eventsoccurring in 3% of patients in any treatment group. The number of Tier 2 events overall
was small and when comparing the incidence of adverse events in the placebo treatmentgroup to either tanezumab treatment group, in all cases, the confidence interval (CI)included 0.

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Deaths: There were three deaths during the study. Two, in patients in the tanezumab
5 mg treatment group (Nasopharyngitis, in an 82-year-old patient, with the cause of deathreported as severe cold with probable influenza virus infection; Cardio-respiratory arrest,in a 77-year-old patient), occurred during the Treatment Period. The cause of death ineach case was not considered by the Investigator to be related to study medication. One
death (Cerebrovascular accident), in a 60-year-old patient in the tanezumab 2.5 mg
treatment group, occurred in a patient who was lost to follow-up; this death was notconfirmed by the family or the treating physician, but stated on a returned letter that wassent to the patient by the site.



Serious Adverse Events: There were 15 SAEs in the placebo treatment group, 34 in thetanezumab 2.5 mg treatment group, and 42 in the tanezumab 5 mg treatment group. The
majority of events had resolved at time of last contact; the exceptions were the following.
In the tanezumab 2.5 mg treatment group, one patient was diagnosed with Diffuse B-cell
lymphoma 202 days after last dose of study medication, and one patient was reported tohave a Cerebrovascular accident, which was fatal, 55 days after last dose of study
medication. In the tanezumab 5 mg treatment group, one patient was reported to have
Cardio-pulmonary failure 204 days after last dose of study medication; one patientreported SAEs of Back pain and Condition aggravated (worsening of low back pain)
110 days after last dose of study medication; one patient was diagnosed with Parkinson’s
disease 351 days after last dose of study medication; and one patient had an adjudicateddiagnosis of Osteonecrosis, 45 days after the last dose of study medication (study Day
106). There were two fatal SAEs: Nasopharyngitis (40 days after last dose of study
medication) and Cardio-respiratory arrest (56 days after last dose of study medication).



Adverse Events of Abnormal Peripheral Sensation (Burning Sensation, Carpal
tunnel syndrome, Decreased vibratory sense, Hypoesthesia, Neuralgia, Neuropathy
peripheral, Paresthesia, Sciatica): The incidence of adverse events related to abnormal
peripheral sensation during the Treatment Period was low overall, but dose-dependent.
Patients in the tanezumab 5 mg treatment group showed a higher incidence of Paresthesia
and Hypoesthesia (12 [4.2%], 6 [2.1%]) than those in the tanezumab 2.5 mg treatmentgroup (5 [1.8%], 4 [1.4%]) or placebo treatment group (5 [1.8%], 2 [0.7%]). All adverse
events of abnormal peripheral sensation during the Treatment Period were mild or
moderate in severity, and most had resolved at the time of last visit.

Peripheral Neurological Consultations: More patients in the tanezumab 2.5 mg
treatment group (12) had adverse events that met the criteria for requiring a neurologic
consultation than in the tanezumab 5 mg treatment group (6) or placebo treatmentgroup (4). Expert primary diagnoses for events that met criteria for consult after review
of all clinical data available for the patients were as follows. Mononeuropathy (Carpal
tunnel syndrome) was diagnosed in six patients: one patient in the placebo treatmentgroup (preexisting); three patients in the tanezumab 2.5 mg treatment group (one preexisting and two new onset); and two patients in the tanezumab 5 mg treatment group(one preexisting and one new onset). In all cases, the presentation was sensory. One
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patient had Carpal tunnel release surgery after the study was completed. The remaining
three cases of Mononeuropathy had an expert diagnosis of Mononeuropathy (Other), twopatients in the tanezumab 2.5 mg treatment group (presentation one sensory, one motor),and one patient in the tanezumab 5 mg treatment group (sensory presentation). The
expert reviewer diagnosed Radiculopathy in eight patients, in all cases the presentation
was sensory: one patient in the placebo treatment group (lumbosacral, new onset); fivepatients in the tanezumab 2.5 mg treatment group (all lumbosacral, new onset); and threecases in the tanezumab 5 mg treatment group (all lumbosacral; two preexisting, one new
onset). One patient in the tanezumab 2.5 mg treatment group was diagnosed with apreexisting sensory polyneuropathy.
Adverse Events Potentially Indicative of Decreased Sympathetic Function: The
incidence of these events was similar across treatment groups. With one exception, allreported adverse events potentially indicative of decreased sympathetic function during
the Treatment Period were mild or moderate in severity. One patient in the tanezumab
5 mg treatment group reported severe adverse events of diarrhea/vomiting of 2 days’
duration due to food poisoning.

