Safety and Efficacy Study of a Biologic to Treat Systemic Lupus Erythematosus

The British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA) is a measure of systemic lupus erythematosus (SLE) response. BICLA is defined as: British Isle Lupus Assessment Group improvement, defined as BILAG As at Baseline improved to B/C/D, and BILAG Bs at baseline improved to C/D, and no BILAG worsening in other BILAG organ systems such that there are no new BILAG As or greater than 1 new BILAG B; and no worsening in the SLEDAI-2K total score compared to Baseline (defined as no increase in SLEDAI total score); and no worsening in the physician's global assessment (MDGA) of disease activity (no worsening is defined as less than 10% worsening, equivalent to a 10mm increase on a 100mm visual analog scale \[VAS\]) compared to Baseline.

Time frame: At Day 169

Population: All Randomized and Treated participants

Mean Change from Baseline Over Time; Measured by Disease Activity Score 28: A single score on a continuous scale (0-9.4). The level of RA disease activity can be interpreted as low (DAS28 \<=3.2),moderate (3.2 \< DAS28 \<=5.1), or as high disease activity (DAS28 \> 5.1)

Time frame: At baseline, Day 85 and Day 169

Population: All Randomized and Treated Participants

Overall British Isles Lupus Assessment Group-2004 score, BILAG Scores: A=Severe disease activity, B=Moderate disease activity, C=Mild disease, D=Inactive disease but previously affected, E=System never involved.The categories are converted to a numeric score (A=9, B=3, C=1, D=0, E=0) and treated as a continuous variable. Higher score= more severe disease activity.

Time frame: At baseline, Day 85 and Day 169

Population: All randomized and treated participants

Physician Global Assessment of Arthritis was measured by asking the physician to assess the participant's current arthritis disease activity by placing a vertical line on a 0 to 100 millimeter (mm) visual analog scale (VAS), where 0 mm = very good and 100 mm = very bad.

Time frame: At baseline, Day 85 and Day 169

Population: All randomized and treated participants

Systemic Lupus Erythematosus Disease Activity Index, SLEDAI; Version 2000, also known as SLEDAI-2K. The SLEDAI-2K score is a weighted, cumulative index of lupus disease activity. SLEDAI-2K is calculated from 24 individual descriptors across 9 organ systems; 0 indicates inactive disease and the maximum theoretical score is 105.

Time frame: At baseline, Day 85 and Day 169

Population: All randomized and treated participants

Pharmacokinetics of BMS-931699 derived from serum concentration versus time data; Ctrough = Trough level serum concentration of BMS-931699 at time point specified Pharmacokinetic Population: defined as all subjects who receive any study medication and have any available concentration-time data.

Time frame: Day 169

Population: Pharmacokinetic population

Percent of participants requiring use of corticosteroids and mmunosuppressants use over time

Time frame: Up to one day prior to the first dose of long-term extension period or up to 42 days post last short-term dose date, which ever is earlier

Population: All randomized and treated participants

Mean change from baseline, CLASI = Cutaneous Lupus Erythematosus Disease Area and Severity Index. Scores can range from 0 to 70 with higher scores denoting greater disease activity or damage.

Time frame: At Day 85 and Day 169

Population: All Randomized and Treated Subjects

CALCIUM, TOTAL MMOL/L H \> 1.1×ULN IF PRE-RX IS MISSING OR \> 1.1×ULN IF PRE-RX \<= ULN OR \> 1.1×PRE-RX IF PRE-RX \> ULN OR \> ULN IF PRE-RX \< LLN; CALCIUM, TOTAL MMOL/L L \< 0.9×LLN IF PRE-RX IS MISSING OR \< 0.9×LLN IF PRE-RX \>= LLN OR \< 0.9×PRE-RX IF PRE-RX \< LLN OR \< LLN IF PRE-RX \> ULN; CHLORIDE, SERUM MMOL/L H \> 1.1×ULN IF PRE-RX IS MISSING OR \> 1.1×ULN IF PRE-RX \<= ULN OR \> 1.1×PRE-RX IF PRE-RX \> ULN OR \> ULN IF PRE-RX \< LLN; CHLORIDE, SERUM MMOL/L L \< 0.9×LLN IF PRE-RX IS MISSING OR \< 0.9×LLN IF PRE-RX \>= LLN OR \< 0.9×PRE-RX IF PRE-RX \< LLN OR \< LLN IF PRE-RX \> ULN;

