SYSTEMIC LUPUS ERYTHEMATOSUS

Primary Objective  The primary objective of this study is to evaluate and compare the efficacy of 3 dose levels of PF-04236921 to placebo in subjects with active SLE using the SLE Responder Index (SRI). Secondary Objectives The secondary objectives of the study include:  Evaluate the safety, tolerability, and immunogenicity of PF-04236921.  Evaluate and compare the clinical response to treatment and changes in disease activity using components of the SRI.  Characterize pharmacokinetics (PK) of PF-04236921 in subjects with SLE.  Assess patient reported outcomes including: global assessment of disease activity by visual analog scale (VAS), Medical Outcome Survey Short Form 36 (SF-36), European Quality of Life 5 Dimensions Questionnaire (EQ-5D), and Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F).  Assess efficacy biomarkers (eg, anti-ds DNA). Exploratory Objectives The exploratory objectives of the study include:  Evaluate other clinical response indices to treatment (eg, higher SLEDAI-2K cutoffs to define the SRI, BILAG in individual organ systems, 28 joint count, etc).  Assess corticosteroid use.  Assess the rates of flare and time to flare.  Additional biomarker analysis.  Characterize pharmacodynamics (PD) effects of PF-04236921.  Population PK and/or PK/PD analysis to explore dose/exposure-response relationships in biomarkers and/or efficacy endpoints.

PF-04236921 Powder for Injection, 106 mg/vial

PF-04236921

SC injection

106mg/vial

Endpoints:
Primary Endpoint
The primary endpoint of the study is the proportion of subjects achieving the SLE Responder
Index (SRI) at Week 24. The components of the SRI are the Systemic Lupus Erythematosus
Disease Activity Index 2000 (SLEDAI-2K), the British Isles Lupus Assessment Group
(BILAG) 2004, and the Physician’s Global Assessment (PhGA). In order to be classified as
a responder, subjects must not meet the definition of a treatment failure (as per Section 5.6) and must meet all of the following compared with baseline:
 4 point reduction in the SLEDAI-2K score, and
 No new BILAG A organ domain score or 2 new BILAG B organ domain scores, and
 No worsening (<0.3 point increase) in PhGA score.
The composite endpoint is designed to assure that if improvements occur, they are not
accompanied by clinically-relevant worsening. The SRI requires demonstration of
improvement in disease activity as measured by at least a 4-point reduction in SLEDAI-2K
score as the first step in identifying a responder. Since the SLEDAI-2K 4-point improvement threshold is based on a published threshold for clinical meaningfulness, and because reduction in the score generally requires normalization of a manifestation, not just improvement, an SRI response is also considered clinically meaningful. Once achieving at least a 4-point reduction in SLEDAI-2K, a subject must also show no worsening of disease as measured by BILAG and PhGA to be considered a responder. If either tool shows worsening, the subject is not considered a responder, despite an improvement in the SLEDAI-2K. All 3 of the components are needed to be scored as a responder. In addition, no increases in concomitant SLE medications beyond protocol-specified thresholds are allowed, since such medication changes are indicative of worsening disease and the subject will be considered a treatment failure.

Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study:
1. Evidence of a personally signed and dated informed consent form document indicating that the subject (or legally acceptable representative) has been informed of all pertinent aspects of the study.
2. Subjects who are willing and able to comply with scheduled visits, treatment plan,
laboratory tests, and other study procedures.
3. Male and/or female subjects between the ages of 18 and 75 years old at the time of
signing of Informed Consent Form (ICF).
4. Have a clinical diagnosis of SLE according to the 1997 update on the 1982 revised
American College of Rheumatology (ACR) criteria (see Appendix 6).
5. Have unequivocally positive anti-nuclear antibody (ANA) test results by either:
 Positive test result from within the study screening period. Screening results must be
based on the study’s central laboratory results. A positive ANA test is defined as an
ANA titer 1:80 and/or a positive anti-dsDNA (> the ULN for the central laboratory
reported result) serum antibody.
OR  One positive historical test result that in the opinion of the investigator and the sponsor (see subject selection above) is unequivocally due to SLE. Historical documentation of a positive test of ANA (eg, ANA by HEp-2 titer, ANA by ELISA) or anti-dsDNA (eg, anti-dsDNA by Farr assay or ELISA) must include the date and type of the test, the testing laboratory name, numerical reference range, and a key that explains values
provided as positive versus negative OR negative, equivocal/borderline, positive. Only
unequivocally positive values as defined in the laboratory’s reference range are
acceptable; borderline values will not be accepted.
6. Active disease at screening defined by both:
 SLEDAI-2K score of 6, and  BILAG Level A disease in 1 organ system [except renal or central nervous system (CNS)] or BILAG B disease in 2 organ systems if no level A disease is present.
7. Are on stable SLE treatment consisting of any of the following medications (alone or in
combination) for at least 30 days prior to the Day 1 visit (first dose of study medication):
 Corticosteroids (prednisone or prednisone equivalent, up to 25 mg/day). For those
patients on alternating day doses of corticosteroids, use the average of two daily doses
to calculate the average daily steroid dose.
 Other immunosuppressive or immunomodulatory agents including methotrexate,
azathioprine, leflunomide, mycophenolate (including mycophenolate mofetil,
mycophenolate mofetil hydrochloride, and mycophenolate sodium), 6-mercaptopurine
or thalidomide.
 Anti-malarials (eg, hydroxychloroquine, chloroquine, quinacrine)
NOTE:
 New SLE therapy must not be added within 60 days prior to Day 1; pre-existing SLE
medications must be stable for at least 30 days prior to Day 1.
 Corticosteroids may be added as new medication or their doses adjusted only up to 30
days prior to Day 1.
8. All women of childbearing potential (WOCBP) must have a negative serum pregnancy test result at screening and a negative urine pregnancy test result at baseline and prior to
receiving each treatment.
 WOCBP are defined as women who are biologically capable of becoming pregnant,
including women who are using contraceptives or whose sexual partners are either
sterile or using contraceptives.
 Women of non-childbearing (WONCBP) potential are defined as either females who
are over the age of 60, females who are 45 to 60 years of age must be amenorrheic for
at least 2 years PLUS have a serum FSH level within the laboratory’s reference range
for postmenopausal, or females who are surgically sterile, such as after hysterectomy,
bilateral oophorectomy, or tubal ligation (procedure performed 52 weeks before
screening). This information must be documented in the subject’s source documents.
 WONCBP do not require a serum and urine pregnancy test.
9. Women of childbearing potential, as well as sexually active males agree that when
sexually active to use highly effective contraceptive methods and abide by the timeframes noted in the Contraception section of the Lifestyle Guidelines (Section 4.4).

