Evaluation of Belimumab Impact on a BLyS Activity Signature Test in the Absence of Confounding Polypharmacy

Primary Objective: This study will determine clinical response to belimumab using the SRI 4
(SLE Responder Index) which was used in the Phase III belimumab trials which led to its
approval by the FDA. The population entered will be similar to the Phase III study population
However, in this case background medications will be withdrawn at entry and brief steroid
rescue with intramuscular depomedrol will provide immediate relief to cover the delay in
belimumab effects. The co-primary objectives will be to determine time to disease flare
compared to a historical control study (Biomarkers of Lupus Disease) and to determine whether
more belimumab responders (defined by the SLE Responder Index) have a 50% decrease in the
predefined BLAST signal (BlyS Activity Signal Test) than non-responders. This pilot study is
not powered to draw firm conclusions about response rates in the absence of ongoing standard
of care medications, but should 7-12 patients (of 20 completing the 6 month endpoint) meet
the SRI response criteria, the feasibility of a larger, placebo controlled trial would be
justified. The following instruments will be used to measure clinical lupus activity during
the study: BICLA, SRI 5, changes in joint counts, global SLEDAI, BILAG, CLASI, PGA, and SF-36
and LFA-REAL measures.

The following are the definitions of these clinical outcome measures: SRI stands for SLE
Responder Index which is a composite score comprised of a 4 (or alternatively 5) point
decrease in the SLEDAI (SLE Disease Activity Index) coupled to no increase in the BILAG
(British Isles Lupus Assessment Group) Index and no more than 10% increase in the Physician's
Global Assessment. The global SLEDAI or BILAG is simply a comparison of the total SLEDAI or
numerical composite BILAG score at baseline and after receiving belimumab. The CLASI refers
to the Cutaneous Lupus Erythematosus Disease Area and Severity Index. the LFA REAL stands for
the Lupus Foundation of America Rapid Evaluation of Activity in Lupus. The latter is a pilot
instrument which will be tested in this study.

We will also integrate exploratory biologic discovery into the clinical trial to support both
pre-specified and exploratory biomarker discovery. Data will be generated that might be used
to help select more appropriate patient subsets for future trials and to guide optimal dosing
strategies. Optimizing patient selection and dosing are important goals for further
increasing demonstrable effect size in trials by increasing the response rates in the
treatment groups. Thus, despite being a small pilot study, an ambitious goal is included to
provide potential preliminary data conducive to optimize the use of belimumab. In general
these analyses will also be descriptive, however our experience in the BOLD study suggests
that comparing a group of 6-12 patients (presumed clinical response rate) who are enriched in
expression of a particular biomarker vs a different group of 14-8 patients (defined in this
case on basis of non-response to belimumab, or in the BOLD study by assignment to IFN high vs
low subgroups) may, by virtue of representing different immunologic subsets of disease,
produce statistically significant results in mean/median values of a number of biomarkers.
More importantly, comparing "before and after" levels of BLyS and other cytokines may be
quite sensitive to belimumab when it has clinical impact as well.

Obtaining this kind of preliminary data to better understand optimal patient selection could
be a valuable approach to further increasing effect size in a future clinical trial. In fact,
the two Parts of this project (single agent assessment and biomarker assessment) are
co-dependent, since each increases the likelihood of interpretable data in patients with
moderate severity. Indeed Part 2 would be less feasible without the strategy of Part 1 to
decrease the conflicting immune signals of background medications, which have clouded
interpretation of many treatments for SLE in the past.

Again, this will be an open label, six month study of belimumab treatment given to patients
who qualify to receive this treatment under the United States labeling. Additionally, at
entry to this study, patients must have a SLEDAI score of at least 6 which is identical to
the disease activity minimum required for belimumab Phase III studies. Entry criteria will
require results of a full clinical evaluation, CBC with differential, comprehensive metabolic
profile (including liver function tests) and urinalysis (with reflex protein/creatinine
ratio) prior to dosing.