Time frame: Up to 42 days post last dose of study medication in short-term or long-term extension period

Population: All treated participants

BICARBONATE MMOL/L H \> 1.2×ULN IF PRE-RX IS MISSING OR \> 1.2×ULN IF PRE-RX \<= ULN OR \> 1.2×PRE-RX IF PRE-RX \> ULN OR \> ULN IF PRE-RX \< LLN; BICARBONATE MMOL/L L \< 0.8×LLN IF PRE-RX IS MISSING OR \< 0.8×LLN IF PRE-RX \>= LLN OR \< 0.8×PRE-RX IF PRE-RX \< LLN OR \< LLN IF PRE-RX \> ULN; POTASSIUM, SERUM MMOL/L H \> 1.1×ULN IF PRE-RX IS MISSING OR \> 1.1×ULN IF PRE-RX \<= ULN OR \> 1.1×PRE-RX IF PRE-RX \> ULN OR \> ULN IF PRE-RX \< LLN; POTASSIUM, SERUM MMOL/L L \< 0.9×LLN IF PRE-RX IS MISSING OR \< 0.9×LLN IF PRE-RX \>= LLN OR \< 0.9×PRE-RX IF PRE-RX \< LLN OR \< LLN IF PRE-RX \> ULN; MAGNESIUM, SERUM MMOL/L H \> 1.1×ULN IF PRE-RX IS MISSING OR \> 1.1×ULN IF PRE-RX \<= ULN OR \> 1.1×PRE-RX IF PRE-RX \> ULN OR \> ULN IF PRE-RX \< LLN MAGNESIUM, SERUM MMOL/L L \< 0.9×LLN IF PRE-RX IS MISSING OR \< 0.9×LLN IF PRE-RX \>= LLN OR \< 0.9×PRE-RX IF PRE-RX \< LLN OR \< LLN IF PRE-RX \> ULN

Time frame: Up to 42 days post last dose of study medication in short-term or long-term extension period

Population: All treated participants

SODIUM, SERUM MMOL/L H \> 1.05×ULN IF PRE-RX IS MISSING OR \> 1.05×ULN IF PRE-RX \<= ULN OR \> 1.05×PRE-RX IF PRE-RX \> ULN OR \> ULN IF PRE-RX \< LLN SODIUM, SERUM MMOL/L L \< 0.95×LLN IF PRE-RX IS MISSING OR \< 0.95×LLN IF PRE-RX \>= LLN OR \< 0.95×PRE-RX IF PRE-RX \< LLN OR \< LLN IF PRE-RX \> ULN PHOSPHORUS, INORGANIC PHOS MMOL/L H \> 1.25×ULN IF PRE-RX IS MISSING OR \> 1.25×ULN IF PRE-RX \<= ULN OR \> 1.25×PRE-RX IF PRE-RX \> ULN OR \> ULN IF PRE-RX \< LLN PHOSPHORUS, INORGANIC PHOS MMOL/L L \< 0.85×LLN IF PRE-RX IS MISSING OR \< 0.85×LLN IF PRE-RX \>=LLN OR \< 0.85×PRE-RX IF PRE-RX \< LLN OR \< LLN IF PRE-RX \> ULN

Time frame: Up to 42 days post last dose of study medication in short-term or long-term extension period

Population: All treated participants

IMMUNE ACTIVATION MARKERS:C-REACTIVE PROTEIN (CRP) CRP MG/L H \> 1.5×ULN; CRP, HIGH SENSITIVITY MG/L H \> 1.5×ULN;

Time frame: Up to 42 days post last dose of study medication in short-term or long-term extension period

