Pharmacodynamic-induced changes in SLE Patients from the ILLUMINATE-2 phase III trial of B cell activating factor blockade with tabalumab

ABSTRACT: Objective: Systemic lupus erythematosus (SLE) has substantial unmet medical need and its pathogenesis is incompletely understood. This study characterized baseline gene expression and pharmacodynamic (PD)-induced changes in whole blood gene expression from two phase III, 52-week (W), randomized, placebo-controlled, double-blind studies of 1,760 SLE patients treated with the B cell activating factor (BAFF)-blocking IgG4 monoclonal antibody, tabalumab. Methods: Patient samples were obtained from ILLUMINATE-1 and -2 while control samples were from healthy donors. Blood was collected in TempusTM tubes at baseline, W16 and W52. RNA was analyzed using the Affymetrix Human Transcriptome Array 2.0 and NanoStringTM. Results: At baseline there was elevation of interferon responsive genes (IRG) in patients compared to controls, with 75% positive for this IRG signature. There was, however, substantial heterogeneity of IRG expression and complex relationships among gene networks. The interferon signature was a predictor of future time to flare, independent of anti-double stranded DNA antibody (dsDNA), C3 and C4 levels, and overall disease activity. PD changes in gene expression following tabalumab treatment were extensive, occurring predominantly in B cell-related and immunoglobulin (Ig) genes, and were consistent with other PD-induced changes including dsDNA, C3, and Ig levels. Conclusions: SLE patients demonstrated elevated expression of an IRG signature, detected in 75% of the patients at baseline in ILLUMINATE-1 and -2. There was substantial heterogeneity of gene expression detected among individual patients and in gene networks. The interferon signature was an independent risk factor for future flares. PD changes in gene expression were consistent with the mechanism of BAFF blockade by tabalumab.

ORGANISM(S): Homo sapiens

PROVIDER: GSE88886 | GEO | 2016/10/25

SECONDARY ACCESSION(S): PRJNA350549

REPOSITORIES: GEO