LAUSR

Background: The Phase 2/3 APRIL-SLE study evaluated the safety and efficacy of atacicept, a dual inhibitor of the B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL), in systemic lupus erythematosus (SLE). Objectives: The goal of this post-hoc analysis was to use cell-based gene signatures on gene expression data from the APRIL-SLE study to identify clusters of patients with potential to flare and to assess clusters for differences in treatment effects of atacicept vs placebo. Methods: A published immune cell deconvolution algorithm (Abbas et al, 2009) was applied to whole-blood gene expression data from APRIL-SLE patients to identify relative proportions of 17 immune cell types. Patients were then grouped into clusters based on these immune cell profiles using a k-medoid clustering algorithm and were compared to each other based on patient characteristics, biomarkers and clinical efficacy. In addition, baseline expression and change in expression of putative APRIL-responder genes were compared among clusters. APRIL-responder genes were identified by combining differential expression results from the APRIL-SLE study (Week 52 vs Day 1 randomization) and tabalumab (targets BLyS only) Phase 3 studies (Week 52 vs baseline; GSE88887). Results: Patient gene expression data (N=105; placebo, n=30; atacicept 75 mg, n=40; atacicept 150 mg, n=35) were used to group patients into five main clusters (P1-P5) by predominant characteristic cells: P1, T helper cells; P2, plasma cells; P3, neutrophils and B cells; P4, B cells; P5, activated dendritic cells. Patients in P2 and P5 were more likely to have positive anti-dsDNA antibodies (≥30 IU/ml), elevated BLyS; ≥1.6 ng/ml, and high interferon gene signature in the blood than other those in other clusters. Patients in P2 were most likely to have low complement C3 and C4 levels. Placebo-group flare rates in P2 (100%), P4 (100%) and P5 (83%) were markedly higher than in P1 (33%) and P3 (29%). In P2, P4, and P5 the median time-to-flare was much lower with placebo (85, 98.5, and 115.5 days, respectively) than with atacicept 150 mg (over 364 days for all three clusters). A comparison of differentially-expressed genes from clinical studies of SLE patients treated with atacicept and tabalumab revealed possible APRIL-responder genes: SDC1, PARM1 and MZB1. These genes had a higher baseline expression in P2 and P4 compared with other clusters. SDC1 was reduced from baseline more in P2, P4, and P5 after atacicept treatment, while PARM1 and MZB1 decreased after atacicept treatment in P2 and P4. Conclusion: These post-hoc analyses revealed different subsets of SLE patients based on their molecular profiles. Atacicept may have different treatment effects in the identified patient subsets vs placebo, providing insights into potential mechanisms of flare in SLE. References: [1] Abbas AR, Wolslegel K, Seshasayee D, Modrusan Z, Clark HF. Deconvolution of blood microarray data identifies cellular activation patterns in systemic lupus erythematosus. PLoS ONE. 2009;4(7):e6098. Disclosure of Interests: Eileen Samy Employee of: Current employees of EMD Serono, Matthew Studham Employee of: Current employees of EMD Serono, Amy Kao Employee of: Current employees of EMD Serono, Philipp Haselmayer Employee of: Current employee of Merck KGaA, Peter Chang Employee of: Current employees of EMD Serono, P. Alexander Rolfe Employee of: Current employees of EMD Serono, David Wofsy Consultant for: GlaxoSmithKline – Member, data safety monitoring board Novartis – Member, data safety monitoring board Celgene – member, scientific advisory board, Julie DeMartino Shareholder of: Shares in Merck & Co, Employee of: Current employees of EMD Serono; Past employee of Merck & Co. & Roche, Robert Townsend Employee of: Current employees of EMD Serono