Population: All treated participants

GLUCOSE TESTS:GLUCOSE, FASTING SERUM MMOL/L H \> 1.3×ULN IF PRE-RX IS MISSING OR \> 1.3×ULN IF PRE-RX \<= ULN OR \> 2×PRE-RX IF PRE-RX \> ULN OR \> ULN IF PRE-RX \< LLN GLUCOSE, FASTING SERUM MMOL/L L \< 0.8×LLN IF PRE-RX IS MISSING OR \< 0.8×LLN IF PRE-RX \>= LLN OR \< 0.8×PRE-RX IF PRE-RX \< LLN OR \< LLN IF PRE-RX \> ULN; PROTEIN TESTS:ALBUMIN G/L L \< 0.9×LLN IF PRE-RX IS MISSING OR \< 0.9×LLN IF PRE-RX \>= LLN OR \< 0.9×PRE-RX IF PRE-RX \< LLN PROTEIN, TOTAL G/L H \> 1.1×ULN IF PRE-RX IS MISSING OR \> 1.1×ULN IF PRE-RX \<= ULN OR \> 1.1×PRE-RX IF PRE-RX \> ULN OR \> ULN IF PRE-RX \< LLN PROTEIN, TOTAL G/L L \< 0.9×LLN IF PRE-RX IS MISSING OR \< 0.9×LLN IF PRE-RX \>= LLN OR \< 0.9×PRE-RX IF PRE-RX \< LLN OR \< LLN IF PRE-RX \> ULN

Time frame: Up to 42 days post last dose of study medication in short-term or long-term extension period

Population: All treated participants

OTHER CHEMISTRY TESTING LIPID TESTS: CHOLESTEROL, TOTAL (TC) MMOL/L H \> 1.2×ULN IF PRE-RX IS MISSING OR \> 1.2×ULN IF PRE-RX \<= ULN OR \> 1.2×PRE-RX IF PRE-RX \> ULN TRIGLYCERIDES, FASTING MMOL/L H \> 1.25×ULN IF PRE-RX IS MISSING OR \> 1.25×ULN IF PRE-RX \<= ULN OR \> 1.5×PRE-RX IF PRE-RX \> ULN PANCREATIC TESTS: AMYLASE, TOTAL U/L H \> 1.5×ULN; LIPASE, TOTAL (TURBIDIMETRIC ASSAY) U/L H \> 1.5×ULN; LIPASE, TOTAL (COLORIMETRIC ASSAY) U/L H \> 1.5×ULN; ENDOCRINE TESTS:CORTISOL, AM NMOL/L L \< 138 THYROID STIMULATING HORMONE (TSH) TSH MU/L H \> 1.5×ULN IF PRE-RX IS MISSING OR \> 1.5×ULN IF PRE-RX \<= ULN OR \> 2×PRE-RX IF PRE-RX \> ULN

Time frame: Up to 42 days post last dose of study medication in short-term or long-term extension period

Population: All treated participants

OTHER CHEMISTRY TESTING CARDIAC TESTS: CREATINE KINASE (CK) CK U/L H \> 1.5×ULN IF PRE-RX IS MISSING OR \> 1.5×ULN IF PRE-RX \<= ULN OR \> 1.5×PRE-RX IF PRE-RX \> ULN; TROPONIN-I, CARDIAC SPECIFIC UG/L H \> ULN; METABOLITE TESTS:URIC ACID URIC MMOL/L H \> 1.2×ULN IF PRE-RX IS MISSING OR \> 1.2×ULN IF PRE-RX \<= ULN OR \> 1.25×PRE-RX IF PRE-RX \> ULN; CHEM TEST, MULTI INDICATIONS : LACTATE DEHYDROGENASE (LD) LD U/L H \> 1.25×ULN IF PRE-RX IS MISSING OR \> 1.25×ULN IF PRE-RX \<= ULN OR \> 1.5×PRE-RX IF PRE-RX \> ULN

Time frame: Up to 42 days post last dose of study medication in short-term or long-term extension period

Population: All treated participants

QUALITATIVE URINE CHEMISTRY: BLOOD, URINE N/A H \>= 2 IF PRE-RX IS MISSING OR \>= 2 IF PRE-RX \< 1 OR \>= 2×PRE-RX IF PRE-RX \>= 1 GLUCOSE, URINE N/A H \>= 1 IF PRE-RX IS MISSING OR \>= 1 IF PRE-RX \< 1 OR \>= 2×PRE-RX IF PRE-RX \>= 1 PROTEIN, URINE UNKNOWN H \>= 2 IF PRE-RX IS MISSING OR \>= 2 IF PRE-RX \< 1 OR \>= 2×PRE-RX IF PRE-RX \>= 1 URINALYSIS II URINE WBC + RBC ; RBC, URINE HPF H \>= 2 IF PRE-RX IS MISSING OR \>= 2 IF PRE-RX \< 2 OR \>= 4 IF PRE-RX \>= 2 WBC, URINE HPF H \>= 2 IF PRE-RX IS MISSING OR \>= 2 IF PRE-RX \< 2 OR \>= 4 IF PRE-RX \>= 2

