Systemic Lupus Erythematosus

The primary objective of this study is to evaluate the efficacy of MEDI-546 compared to placebo in subjects with chronic, moderately-to-severely active systemic lupus erythematosus (SLE) with an inadequate response tostandard of care treatment for SLE (SOC SLE) at Day 169 (Week 24). The secondary objectives of this study are: • To evaluate the efficacy of MEDI-546 compared to placebo at Day 365 (Week 52) • To evaluate the effect of MEDI-546 compared to placebo in reducing background oral corticosteroid (OCS) dosage • To evaluate the safety profile of MEDI-546 • To evaluate the pharmacokinetics, immunogenicity, and pharmacodynamics of MEDI-546 The exploratory objectives of this study are: • To study the role of the 4-gene diagnostic test in efficacy and safety of MEDI-546 • To evaluate the effect of MEDI-546 compared to placebo in improving inflammatory cutaneous lupuslesions • To evaluate the effect of MEDI-546 compared to placebo in improving fatigue • To evaluate other measures of clinical activity of MEDI-546 • To evaluate the impact of MEDI-546 on inflammatory biomarkers and other genes and/or proteins in either whole blood or serum • To evaluate the effect of MEDI-546 on other potential disease mechanisms in SLE

MEDI-546

Human IgG1κ MAb

vial

100mg

The primary endpoint for this study is the proportion of subjects achieving a response in an SLE responder index (4) [SRI(4), where (4) represents a 4-point reduction in Day 1 SLEDAI-2K disease activity score] at Day 169 in subjects with chronic, moderately-to-severely active SLE. Subjects who are unable to taper OCS to < 10 mg/day and ≤ Day 1 dose of prednisone or equivalent by Day 85 and maintain OCS doses < 10 mg/day and
≤ Day 1 dose until Day 169 will be declared non-responders for the primary endpoint at Day 169.
There will be 4 primary comparisons for the primary endpoint. MEDI-546 1000 mg versus placebo and MEDI-546 300 mg versus placebo will be compared for the overall population. The same 2-dose comparisons will also be performed for the subpopulation of subjects with a positive diagnostic test result for type I IFN signature at screening. The primary endpoint will be analyzed using a logistic regression model. Theindependent variables in the model will include treatment groups and randomization stratification factors.
The following secondary efficacy endpoints will be evaluated in the overall population of subjects with chronic, moderately-to-severely active SLE.
• The proportion of subjects who achieve a response in an SRI(4) at Day 365 will be compared between treatment groups using logistic regression model. Subjects who are unable to reduce OCS to < 10 mg/day and ≤ Day 1 dose of prednisone or equivalent by Day 281 will be declared as non-responders
• The proportion of subjects on OCS ≥ 10 mg/day prednisone or equivalent at Day 1 who are able to taper to ≤ 7.5 mg/day at Day 365 will be compared between treatment groups using logistic regression model Exploratory endpoints include the subgroup analysis that will be performed on primary and secondary endpoints based on the 4-gene type I IFN diagnostic score (positive vs negative). Clinical test utility of the diagnostic will be explored using positive predictive value, negative predictive value, sensitivity, and specificity by an outside vendor.

