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entered will be similar to the Phase III study population However, in this case background medications will be withdrawn at entry and brief steroid rescue with intramuscular depomedrol will provide immediate relief to cover the delay in belimumab effects.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.