Time frame: Up to 42 days post last dose of study medication in short-term or long-term extension period

Population: All treated participants

Although there are no identified risks for BMS-931699, BMS has developed a list of events of special interest for the BMS-931699 program based on the known biologic class effects, the mechanism of action of BMS-931699, overall potential consequences of mmunosuppression, and preliminary data from unblinded clinical trials. Event categories of special interest for this study may include, but are not limited to: Infections, Autoimmunity, Malignancies, Injection-related reactions

Time frame: On or after the first dose date of short-term study medication and up to 42 days post last short-term dose date or up to the day prior to the first dose of long-term extension period, whichever is earlier

Population: All treated subjects

HEMATOLOGY I: ERYTHROCYTE/PLATELET ATTRIBUTES HEMOGLOBIN G/L L \< 0.85×PRE-RX; HEMATOCRIT VOL L \< 0.85×PRE-RX; PLATELET COUNT X10\*9 C/L H \> 1.5×ULN (ULN = Upper Limit of Normal) IF PRE-RX IS MISSING OR \> 1.5×ULN PLATELET COUNT X10\*9 C/L L \< 0.85×LLN (LLN = Lower Limit of Normal) IF PRE-RX IS MISSING OR \< 0.85×LLN IF PRE-RX \>= LLN OR \< 0.85×PRE-RX IF PRE-RX \< LLN; ERYTHROCYTES RBC X10\*12 C/L L \< 0.85×PRE-RX HEMATOLOGY II QUANTITATIVE WBC : LEUKOCYTES X10\*9 C/L H \> 1.2×ULN IF PRE-RX IS MISSING OR \> 1.2×ULN IF LLN \<= PRE-RX \<= ULN OR \> 1.5×PRE-RX IF PRE-RX \> ULN OR \> ULN IF PRE-RX \< LLN; LEUKOCYTES WBC X10\*9 C/L L \< 0.9×LLN IF PRE-RX IS MISSING OR \< 0.9×LLN IF LLN \<= PRE-RX \<= ULN OR \< 0.85×PRE-RX IF PRE-RX \< LLN OR \< LLN IF PRE-RX \> ULN

Time frame: Up to 42 days post last dose of study medication in short-term or long-term extension period

Population: All treated participants

WBC DIFFERENTIAL COUNT: BASOPHILS (ABSOLUTE) X10\*9 C/L H \> 0.4; BLASTS (ABSOLUTE) X10\*9 C/L H \> 0; EOSINOPHILS (ABSOLUTE) EOSA X10\*9 C/L H \> 0.75; LYMPHOCYTES (ABSOLUTE) X10\*9 C/L H \> 7.5; LYMPHOCYTES (ABSOLUTE) X10\*9 C/L L \< 0.75; MONOCYTES (ABSOLUTE) X10\*9 C/L H \> 2; NEUTROPHILS (ABSOLUTE) X10\*9 C/L L \< 1.5 IF PRE-RX IS MISSING OR \< 1.5 IF PRE-RX \>= 1.5 OR \< 0.85×PRE-RX IF PRE-RX \< 1.5; COAGULATION activated Partial thromboplastin time (APTT) SEC H \> 1.5×ULN; INTL NORMALIZED RATIO (INR) INR FRACTION H \> 1.5×ULN PROTHROMBIN TIME (PT) PT SEC H \> 1.5×ULN

Time frame: Up to 42 days post last dose of study medication in short-term or long-term extension period

