Trial of Belimumab in Early Lupus

This protocol proposes that early treatment of Systemic Lupus Erythematous (SLE) may prevent
tissue damage and may even lead to long-term remission of disease. This concept is supported
by reports of SLE-associated autoimmunity that are detected serologically many years prior to
any constitutional symptoms or specific tissue inflammation and immune dysregulation precedes
the development of clinically apparent SLE. Belimumab (Benlysta) is an FDA approved
medication and is a monoclonal antibody directed against B cell-activating factor (BAFF)/ B
Lymphocyte Stimulator (BLyS). B cells maturing in environments with high BAFF levels are more
likely to be autoreactive B cells. This is a double-blind placebo controlled trial of
belimumab, in patients with early lupus, ie lupus diagnosed within 2 years. Thirty subjects
will be randomized (2:1) to receive subcutaneous belimumab weekly or placebo. After a year of
treatment, subjects receiving belimumab will be rerandomized (1:1) to receive belimumab or
placebo. The primary outcome is B cell autoreactivity. Clinical efficacy including disease
activity, flares, attainment of low disease activity or remission as well as surrogate
cardiovascular biomarkers will also be assessed.

Inclusion Criteria:

- Diagnosis of SLE per current ACR classification criteria

- Date of SLE diagnosis within 2 years of screening

- ANA positive (with a titer ≥ 80)

- anti-ds DNA antibody positive

- Mild to moderate disease activity define by a SLEDAI-2K ≥4

- Stable corticosteroid dose in the 4 weeks prior to screening ≤ 30mg/day.

- Concomitant treatment with hydroxychloroquine unless documented inability to tolerate

- Able and willing to give written informed consent and comply with the requirements of
the study protocol

- Negative serum pregnancy test (for women of child bearing potential)

- Men and women of reproductive potential must agree to use an acceptable method of
birth control during treatment and for 16 weeks after completion of treatment

Exclusion Criteria:

- Previous exposure to disease modifying drugs such as azathioprine, mycophenolate
mofetil, cyclophosphamide, methotrexate, or cyclosporine.

- Previous exposure to biologic therapies including rituximab, belimumab or other agents
that have been investigated for SLE.

- Active renal or nervous system disease or disease activity fulfilling BILAG A criteria

- Use of high dose steroids (>0.5 mg/kg/ day) within the 4 weeks prior to screening

- Expectation (by the investigator) that the subject will require treatment with a
disease modifying drug within the first 52 weeks of the study

- Hemoglobin: < 8.0 gm/dL

- Platelets: < 50,000/mm

- ANC < 1.0 x 103/mm

- AST or ALT >2.5 x Upper Limit of Normal unless related to primary disease.

- Creatinine clearance ≤ 25ml/min per 1.73 m2

- Positive Hepatitis B or C serology (Hep B Surface antigen, Hep B core Ab or Hepatitis
C antibody)

- History of positive HIV (HIV conducted during screening if applicable)

- Treatment with any investigational agent within 4 weeks of screening or 5 half-lives
of the investigational drug (whichever is longer)

- Receipt of a live vaccine within 30 days prior to baseline or concurrently with
belimumab

- Have a history of an anaphylactic reaction to parenteral administration of contrast
agents, human or murine proteins or monoclonal antibodies

- 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 0.

- Use of parenteral (IV or IM) antibiotics (antibacterials, antivirals, anti-fungals, or
anti parasitic agents) within 60 days of Day 0

- History of serious recurrent or chronic infection

- Lack of peripheral venous access

- History of drug, alcohol, or chemical abuse within 365 days prior to Day 0

- Pregnancy (a negative serum pregnancy test must be obtained for all women of
childbearing potential at screening; a urine pregnancy test must be negative < 7 days
prior to first dose and monthly)

- Lactation

- History of psychiatric disorder that would interfere with normal participation in this
protocol

- Significant cardiac or pulmonary disease (including obstructive pulmonary disease)

- Any other disease, metabolic dysfunction, physical examination finding, or clinical
laboratory finding giving reasonable suspicion of a disease or condition that
contraindicates the use of an investigational drug or that may affect the
interpretation of the results or render the patient at high risk from treatment
complications

- History of malignant neoplasm within the last 5 years with the exception of adequately
treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the
cervix

- Evidence of serious suicide risk including any history of suicidal behaviour in the
last 6 months and/or any suicidal ideation in the last 2 months or who in the
investigator's judgment, pose a significant suicide risk

- History of a primary immunodeficiency

- Have a significant IgG deficiency (IgG level < 400 mg/dL)

- Have an IgA deficiency (IgA level < 10 mg/dL)

- Have any other clinically significant abnormal laboratory value in the opinion of the
investigator

- Comorbidities requiring corticosteroid therapy, including those which have required
two or more courses of systemic courses of systemic corticosteroids within the
previous 12 months

- Inability to comply with study and follow-up procedures