Consultations for Adverse Events Potentially Indicative of Decreased Sympathetic
Function: Nineteen (19) patients overall, 6 (2.1%) in the placebo treatment group,
5 (1.8%) in the tanezumab 2.5 mg treatment group, and 8 (2.8%) in the tanezumab 5 mg
treatment group were reported to have at least one potential sympathetic event requiring a
consultation. No confirmed cases of sympathetic neuropathy were present and there was
no evidence of study medication effect on sympathetic function.



Neuropathy Impairment Score: The conclusion from the neurological examinations at
the last assessment for over 94% of patients was no new or worsened neurologicalexamination abnormality. Less than 1% of patients in any treatment group had a new orworsened neurological exam abnormality that was considered clinically significant by theInvestigator.



Total Joint Replacements: Patients who opted to have TJR during the study wererequired to discontinue from treatment and enter the Safety Follow-up until the time thesurgery became imminent, at which time the patients were to discontinue from study andenter observational Study A4091064, provided they consented to participate. Patients
who informed the Investigator that they had had a TJR during participation in Study
A4091057 were also eligible for Study A4091064. The number of TJRs was similar
across treatment groups; a total of 61 patients had at least one TJR: 19 (6.7%) in theplacebo treatment group, 22 (7.8%) in the tanezumab 2.5 mg treatment group, and20 (7.0%) in the tanezumab 5 mg treatment group. Of the 61 patients who had orplanned a TJR while participating in Study A4091057, 48 agreed to participate in Study
A4091064 at the time of discontinuation from Study A4091057. The majority of the
TJRs were adjudicated as normal progression of OA: 17/19 (89.5%) in the placebo
treatment group, 20/22 (90.9%) in the tanezumab 2.5 mg treatment group, and
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16/20 (80.0%) in the tanezumab 5 mg treatment group. Four TJRs, 2 each in thetanezumab 2.5 mg treatment group and tanezumab 5 mg treatment group, contributed tothe composite joint safety endpoint.


Adjudication: A total of 84 events in 79 patients met criteria for adjudication and werereviewed by the Adjudication Committee. These included all TJRs, possible or probablejoint safety events as identified on X-ray or magnetic resonance imaging (MRI) by theCentral Reader based on the tanezumab program imaging charter, and Investigatorreported joint safety events. There were 22 events (19 patients) reviewed for the placebo
treatment group, 27 events (27 patients) for the tanezumab 2.5 mg treatment group, and35 events (33 patients) for the tanezumab 5 mg treatment group. Most of the adjudication
events within each treatment group were adjudicated as normal progression of OA by the
Adjudication Committee (18 of 22 events [81.8%] in the placebo treatment group, 22 of
27 events [81.5%] in the tanezumab 2.5 mg treatment group, and 21 of 35 events [60.0%]
in the tanezumab 5 mg treatment group). One patient in the tanezumab 2.5 mg treatmentgroup had an adjudicated diagnosis of Subchondral insufficiency fracture of the left (nonindex) knee (Baseline KL grade=2); the adverse event was identified via imaging on
study Day 233. One patient in the tanezumab 5 mg treatment group had an adjudicateddiagnosis of Primary osteonecrosis in the left (non-index) hip (Baseline KL grade=0); theadverse event was identified via imaging on study Day 106. Outcomes of Rapidly
progressive OA were assigned to four adjudicated cases in the tanezumab 2.5 mg
treatment group, eight adjudicated cases in the tanezumab 5 mg treatment group, andnone in the placebo treatment group. Additional information on cases of Rapidly
progressive OA is provided in Table S7.

Table S7. Adjudicated Cases: Rapidly Progressive Osteoarthritis (RPOA)
Adjudicateddiagnosis

Treatment Group

Affected
Joint

Index
Joint?