Population: All treated participants

KIDNEY FUNCTION TESTS:BLOOD UREA NITROGEN MMOL/L H \> 1.1×ULN IF PRE-RX IS MISSING OR \> 1.1×ULN IF PRE-RX \<= ULN OR \> 1.2×PRE-RX IF PRE-RX \> ULN CREATININE UMOL/L H \> 1.5×ULN IF PRE-RX IS MISSING OR \> 1.5×ULN IF PRE-RX \<= ULN OR \> 1.33×PRE-RX IF PRE-RX \> ULN GLOMERULAR FILTRATION RATE, CALC. ML/S/M\*2 L \< 0.8×PRE-RX; UREA UREA MMOL/L H \> 1.1×ULN IF PRE-RX IS MISSING OR \> 1.1×ULN IF PRE-RX \<= ULN OR \> 1.2×PRE-RX IF PRE-RX \> ULN

Time frame: Up to 42 days post last dose of study medication in short-term or long-term extension period

Population: All treated participants

LIVER FUNCTION TESTS:ALKALINE PHOSPHATASE (ALP) ALP U/L H \> 1.25×ULN IF PRE-RX IS MISSING OR \> 1.25×ULN IF PRE-RX \<= ULN OR \> 1.25×PRE-RX IF PRE-RX \> ULN; ALANINE AMINOTRANSFERASE (ALT) ALT U/L H \> 1.25×ULN IF PRE-RX IS MISSING OR \> 1.25×ULN IF PRE-RX \<= ULN OR \> 1.25×PRE-RX IF PRE-RX \> ULN; ASPARTATE AMINOTRANSFERASE (AST) AST U/L H \> 1.25×ULN IF PRE-RX IS MISSING OR \> 1.25×ULN IF PRE-RX \<= ULN OR \> 1.25×PRE-RX IF PRE-RX \> ULN; BILIRUBIN, DIRECT UMOL/L H \> 1.1×ULN IF PRE-RX IS MISSING OR \> 1.1×ULN IF PRE-RX \<= ULN OR \> 1.25×PRE-RX IF PRE-RX \> ULN G-GLUTAMYL TRANSFERASE (GGT) GGT U/L H \> 1.15×ULN IF PRE-RX IS MISSING OR \> 1.15×ULN IF PRE-RX \<= ULN OR \> 1.2×PRE-RX IF PRE-RX \> ULN BILIRUBIN, TOTAL UMOL/L H \> 1.1×ULN IF PRE-RX IS MISSING OR \> 1.1×ULN IF PRE-RX \<= ULN OR \> 1.25×PRE-RX IF PRE-RX \> ULN

Time frame: Up to 42 days post last dose of study medication in short-term or long-term extension period

Population: All treated participants

QTc (corrected QT) Fridericia, PR Interval, QRS Interval and Change from baseline in QTCF

Time frame: Up to 42 days post last dose of short-term double-blind study medication or up to the day prior to the start of long-term extension period, whichever is earlier.

Population: All treated participants

SRI is the Systemic Lupus Erythematosus Responder Index. An SRI(4) Response is defined as a reduction in Day 1 SLEDAI-2K disease activity score of ≥ 4 points AND (a)no worsening in the physician's global assessment (MDGA) of disease activity (no worsening is defined as less than 10% worsening, equivalent to a 10mm increase on a 100mm visual analog scale \[VAS\]) compared to Baseline) AND (b) no new BILAG-2004 Index A organ system score AND (c)no more than one new or worsening BILAG-2004 Index B organ system scores. An SRI(5) Response is defined as a reduction in Day 1 SLEDAI-2K disease activity score of ≥ 5 points AND (a) AND (b) AND (c). An SRI(6) Response is defined as a reduction in Day 1 SLEDAI-2K disease activity score of ≥ 6 points AND (a) AND (b) AND (c) The outcomes are better in increasing order from SRI(4) to SRI(5) to SRI(6)

Time frame: At Day 169

Population: All randomized and treated participants

SRI is the Systemic Lupus Erythematosus Responder Index. An SRI(4) Response is defined as a reduction in Day 1 SLEDAI-2K disease activity score of ≥ 4 points AND (a)no worsening in the physician's global assessment (MDGA) of disease activity (no worsening is defined as less than 10% worsening, equivalent to a 10mm increase on a 100mm visual analog scale \[VAS\]) compared to Baseline) AND (b) no new BILAG-2004 Index A organ system score AND (c)no more than one new or worsening BILAG-2004 Index B organ system scores. An SRI(5) Response is defined as a reduction in Day 1 SLEDAI-2K disease activity score of ≥ 5 points AND (a) AND (b) AND (c). An SRI(6) Response is defined as a reduction in Day 1 SLEDAI-2K disease activity score of ≥ 6 points AND (a) AND (b) AND (c) The outcomes are better in increasing order from SRI(4) to SRI(5) to SRI(6)

Time frame: At Day 85

Population: All Randomized and Treated participants

Mean change from baseline, CLASI = Cutaneous Lupus Erythematosus Disease Area and Severity Index. Scores can range from 0 to 70 with higher scores denoting greater disease activity or damage.