The first dose will be given within 4 weeks of the screening visit and may take place as soon
as the entry laboratories are returned. However, those patients who are stopping a major
immune suppressant and/or those who require a steroid injection at entry will be encouraged
to wait a minimum of 3 weeks before the initial belimumab dose. Blood samples for biomarkers
(see below) will be drawn at the screening visit and just prior to the first dose to maximize
disease assessment prior to steroid rescue as well as after withdrawal of background
treatments. These will provide baseline data on the BLAST expression profile for each
patient, which will be derived and standardized through the study of active SLE B Cells and
in vitro B Cell gene expression responses to BLyS signaling. The highest BLAST signal
recorded at either screening (prior to steroids) or baseline (after immune suppression
withdrawal) will be employed as the baseline BLAST signal.

Subjects will be evaluated monthly by an investigator/subinvestigator who are trained for
SLEDAI, BILAG 2004, and CLASI. Additional assays will be patient reported outcomes including
the Short Form 36 (SF36) and the LFA REAL physician and patient endpoints. The co-primary
clinical endpoint will be time to flare after the last steroid injection compared to the
results of the BOLD study. The co-primary mechanistic endpoint will be measured at 3 months.
This will be a comparison of rates of BLAST 50 response (50% decrease in fold change
expression of BLAST panel genes as compared to healthy controls) in those who do or do not
meet the clinical endpoint of SRI 4 without use of off-protocol medications. The SRI 4
endpoint will be met by meeting both the SRI criteria and no initiation of off- protocol
immune suppressants or steroids. Although the stipulation of no off-protocol medications was
not integrated into the initial definition of SRI it was required to meet the endpoint of the
Phase III belimumab trials, since those who received off protocol treatments were removed
from those studies and counted as non-responders. This brings our primary clinical endpoint
in line with the intent of the primary endpoint in the Phase III belimumab studies. However
our patients will not necessarily be removed from study for use of off protocol medications.
After being designated a permanent non-responder in the primary endpoint such a patient might
be further followed for exploratory analysis of improvement on additive medications.

This study will enroll patients until 20 have completed the protocol through the six month
point. All patients will receive belimumab 10 mg/kg at baseline, 2 weeks later, 2 weeks after
that and then q month. At each monthly visit history, physical, and blood tests (appropriate
and as scheduled) to complete the outcome measures will be performed, and adverse event
reporting and medication updates will be performed. Subjects may continue to take
nonsteroidal anti-inflammatory medications (including prn NSAIDS) and up to 20 mg prednisone
(or oral steroid equivalent) daily at screening and during the study although steroids will
be tapered as tolerated. If the patient is taking hydroxychloroquine or an immune suppressant
(e.g. mycophenolate mofetil, azathioprine, leflunomide, methotrexate, or a calcineurin
inhibitor) at screening, these standard of care treatments must be stopped prior to the
baseline visit, preferably a minimum of two weeks before baseline. Patients can elect to
receive one or more depomedrol injection(s) up to a total of 320 mg total in individualized
increments beginning at the time of the screening visit (if necessary) and/or up to and
including the Month 2 visit. Daily oral steroids will be tapered as tolerated if and when the
patient begins to improve.

Inclusion Criteria:

1. Patients who meet 1987 ACR criteria for SLE with 1996 modifications

2. SLEDAI >/= 6 at screening visit

3. Positive ANA OR anti-dsDNA within one year of screening

4. In the opinion of the investigator there is intent to treat with a biologic (e.g.
patient failed standard of care treatment) however there is no organ threatening
disease

Exclusion Criteria:

1. Hg less than 8.0 or hemolytic anemia

2. Lymphocyte count less than 0.4

3. AST/ALT greater than 2.5 times ULN

4. Infection requiring IV antibiotics within a month of screening or oral antibiotics
within two weeks of first dose

5. Active chronic infections (such as tuberculosis) which have not been treated or tb
exposure in a person under 40 who has not received suppressive therapy for at least 3
months. Herpes zoster outbreak within three months of dosing. (Suppressive therapy for
herpes simplex is not an exclusion criterion).

6. Cancer within 5 years (except for completely excised cervical carcinoma in situ or
excised non-melanoma skin cancer)

7. Inability or unwillingness to follow the protocol

8. If WOCBP, inability or unwillingness to practice an acceptable method of contraception
(including abstinence, barrier method with spermicide, or hormonal treatment

9. Inability or unwillingness to withdraw from hydroxychloroquine and/or any immune
suppressive therapy being taken despite option for immediate steroid treatment and
later treatment rescues as needed.

10. Any illness or condition that, in the opinion of the investigator, would cause undue
hardship or risk to the subject by participating in the protocol