Subjects must meet all of the following criteria:
1) In the opinion of the investigator, must have adequate reading and writing abilities (in
their native language) such that the subject can comprehend and complete the informed consent, and all protocol-related subject assessments
2) Age 18-65 years at the time of screening
3) Written informed consent and any locally required authorization (eg, HIPAA in the
USA, EU Data Privacy Directive in the EU) obtained from the subject prior to performing any protocol-related procedures, including screening evaluations 4) Fulfills at least 4 of the 11 American College of Rheumatology (ACR) classification criteria for SLE (see Appendix 2), one of which must be:
a. Positive antinuclear antibody (ANA) test ≥ 1:80 at screening by immunofluorescent assay at central laboratory; OR
b. Elevated anti-dsDNA or anti-Sm antibody at screening as determined by
central laboratory
5) Weight ≥ 40.0 kg at screening
6) Diagnosis of pediatric or adult SLE with chronic disease activity requiring ongoing
treatment or observation for ≥ 24 weeks prior to screening
7) Currently receiving at least one of the following:
a. Oral prednisone (or equivalent) ≤ 40 mg/day (see Appendix 4 for examples of
prednisone equivalency) from at least 2 weeks prior to signing of the informed
consent to Day 1, which must remain stable at least 2 weeks prior to Day 1
b. Any one of the following medications administered for a minimum of 12 weeks and at a stable dose for a minimum of 8 weeks prior to signing of the informed consent through Day 1:
i. Azathioprine ≤ 200 mg/day
ii. Antimalarial (eg, chloroquine, hydroxychloroquine, quinacrine)
iii. Mycophenolate mofetil/ mycophenolic acid ≤ 2.0 g/day
iv. Weekly administrations of oral, SC, or intramuscular methotrexate
≤ 25 mg/day
8) Prior to Day 1, External Adjudication Group confirmation of both:
a. At screening, SLEDAI-2K score ≥ 6 points and “Clinical” SLEDAI-2K score ≥ 4 points (The “Clinical” SLEDAI-2K is the SLEDAI-2K assessment score without the inclusion of points attributable to any urine or laboratory results including immunologic measures):
i. Including points from at least one of the following clinical components: arthritis, myositis, rash, alopecia, mucosal ulcers, pleurisy, pericarditis, vasculitis
ii. Excluding points attributed to an SLE headache and organic brain syndrome
b. At least one of the following:
i. BILAG-2004 Index A disease in ≥ 1 body/organ system
ii. BILAG-2004 Index B disease in ≥ 2 body/organ systems
9) Day 1 “Clinical” SLEDAI-2K score ≥ 4 points
10) Physicians Global Assessment (MDGA) ≥ 1.0 on a 0-3 scale at screening
11) Females of childbearing potential must use 2 effective methods of avoiding pregnancy from screening through 85 days after the final dose of investigational product unlesssurgically sterile (ie. bilateral tubal ligation, bilateral oophorectomy, or complete
hysterectomy), has a sterile male partner, is 1 year postmenopausal, or practices
abstinence. Cessation of birth control after the 85-day follow up period should be
discussed with a responsible physician
a. Effective methods of birth control are summarized in Table 4.2.1-1
b. Sustained abstinence is an acceptable practice; however, periodic abstinence,
the rhythm method, and the withdrawal method are not acceptable methods of
contraception
c. Postmenopausal: At least 1 year since last menses and having an elevated follicle-stimulating hormone (FSH) > central laboratory value of postmenopausal at screening
12) Nonsterilized males who are sexually active with a female partner of childbearing
potential must use 2 acceptable methods of effective contraception (see Table 4.2.1-1)
from Day1 through at least 85 days after receipt of the final dose of investigational
product
13) Females with an intact cervix must have documentation of a Pap smear with no
documented malignancy (eg, cervical intraepithelial neoplasia grade III [CIN III],
carcinoma in situ [CIS], or adenocarcinoma in situ [AIS]) within 2 years prior to
Day 1
14) Willing to forego other forms of experimental treatment for SLE during the study
15) Meets all of the following tuberculosis (TB) criteria:
a. No history of latent or active TB prior to screening, with the exception of latent TB prior to screening with documented completion of appropriate treatment
b. No signs or symptoms of active TB upon medical history or physical examination
c. No recent contact with a person with active TB OR, if there has been such contact, referral to a physician specializing in TB to undergo additional evaluation prior to randomization and, if warranted, receipt of appropriate treatment for latent TB at or before the first administration of investigational product
d. Negative diagnostic TB test within 3 months prior to randomization (defined as a negative QuantiFERON-TB Gold [QFT-G] test for TB screening) OR a positive diagnostic TB result (defined as a positive QFT-G test for TB obtained during the screening period) for which active TB has been ruled out and for which appropriate treatment for latent TB has been initiated either at or before the first administration of investigational product OR a confirmed indeterminate QFT-G test for TB obtained during the screening period with
ongoing QFT-G testing for TB at Day 57, Day 169, and Day 253
e. A chest radiograph with no evidence of current active infection (eg, TB) or old active TB, malignancy, or clinically significant abnormalities (unless due to SLE) obtained during the screening period or anytime within 90 days prior to signing of the informed consent form
16) Adequate peripheral venous access.
17) Ability to complete and meet all requirements for randomization within 28 days after
signing the informed consent form