Time frame: At Day 85 and Day 169

Population: All randomized and treated participants

BICLA is defined as: British Isle Lupus Assessment Group improvement, defined as BILAG As at Baseline improved to B/C/D, and BILAG Bs at baseline improved to C/D, and no BILAG worsening in other BILAG organ systems such that there are no new BILAG As or greater than 1 new BILAG B; and no worsening in the SLEDAI-2K total score compared to Baseline (defined as no increase in SLEDAI total score); and no worsening in the physician's global assessment (MDGA) of disease activity (no worsening is defined as less than 10% worsening, equivalent to a 10mm increase on a 100mm visual analog scale \[VAS\]) compared to Baseline; No changes in concomitant medications according to the following criteria: No increase of or addition of a new immunosuppressant agent (azathioprine,mycophenolic acid/mycophenolate mofetil, methotrexate, anti-malarial, leflunomide) over baseline levels; No increase in corticosteroid dose above baseline level outside of those allowed per protocol.

Time frame: At Day 85

Population: All Randomized and Treated Participants

Immunogenicity defined as positive for anti-drug antibodies post-baseline measurement if baseline missing or negative. If baseline is positive, then immunogenicity is defined as a positive post-baseline measurement with titer value 4 times greater than baseline. (A) all subjects with a laboratory reported positive antibody responses to BMS-931699 during the short-term double-blind treatment period are included. Overall: At least one positive sample relative to baseline during short-term double-blind and follow-up period.

Time frame: Day 169

Population: All Treated participants with at Least One Post-Treatment Immunogenicity Assessment Who Developed Laboratory Reported Positive Antibody Responses to BMS-931699

HEART RATE (HR) Beats per min (BPM): HR \> 100 AND CHANGE FROM BASELINE \> 30 OR HR \< 55 AND CHANGE FROM BASELINE \< -15

Time frame: At Day 85 and Day 169

Population: All Treated participants

RESPIRATION RATE (RESP) (PER MIN) RESP \> 16 OR RESP CHANGE FROM BASELINE \> 10

Time frame: At Day 85 and Day 169

Population: All Treated participants

SYSTOLIC BLOOD PRESSURE (SYSBP) (MMHG); SYSBP \> 140 AND CHANGE FROM BASELINE \> 20 OR SYSBP \< 90 AND CHANGE FROM BASELINE \< -20; DIASTOLIC BLOOD PRESSURE (DIABP) \> 90 AND CHANGE FROM BASELINE \> 10 OR DIABP \< 55 AND CHANGE FROM BASELINE \< -10;

Time frame: At Day 85 and Day 169

Population: All Treated participants

TEMPERATURE (TEMP) (C) TEMP \> 38.3 OR TEMP CHANGE FROM BASELINE \> 1.6

Time frame: At Day 85 and Day 169

Population: All Treated participants

Serum biomarkers C3, C4, anti-double-stranded deoxyribonucleic acid (anti-dsDNA), anti-nuclear antibody (ANA) and other autoantibodies were measured from blood serum samples collected on Day 85 and Day 169. No anti-dsDNA data was available for this report

Time frame: At Day 85 and Day 169

Population: All Treated participants with at Least One Post-Treatment Biomarker Measurement

Serum biomarkers C3, C4, anti-double-stranded deoxyribonucleic acid (anti-dsDNA), anti-nuclear antibody (ANA) and other autoantibodies were measured from blood serum samples collected on Day 85 and Day 169

Time frame: At Day 85 and Day 169

Population: All Treated participants with at Least One Post-Treatment Biomarker Measurement

Percent CD4+ Receptor Occupancy and percent CD8+ Receptor Occupancy

Time frame: At Day 85 and Day 169

Population: All Treated participants with at Least One Post-Treatment Biomarker Measurement