RPOA type 1

Tanezumab 2.5 mg

Right hipLeft knee
Right knee
Right knee
Left knee
Left knee
Right knee
Right knee
Left hip
Right hip
Right hip
Right hip

Yes
No
No
Yes
Yes
Yes
No
No
Yes
No
Yes
No

Tanezumab 5 mg

RPOA type 2Tanezumab 2.5 mg
Tanezumab 5 mg

KL Grade of
Affected Joint at
Screening
3
1
0
2
2
2
2
3
4
3
3
3

AE Start Day(Study Day)

SAE?

TJR?

225
248
191
170
336
221
323
267
170
149

No
No
No
No
No
No
No
No
No
No

219

Yes

Yes
No
No
No
No
No
No
Yes
Yes
No
Yes
No

Laboratory Parameters: The incidence of patients with normal Baseline who had
post-Baseline laboratory test abnormalities that met pre-specified threshold for change
from Baseline was low, affected no more than four patients within a treatment group, and
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was generally distributed across treatment groups, with the following exceptions. Eight(8 [3.1%]) patients in the placebo treatment group showed basophils/leukocytes (%)>1.2× upper limit of normal (ULN); triglycerides >1.3× ULN were seen in 4 (1.7%),
7 (2.8%), and 9 (3.5%) of patients in the placebo, tanezumab 2.5 mg, and tanezumab
5 mg treatment groups, respectively; and glucose >1.5× occurred in 3 (2.0%), 4 (2.6%),
and 8 (5.1%) of patients in the placebo, tanezumab 2.5 mg, and tanezumab 5 mg
treatment groups, respectively. Observations were similar for patients with an abnormal
Baseline except for blood glucose for which values meeting the pre-specified threshold of>1.5× the upper limit of normal and >1.25× the Baseline value were seen for 9 patients inthe placebo treatment group (9 of 115 [7.8%] patients with an abnormal glucose at
Baseline), 16 patients in the tanezumab 2.5 mg treatment group (16 of 118 [13.6%]
patients with an abnormal glucose at Baseline), and 12 in the tanezumab 5 mg treatmentgroup (12 of 116 [10.3%] patients with an abnormal glucose at Baseline). Laboratory
abnormalities considered clinically significant by the Investigator post-Baseline were to
be reported as adverse events. All laboratory abnormalities reported as adverse events in
the Treatment Period were reported in one patient each, with the exception of Bloodcreatinine phosphokinase increased, which was reported in 2 (0.7%) patients in theplacebo treatment group and 4 (1.4%) patients in the tanezumab 2.5 mg treatment group.


Vital Signs: A higher proportion of patients in the tanezumab 2.5 mg (23 [8.2%])
treatment group and tanezumab 5 mg (26 [9.3%]) treatment group than in the placebo
treatment group (8 [2.9%]) showed a decrease in the sitting systolic BP measurement(change >-30 to -20), and a higher proportion of patients in the placebo treatment group(112 [40.0%]) than in the tanezumab 2.5 mg treatment group (94 [33.5%]) or tanezumab
5 mg treatment group (97 [34.5%]) showed a decrease in the sitting systolic BP
measurement (change >-10 to 0); and more patients in the tanezumab 2.5 mg treatmentgroup (142 [50.5%]) and tanezumab 5 mg treatment group (137 [48.8%]) than in theplacebo treatment group (123 [43.9%]) showed a decrease in the sitting diastolic BP
measurement (change >-10 to 0). A higher proportion of patients in the tanezumab 2.5
mg treatment group (120 [42.7%]) and tanezumab 5 mg treatment group (132 [47.0%])
than in the placebo treatment group (107 [38.2%]) showed an increase in the sitting
systolic BP measurement (change >0 to 10), and a higher proportion of patients in thetanezumab 2.5 mg treatment group (82 [29.2%]) and tanezumab 5 mg treatment group(89 [31.7%]) than in the placebo treatment group (63 [22.5%]) showed only a decrease or
no change in the sitting diastolic blood pressure measurement. A higher proportion ofpatients in the tanezumab 2.5 mg treatment group (39 [13.9%]) and tanezumab 5 mg
treatment group (42 [14.9%]) than in the placebo treatment group (21 [7.5%]) showed adecrease in the sitting systolic BP measurement (change -30 to <-20), and a higher
proportion of patients in the tanezumab 2.5 mg treatment group (14 [5.0%]) andtanezumab 5 mg treatment group (14 [5.0%]) then in the placebo treatment group(7 [2.5%]) showed a decrease in the sitting diastolic BP measurement (change <-20).
Vital sign abnormalities during the Treatment Period that were considered clinicallysignificant by the Investigator, and any confirmed episode of Orthostatic hypotension
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were to be reported as adverse events. All adverse events associated with vital signs,
with the exception of Blood pressure fluctuation, Hypertension, and Orthostatic
hypotension were reported in only one patient in any treatment group. In the placebo
treatment group, two patients reported Blood pressure fluctuation and six patients
reported Hypertension. In the tanezumab 2.5 mg treatment group, one patient reported
Blood pressure fluctuation and two patients reported Hypertension. In the tanezumab
5 mg treatment group, six patients reported Hypertension. Three patients in thetanezumab 5 mg treatment group had an adverse event of Orthostatic hypotension,compared to none in each of the other treatment groups.