Any of the following would exclude the subject from participation in the study:
General Exclusion Criteria
1) Any condition that, in the opinion of the investigator, would interfere with evaluation
of the investigational product or interpretation of subject safety or study results
2) Concurrent enrollment in another clinical study with an investigational product within
4 weeks prior to Day 1 or within 5 half-lives of the investigational product used in that clinical study, whichever is longer
3) Employees of the clinical study site or any other individuals involved with the conduct of the study, or immediate family members of such individuals
4) Lactating or pregnant females or females who intend to become pregnant anytime
from initiation of screening through the 85-day safety follow-up period following last
dose of investigational product
5) Current suggestion of alcohol, drug or chemical abuse, or a recent history of such
abuse < 1 year before randomization into the study
6) Major surgery within 8 weeks before signing the informed consent form or elective
major surgery planned during the study period (see Appendix 5 for guidance on major
surgery)
7) Spontaneous or induced abortion, still or live birth, or pregnancy ≤ 4 weeks prior to
signing the informed consent form
8) At screening (within 4 weeks before Day 1), any of the following:
a) Aspartate transaminase (AST) > 2.0 × upper limit of normal (ULN). Subjects with AST > 2.0 × ULN may be allowed if, in the opinion of the investigator, is caused by SLE and discussed with the medical monitor.
b) Alanine transaminase (ALT) > 2.0 × ULN. Subjects with ALT > 2.0 × ULN may be allowed if, in the opinion of the investigator, is caused by SLE and discussed with the medical monitor.
c) Total bilirubin > ULN (unless due to Gilbert’s syndrome)
d) Serum creatinine > 2.0 mg/dL (or > 181 μmol/L)
e) Urine protein/creatinine ratio > 2.0 mg/mg (or > 226.30 mg/mmol)
f) Glomerular filtration rate (using Modification of Diet in Renal Disease formula) < 30 mL/min/1.73 m2
g) Neutrophil count < 1,000/μL (or < 1.0 × 109/L) or < 500/μL (or < 0.5 × 109/L) if related to subject’s SLE disease
h) Platelet count < 25,000/μL (or < 25 × 109/L) or < 15,000/μL (or < 15 × 109/L) if related to subject’s SLE disease
i) Hemoglobin < 8 g/dL (or < 80 g/L) or < 7 g/dL (or < 70 g/L) if related to subject’s SLE disease
j) Glycosylated hemoglobin (HbA1c) > 8% (or > 0.08) at screening (diabetic subjects only)
(Note: Abnormal liver function tests not caused by SLE or abnormal bilirubin may be
repeated ONE time on a separate sample before subject is declared a screen failure.)
Exclusion Criteria Related to Concomitant Medications
9) Receipt of any of the following:
a) Any new oral prednisone therapy (or equivalent) anytime from 2 weeks prior to signing of the informed consent through Day 1 or any change in current oral prednisone dose (or equivalent) anytime from 2 weeks prior to Day 1 (see Appendix 4 for examples of prednisone equivalency)
b) Any new dose of any of the following anytime in the 12 weeks prior to signing of the informed consent or change in current dose anytime in the 8 weeks prior to signing of the informed consent through Day 1: azathioprine; any antimalarial (eg, chloroquine, hydroxychloroquine, quinacrine); mycophenolate mofetil/mycophenolic acid; oral, SC, or intramuscular methotrexate
10) Receipt of any of the following:
a) Azathioprine > 200 mg/day
b) Mycophenolate mofetil/mycophenolic acid > 2.0 g/day
c) Oral, SC, or intramuscular methotrexate > 25 mg/week
d) Any change in route of administration of oral, SC, or intramuscular methotrexate anytime within the 8 weeks prior to signing of the informed consent
11) Receipt of any of the following slow-acting immunosuppressants:
a) Etanercept ≤ 4 weeks prior to signing the informed consent form
b) Adalimumab, infliximab, or golimumab ≤ 12 weeks prior to signing the informed consent form
c) Rituximab or belimumab ≤ 48 weeks prior to signing the informed consent form
12) Receipt of a biologic agent (other than those listed in Exclusion Criterion #11) within
5 half-lives or prior to loss of PD and/or clinical effect, whichever is longer, prior to
signing of the informed consent form
13) A known history of allergy or reaction to any component of the investigational
product formulation or history of anaphylaxis to any human gamma globulin therapy
14) Receipt of more than one prescribed NSAID at an anti-inflammatory dose within
2 weeks prior to Day 1; OR receipt of fluctuating doses of a prescribed NSAID within
2 weeks prior to Day 1
15) Receipt of any of the following:
