Background/Purpose: To evaluate the effects of subcutaneously-administered blisibimod (A-623, AMG 623), an inhibitor of B-cell activating factor (BAFF), on IgG, IgM and infection risk in patients with systemic lupus erythematosus (SLE) during the phase 2b clinical trial PEARL-SC (NCT01162681) and the ensuing open-label extension (OLE) study (NCT01305746).

Methods: 547 SLE patients with anti-double-stranded DNA or anti-nuclear antibodies and SELENA-SLEDAI score ≥6 at baseline were enrolled into the PEARL-SC study, and randomized 1:1 to receive placebo or blisibimod administered at 1 of 3 dose levels, 100 mg weekly (QW), 200 mg QW, or 200 mg every 4 weeks. In the PEARL-SC study, subjects received blinded study drug for up to 52 weeks (with a median of 37 weeks) or until the last subject completed 6 months of study drug therapy.  A total of 382 subjects enrolled in the OLE study and received blisibimod. The efficacy, safety and tolerability of blisibimod in the combined studies were evaluated through March 2013 using clinical evaluations, adverse event reporting and laboratory data. 

Results: Consistent with the effects of blisibimod on inflammation biomarkers reported previously (total B cell counts, C3, C4), significant decreases in immunoglobulins IgG and IgM were evident in patients in the pooled blisibimod group compared with placebo from Week 8 through Week 52 (percent changes with blisibimod vs placebo in IgG= -14.1% vs -3.9%, and IgM= -34.6% vs -9.3%, p≤0.003, N=94 at Week 52). Similarly, significant decreases in anti-dsDNA antibody titers were observed with blisibimod from Week 4 through Week 52 (-23.5% vs 7.9%, p=0.008, N=90 at Week 52).  The effects of blisibimod 200mg QW were similar to those observed in the pooled blisibimod group. In addition, after the end of the placebo-controlled study, IgG, IgM, and anti-dsDNA levels continued to be lower compared with pre-treatment levels through Week 80 (changes in IgG= -10.7%, IgM= -34.6%, N=31; change in anti dsDNA= -26.6%, N=20). 

There was no difference between treatments in the numbers of subjects reporting infections: placebo 62.0% and blisibimod 58.2%.  Furthermore, the mean concentrations of IgG in patients who reported infections were similar between the pooled placebo group (14.6-16.2 g/L) and the pooled blisibimod group (12.9-16.6 g/L).

Blisibimod was safe and well-tolerated at all dose levels with no meaningful imbalances in serious adverse events or infections between blisibimod and placebo.  Amongst the commonly-reported AEs, imbalance was observed only with injection site reactions (200mg QW blisibimod=15%, matched placebo=7%), but these were not serious or severe and did not result in discontinuation of treatment.  During the placebo-controlled study, critically low IgG levels (<4g/L) were observed in 1/280 subjects in blisibimod group compared with 0/266 subjects on placebo. 

Conclusion: In patients with SLE, blisibimod induces pharmacological effects on immunoglobulins that are consistent with a BAFF-mediated inhibition of B cells and plasma cells, without adversely impacting the risk of infection. These data support further evaluation of blisibimod in patients with SLE and other B cell-mediated diseases. 

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/effects-of-blisibimod-an-inhibitor-of-b-cell-activating-factor-on-serum-immunoglobulins-and-infection-risk-in-patients-with-systemic-lupus-erythematosus-observations-from-the-placebo-controlled-pea/