Subjects presenting with any of the following will not be included in the study:
1. Any prior history of treatment with PF-04236921, or anti-IL-6 agent.
2. Have received any of the following within 364 days of Day 1:
 A biologic investigational agent other than those noted below (eg, abatacept or
interferon alpha inhibitors). (Investigational agent is defined as any drug not approved
for sale in the country in which it is being used).
 Have required 3 or more courses of systemic corticosteroids for concomitant
conditions (eg, asthma, Crohn’s disease, ulcerative colitis, systemic vasculitis, atopic
dermatitis) within 364 days of Day 1 (Topical or inhaled steroids are permitted).
3. Received IV cyclophosphamide within 180 days of Day 1.
4. Have received any of the following within 90 days of Day 1:
 Anti-TNF therapy (eg, adalimumab, etanercept, infliximab).
 Interleukin-1 receptor antagonist (anakinra).
 Intravenous immunoglobulin (IVIG).
 High dose corticosteroids (>100 mg/day prednisone or equivalent) or pulse IV doses.
 Plasmapheresis.
5. Have received any of the following within 60 days of Day 1:
 Any intramuscular, or intravenous steroid injection.
 Any new immunosuppressive/immunomodulatory agent, or anti-malarial agent. (See
Inclusion Criteria #7). New inhaled and/or new topical immunosuppressive agents(eg, eye drops, topical creams) are allowed.
6. Have received any of the following within 30 days of Day 1:
 A live vaccine.
 Any new or change in dose of a corticosteroid, any change in dose of a immunosuppressive/immunomodulatory or anti-malarial agent (See Inclusion Criteria #7). Any intraarticular steroid injection.
7. Has been treated with any B-cell depleting agents such as rituximab (or other
CD20+ directed therapies), epratuzumab, anti-CD52 [alemtuzumab], or TACI-Ig, within
the last 12 months unless it is determined that the B cell counts have normalized prior to
their screening visit (eg, B cell counts are at least as high as the patient’s last value prior to receiving the B-cell depleting agent). Subjects that have been treated with TACI-Ig must
have also normalized their plasma cells and serum immunoglobulin levels (returned to
pre-treatment levels).
8. Has been treated with belimumab or any anti-Blyss (or anti-BAFF) agent within the past
180 days.
9. Have severe lupus kidney disease (defined by proteinuria 6 g/24 hour or equivalent using spot urine protein to creatinine ratio, or serum creatinine 2.0 mg/dL), or have active nephritis (eg, BILAG A renal disease), or have required hemodialysis or high-dose
corticosteroid (>100 mg/day prednisone or equivalent) within 90 days of Day 1.
10. Have active central nervous system (CNS) lupus (eg, BILAG A neurological disease
and/or active, poorly controlled seizure disorder, acute confusional state, myelitis, stroke
or stroke syndrome, cerebellar ataxia or dementia related to SLE, psychosis, organic brain syndrome, cerebrovascular accident [CVA], cerebritis or CNS vasculitis) requiring
therapeutic intervention within 60 days of Day 1. Patients with manageable chorea are not excluded as long as they meet all other qualifying criteria for the study.
11. Have a history of a major organ transplant (eg, heart, lung, kidney, liver) or hematopoietic stem cell/marrow transplant.
12. Any major illness/condition or evidence of an unstable condition (eg, renal, hepatic,
hematologic, gastrointestinal, endocrine, pulmonary, immunologic disorder, or infectious illness) that in the investigator’s judgment, will substantially increase the risk to the subject if he or she participates in the study.
13. Has a history of thromboses (venous or arterial) or other vascular complications within the last 6 months due to antiphopholipid syndrome or anticardiolipin antibodies.
 Note: Any subject being treated for recurrent antiphospholipid syndrome or
anticardiolipin antibodies must be adequately anticoagulated according to current
guidelines.
14. Pregnant or breastfeeding women or women planning to become pregnant during study period.
15. Known active or history of recurrent bacterial, viral, fungal, mycobacterial or other
infections (including but not limited to tuberculosis and atypical mycobacterial disease,
granulomatous disease on chest x-ray, and herpes zoster) that in the investigator’s
judgment, will substantially increase the risk to the subject if he or she participates in
the study.
16. Known history of human immunodeficiency (HIV) based on documented history with
positive serological test, or positive HIV serological test at screening. (Note: a
documented negative HIV test within 12 months of screening is acceptable and does
not need to be repeated).
17. Positive test for hepatitis B surface antigen (HBsAg), total hepatitis B core antibody
(anti-HBcAb; also called anti-HBc), and/or hepatitis C antibody (HCVAb).
18. Clinically significant finding on a chest radiograph (or other appropriate diagnostic
imaging study such as computed tomography [CT] or magnetic resonance imaging
[MRI]) such as the presence of tuberculosis (TB), general infection, heart failure or
malignancy. Chest imaging must be performed during the screening period or within
12 weeks prior to Day 1. Findings that are clinically significant but due to SLE
activity may not require the subject to be excluded, but should be discussed with the
sponsor prior to the subject being enrolled in the study.
19. Have required management of acute or chronic infections as follows:
 Currently on any suppressive therapy for a chronic infection (such as tuberculosis,
pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster and atypical
mycobacteria).
 Hospitalization for treatment of infection within 60 days of Day 1.
 Use of parenteral (IV or IM) antibiotics (antibacterials, antivirals, anti-fungals, or antiparasitic agents) within 60 days of Day 1.
20. Any history of previously untreated or current evidence of active or untreated latent
infection with Mycobacterium tuberculosis (TB), evidence of prior untreated or currently
active tuberculosis by chest radiography, residing with or frequent close contact with an
individual with active tuberculosis. Subjects who have a positive Mantoux (PPD)
tuberculin skin test or positive Interferon Gamma Release Assay (IGRA) (with the
following acceptable assays: QuantiFERON
-TB Gold test (QFT-G) test, QuantiFERON-TB Gold In-Tube test (QFT-GIT) and T-SPOT TB test) during screening or within 12 weeks prior to Study Day 1.
 A positive Mantoux Purified Protein Derivative skin test result of 5 mm of induration
(or as performed by country specific or local standards) at 48-72 hours without
consideration of prior Bacille Calmette Guerin (BCG) vaccination. Documentation of
the dose and product used as well as the official test reading must be obtained and
available in the subject’s study file.
 An IGRA is preferred for subjects with prior BCG vaccination. Documentation of
IGRA product used and the test result must be in the subject’s source documentation.
 If a patient has a positive QFT Gold or PPD test, he/she may be eligible if he/she has
completed and has documented evidence of an appropriate treatment regimen for TB
(eg, 9 months of isoniazid in a locale where rates of primary multi-drug TB resistance
are <5%1) and has a chest radiograph (or other appropriate diagnostic imaging study)
within 12 weeks prior to Study Day 1 that shows no evidence of active TB. Such
subjects should be discussed with the sponsor prior to randomization.
 If a patient has previously received an adequate course of therapy for either latent
(9 months of isoniazid in a locale where rates of primary multi-drug resistant TB
infection are <5%) or active TB infection, neither a PPD test nor a QFT Gold test need
be obtained, but a chest radiograph or other appropriate image must still be obtained if
not done so within the prior 3 months.
21. History of severe allergic or anaphylactoid reaction to monoclonal antibodies, murine
proteins, or corticosteroid preparations.
22. Have a known IgA deficiency or IgA level < LLN for the reference laboratory.
23. Known history of diverticulitis or symptomatic diverticulosis, perineal abscess or fistulae.
24. Cancer, or a history of cancer within the previous 5 years of screening (other than
adequately treated cutaneous basal cell, squamous cell carcinoma, or carcinoma in situ
of the uterine cervix with no evidence of recurrence).
25. Class III or IV congestive heart failure as defined by the New York Heart Association.
26. Acute coronary syndrome (eg, myocardial infarction, unstable angina pectoris) or any
history of significant cerebrovascular disease within 24 weeks of screening.
27. Pre-existing demyelinating disorder such as multiple sclerosis, or other severe neurological deficits.
28. Has a current serious psychiatric disorder, alcohol or drug abuse or a history in the past two years which, in the opinion of the investigator could create a risk for the patient’s health or protocol adherence29. Major surgery within 4 weeks of screening or scheduled to occur during the study, excluding diagnostic surgery.
30. Previous treatment with total lymphoid irradiation.
31. Presence of any of the following laboratory abnormalities:
 Alanine aminotransferase (ALT) or asparatate aminotransferease (AST) levels 1.5 x
the upper limit of normal (ULN).  Absolute Neutrophil Count (ANC) <1500/mm3
(1.5 x 109/L).
 Hemoglobin <8.0 g/dL (80 g/L).
 Platelet count <50,000/L (50 x 109/L).
 Serum creatinine 2.0 mg/dL (177 mol/L).
 Urine Protein/Creatinine ratio (Upr/cr) 6.0.
Screening laboratory tests with abnormal results may be repeated once to confirm abnormal results. If results return to normal within the 4-week screening period, the subject may enter the study.
32. For screening laboratory parameters not included in exclusion 32 above, have a Grade 3 or greater laboratory abnormality based on the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 toxicity scale (see Appendix 11) except for the following that are allowed:
 Grade 3 prothrombin time (PT) secondary to warfarin treatment.
 Grade 3 partial thromboplastin time (PTT) due to lupus anticoagulant and not related
to liver disease or anti-coagulant therapy.
 Grade 3/4 proteinuria (<6 g/24 hour equivalent by spot urine protein to creatinine ratio
allowed).
 Grade 3 hypoalbuminemia due to lupus nephritis, and not related to liver disease or
malnutrition.
33. Subjects who are investigational site staff members or subjects who are Pfizer employees directly involved in the conduct of the trial.
34. Treatment with a non-biologic investigational drug within 30 days (or as determined by the local requirement, whichever is longer) or 5 half-lives preceding the first dose of study medication (Investigational agent is defined as any drug not approved for sale in the country in which it is being used).
35. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.