ECG: There was no evidence of an effect of tanezumab on safety related to ECG
measures. The maximum changes in all ECG parameters were similar across treatmentgroups.



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 24)
in the tanezumab treatment groups. The overall percent incidence of adverse events andinjection site reactions in the combined TE ADA+ tanezumab treatment group wascomparable to the corresponding TE ADA- combined tanezumab treatment group andthere was no association between TE ADA+ and potential hypersensitivity reactions.

CONCLUSIONS

Treatment with tanezumab 5 mg met all three co-primary endpoints (WOMAC Pain andPhysical Function and PGA-OA) at Week 24.

The tanezumab 2.5 mg treatment group met two co-primary endpoints (WOMAC Pain
and Physical Function Subscales), but not the third co-primary endpoint (PGA-OA), andso did not meet the overall primary objective. Further hypothesis testing of the three key
secondary endpoints for both tanezumab treatment groups could not be performed
because significance for the PGA-OA was not met.



The results for all key secondary efficacy endpoints (Patients with 50% reduction fromBaseline in WOMAC Pain at Week 24; Change from Baseline to Week 2 in the
WOMAC Pain Subscale; Change from Baseline to Week 1 in the average pain in theindex joint) were deemed not significant due to the testing strategy, although both thetanezumab 5 mg treatment group and the tanezumab 2.5 mg treatment group had
favorable observed percentages of patients compared to placebo for all key secondary
efficacy endpoints (unadjusted p-values≤0.05).

Of the remaining secondary endpoints 10 of 10 had unadjusted p≤0.05 at Week 24 for thetanezumab 5 mg treatment group and 7 of 10 had unadjusted p≤0.05 at Week 24 for thetanezumab 2.5 mg treatment group.

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Collectively, the efficacy data across the primary and secondary endpoints indicate
tanezumab 5 mg and 2.5 mg are efficacious in patients with moderate to severe OA.
Moreover, the results for the Patient’s Global Assessment of OA at Week 24 and theresults for the secondary endpoints (unadjusted p-values) provide evidence that treatment
with tanezumab 5 mg provides additional benefit above treatment with 2.5 mg.



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



The adverse event data related to abnormal peripheral sensation were consistent withprevious studies; the incidence of events was more frequent in the tanezumab treatmentgroups. As in prior studies, Paresthesia and Hypoesthesia were the most commonly
reported adverse events of abnormal peripheral sensation.
o Based on blinded external neurologist's reviews of peripheral neurologic consultation
data, the most common diagnoses were Radiculopathy and Mononeuropathy(primarily Carpal tunnel syndrome) and overall, the results do not indicate thattanezumab treatment is associated with a peripheral polyneuropathy.

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



A similar number of total joint replacements were reported in patients receiving placebo
and tanezumab 2.5 or 5 mg; there was no difference across treatment groups for theincidence or observation-adjusted incidence.

No placebo-treated patient had an adjudicated joint safety outcome included in thecomposite joint safety endpoint, whereas 14 tanezumab-treated patients had an outcome
included in the composite joint safety endpoint. The tanezumab 5 mg treatment group
had the highest incidence of Rapidly progressive OA type 1, Rapidly progressive OA
type 2, and the only case of Primary osteonecrosis; the only Subchondral insufficiency
fracture was observed in the tanezumab 2.5 mg treatment group.



The immunogenicity results do not provide any evidence that the presence of treatmentemergent ADA affects the PK, safety, or efficacy profile of tanezumab.

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