Background:
Ianalumab (VAY736) is an afucosylated monoclonal antibody targeting the B cell activating factor receptor (BAFFR). It depletes B cells by enhanced cellular elimination via antibody dependent cellular cytotoxicity and blockade of the BAFF:BAFFR pathway and maintains B cell suppression by blocking BAFF-R-mediated survival and differentiation. Objectives:
Here we assessed changes in B-cell subsets, whole blood transcriptome and antibodies against extractable nuclear antigens (ENA) in patients with systemic lupus erythematosus (SLE) pre- and post-treatment with ianalumab to characterize pharmacodynamic (PD) biomarkers and biological pathways linked to mechanism of action and clinical response. Methods:
A phase 2 clinical trial (NCT03656562) evaluated the PD and preliminary clinical efficacy of ianalumab in patients with moderate to severe SLE; a multicenter randomized, parallel group, double blind, placebo-controlled trial with patients on monthly s.c. injection of ianalumab 300 mg or placebo. Blood samples were collected from placebo and ianalumab treated patients at baseline through to week 28 (double-blind treatment) and up to week 52 (open label treatment) and week 68 (safety follow up) post treatment. Targeted cellular analysis was performed by flow cytometry, whole blood transcriptome analysis was performed using an Illumina Stranded kit, and (ENA) autoantibodies were analyzed using an established assay (FIDIS™ system Connective assay panel, Theradiag©). Treatment and placebo groups were compared over time using multivariate linear regression models to identify cellular markers, autoantibodies and transcripts that were differentially modulated by ianalumab. Results:
Analysis of circulating immune cell subsets demonstrated a statistically significant reduction of CD19+ B cell counts by ianalumab by week 28, with absence of measurable B cell subsets such as transitional, naïve and memory B cells as well as plasmablasts/plasma cells (Figure 1). Transcriptome analysis of whole blood samples corroborated the cellular analysis findings demonstrating profound reduction in B cell related genes at week 28, correlating with decreases in B cell subsets as measured by flow cytometry. Reductions in autoantibody titers e.g. anti-dsDNA, anti-C1q, anti-ENAs were also observed from week 12 through to week 68 with ianalumab treatment compared with placebo. U1RNP kinetics are provided as an example of consistent reductions observed across the different autoantibodies represented in the Theradiag panel for ianalumab-treated patients (Figure 2). Finally, ianalumab treated patients achieving a composite of SRI-4 response and corticosteroid responder status at week 28 demonstrated a within normal range decrease in neutrophil cell counts and a decrease in the interferon gene signature (IFNGS) over time compared to non-responders. Conclusion:
Ianalumab treatment of patients with SLE led to a profound B cell depletion, as confirmed by flow cytometry and transcriptomic assessments and a concomitant reduction in autoantibodies. Initial evidence suggests that reductions in B cell numbers and autoantibodies levels seen in patients treated with ianalumab were accompanied by a within normal range decrease in neutrophil cell counts and a decrease in the IFNGS specifically in composite SRI-4 responders at w28. Further biomarker analyses are ongoing to characterize the effects of ianalumab on these patients. REFERENCES:
NIL. Acknowledgements:
NIL. Disclosure of Interests:
Thomas Dörner AbbVie, Celgene, Eli Lilly, EMD MerckSerono, GSK, Janssen, Novartis, and Roche (Grants and consultancy fees); UCB, Sanofi, Deutsche Forschungsgemeinschaft, and EU Horizon2020 HarmonicSS (Grants); Gilead/Galapagos (Consultancy fees), Aida Santos da Costa Holds Novartis shares, Novartis employee, Alexandre Avrameas Holds Novartis shares, Novartis employee, Ulrike Sommer Holds Novartis shares, Novartis employee, Rainer Hillenbrand Holds Novartis shares, Novartis employee, Valeria De Luca Holds Novartis shares, Novartis employee, Enrico Ferrero Holds Novartis shares, Novartis employee, Andre da Costa Holds Novartis shares, Novartis employee, Carole Sips Holds Novartis shares, Novartis employee, Claire Bonal Holds Novartis shares, Novartis employee, Marianna Rowlands Holds Novartis shares, Novartis employee, Isabelle Isnardi Holds Novartis shares, Novartis employee, Stephen Oliver Holds Novartis shares, Novartis employee.