a) Intra-articular, intramuscular or intravenous glucocorticoids within 6 weeks prior to Day 1
b) Any live or attenuated vaccine within 4 weeks prior to signing the informed consent form (administration of killed vaccines is acceptable, the sponsor recommends
investigators ensure all subjects are up to date on required vaccinations prior to study entry)
c) Oral anti-infectives (including antivirals) for active infection within 2 weeks prior to Day 1
d) Bacillus of Calmette and Guérin (BCG) vaccine within 1 year of signing the informed consent form
e) Any restricted medication listed in Appendix 3.
f) Blood transfusion within 4 weeks prior to signing the informed consent. Exclusion Criteria Related to SLE and Other Diseases
16) Active severe or unstable neuropsychiatric SLE that would make the subject
unsuitable for the study or unable to fully understand the informed consent, including
but not limited to: aseptic meningitis; cerebral vasculitis; myelopathy; demyelination
syndromes (ascending, transverse, acute inflammatory demyelinating polyradiculopathy); acute confusional state; impaired level of consciousness;
psychosis; acute stroke or stroke syndrome; cranial neuropathy; status epilepticus;
cerebellar ataxia; and mononeuritis multiplex
17) Within 8 weeks prior to screening, active severe SLE-driven renal disease or unstable
renal disease (eg, clinically significant increase in creatinine or active urinary
sediment) that in the opinion of the investigator would make the subject unsuitable for
this study
18) A diagnosis (within 1 year of signing the informed consent form) of mixed connective
tissue disease or any history of overlap syndromes of SLE with erosive arthritis or
SSc. (Note: An overlap syndrome of SLE with myositis or rheumatoid arthritis at
screening is permitted provided the subject also meets the criteria for the classification
as SLE or a history of mixed connective tissue disease, which over time has developed into a diagnosis of SLE (where diagnosis of SLE has been present for at
least 1 year)
19) History of, or current diagnosis of severe anti-phospholipid syndrome within 1 year
prior to signing the informed consent form. Clinical symptoms include but are not
limited to arterial or venous thromboembolism, disseminated intravascular
coagulation, or pulmonary embolism. History of positive anti-phospholipid antibody
alone with no associated clinical symptoms is allowed
20) History of, or current, inflammatory joint or skin disease other than SLE that in the
opinion of the investigator could interfere with the inflammatory arthritis or skin
assessments and confound the disease activity assessments
21) History of, or current diagnosis of a clinically significant vasculitis syndrome (see
Appendix 16 for list of exclusionary vasculitic syndromes). Vasculitis due to SLE is
allowed in the study
22) History of any non-SLE disease that has required treatment with oral or parenteral
corticosteroids for more than a total of 2 weeks within the last 24 weeks prior to
randomization
Exclusion Criteria Related to Infectious and Malignancy Risk Factors
23) Known history of a primary immunodeficiency or an underlying condition such as
human immunodeficiency virus infection or splenectomy that predisposes the subject
to infection
24) Confirmed positive test for hepatitis B serology for:
a) Hepatitis B surface antigen serology
b) Hepatitis B core antigen (HBc) with hepatis B virus DNA (HBV DNA)
detected by reflex testing by the central laboratory at screening or at any time for the duration of the study
25) Confirmed test for hepatitis C serology as confirmed by central laboratory
26) Any serious herpes infection at any time prior to randomization, including but not
limited to disseminated herpes, herpes encephalitis, recurrent herpes zoster (defined as
2 episodes within 2 years) or ophthalmic herpes
27) Any herpes zoster infection that has not completely resolved within 12 weeks prior to
signing of the informed consent form
28) Any of the following within 60 days prior to signing the informed consent form
a) Clinically significant active infection, including ongoing, and chronic
infection (ie, osteomyelitis, bronchiectasis, etc) but allowing chronic nail infections
b) Any infection requiring hospitalization or treatment with IV anti-infectives
28) History of cancer, apart from
a) Squamous or basal cell carcinoma of the skin treated with documented success
of curative therapy ≥ 3 months before randomization into the study
b) Cervical cancer in situ treated with apparent success with curative therapy
≥ 1 year before randomization into the study