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Abstract Number: 1603

Sustained Reductions In Circulating B Cell Populations and Immunoglobulin G Levels With Long-Term Belimumab Treatment In Patients With Systemic Lupus Erythematosus

Herbert Struemper1, William Freimuth2, Christi Kleoudis3, Thi-Sau Migone4, David Roth3 and William Stohl5, 1GlaxoSmithKline, Research Triangle Park, NC, 2Human Genome Sciences, Inc., Rockville, MD, 3GlaxoSmithKline, King of Prussia, PA, 4Igenica, Burlingame, CA, 5Division of Rheumatology, University of Southern California Keck School of Medicine, Los Angeles, CA

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: B cells, SLE and belimumab

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Session Information

Session Title: Systemic Lupus Erythematosus - Clinical Aspects II: Central Nervous System Manifestations, Therapeutics

Session Type: Abstract Submissions (ACR)

Background/Purpose: Belimumab treatment in autoantibody-positive systemic lupus erythematosus (SLE) patients for up to 76 weeks results in sustained reduction in several circulating B cell subsets, including naïve and activated B cells, as well as in serum immunoglobulin (Ig) levels. The purpose of the present analysis was to examine long-term changes in B cell subsets and IgG beyond 76 weeks through 172 weeks of continued belimumab treatment.

Methods: B cell, B cell subset and IgG data were collected in the Phase 3 Study BLISS-76 (NCT00410384; N=819) and in its US extension study (NCT00724867; N=268). All B cell subsets were measured at baseline, Weeks 8, 24, 52, 76, 100, 124, 148 and 172. Subjects randomized to 1 mg/kg or 10 mg/kg cohorts in BLISS-76 received bi-weekly doses of belimumab for the first month followed by dosing every 4 weeks thereafter. Placebo subjects, who chose to enter the extension study, received 10 mg/kg belimumab every 4 weeks starting at Week 76.  Subjects in all cohorts received standard of care SLE agents (eg. corticosteroids, immunosuppressants, and/or antimalarials).

Results:

Most B cell subsets in peripheral blood showed a rapid initial decline over the first 24 weeks followed by a comparatively slower decline or sustained suppression. Memory B cells were an exception and roughly doubled by Week 8, followed by a slow and sustained decline through Week 172.  Beyond 76 weeks of treatment, B cell reductions either stabilized (naïve and plasma B cells), or continued to gradually decrease (CD19+ /CD20+ B cells, memory cells, plasmacytoid B cells) leading to net reductions of about 80–90% for naïve, activated, and plasmacytoid B cells, 70–75% for CD19+/CD20+ B cells and 50–60% for plasma cells after 172 weeks of continued belimumab dosing.  Over 172 weeks, a 20–30% reduction in IgG levels was observed. Only 1 completer (10 mg/kg) experienced a shift from no to Grade 3 hypogammaglobulinemia (HGG; <400 mg/dL). Of all belimumab treated subjects, 3 subjects (0.5%) experienced a Grade 3/4 HGG shift. Development of Grade 3/4 HGG was not associated with severe infections.

Results for 1 and 10 mg/kg groups in the timing and magnitude of the response were similar for most measures.  Results for placebo patients, who received 10 mg/kg at Week 76, confirmed the response patterns observed for patients who received belimumab at Week 0.

Response in Week 172 completers:

Response parameter

Median % change from baseline (N)

Placebo → 10 mg/kg

1 mg/kg

10 mg/kg

CD20+ B cells

-69.3 (57)

-74.3 (63)

-72.2 (46)

CD19+ B cells

-69.2 (65)

-70.6 (68)

-72.2 (51)

CD20+/CD27+ memory B cells

-16.7 (57)

-35.6 (63)

-37.7 (46)

CD20+/CD27– naïve B Cells

-79.4 (57)

-79.7 (63)

-81.6 (46)

CD20+/CD69+ activated B cells

-90.8 (68)

-89.9 (80)

-85.5 (54)

CD20+/CD138+ plasmacytoid B cells

-88.6 (61)

-89.8 (70)

-87.9 (50)

CD20–/CD138+ plasma B cells

-64.1 (61)

-47.2 (70)

-57.9 (51)

IgG

-19.6 (65)

-23.4 (69)

-26.2 (53)

Conclusion:

Treatment of SLE patients with belimumab for 172 weeks results in substantial, but subtotal, declines in circulating B cell subsets. These declines are associated with a modest decline in IgG levels and do not appear to be associated with development of severe infections.


Disclosure:

H. Struemper,

GlaxoSmithKline,

1,

GlaxoSmithKline,

3;

W. Freimuth,

Human Genome Sciences, Inc.,

1,

Human Genome Sciences, Inc.,

3;

C. Kleoudis,

GlaxoSmithKline,

1,

GlaxoSmithKline,

3;

T. S. Migone,

Igenica,

1,

Igenica,

3;

D. Roth,

GlaxoSmithKline,

1,

GlaxoSmithKline,

3;

W. Stohl,

Pfizer Inc,

2,

GlaxoSmithKline,

2,

Xencor,

2,

Eli Lilly and Company,

5,

Novartis Pharmaceutical Corporation,

5.

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