P022 Pharmacodynamic effects of obinutuzumab on B cells and serological markers in patients with active lupus nephritis: results from the REGENCY trial

Abstract

Background/Aims Lupus nephritis (LN) is marked by kidney inflammation and damage. Obinutuzumab, a type II CD20 antibody, demonstrated effective B-cell depletion, reduced serum anti-double-stranded DNA (anti-dsDNA) antibodies and increased complement C3 and C4 levels in the NOBILITY (NCT02550652) trial. The Phase III REGENCY trial (NCT04221477) of obinutuzumab plus standard therapy in patients with LN demonstrated significant improvement in complete renal response. Exploratory analyses of B-cell populations and serological markers were performed for the REGENCY trial. Methods Adults with active LN received placebo or obinutuzumab plus standard therapy. Peripheral B cells and B-cell subsets were assessed using validated high-sensitivity flow cytometry assays. Complement and anti-dsDNA antibody levels were measured by nephelometry and ELISA. Peripheral B-cell and serum biomarker assessments were performed at weeks 0, 4, 12, 24, 50 and 76. Results Baseline biomarker levels were comparable between arms. At week 4, mean total CD19+ B-cell levels were reduced with obinutuzumab (mean cells/μL [SD]: 4.7 [45.6], −99.8 median percentage change from baseline) vs placebo (mean cells/μL [SD]: 317.8 [338.5], −4.2 median percentage change) and remained low up to week 76. Similar decreases in B-cell subsets were observed with obinutuzumab vs placebo from week 4-76. Obinutuzumab treatment also showed greater reductions in anti-dsDNA antibody levels and increases in complement C3 and C4 vs placebo. In patients with abnormal baseline serologies, higher normalisation rates for C3 (43% vs 14%), C4 (70% vs 39%) and anti-dsDNA antibody levels (45% vs 11%) were observed at week 12 vs placebo, which were sustained or further improved through week 76, with normalisation rates of 62% vs 29% for C3, 88% vs 55% for C4 and 56% vs 16% for anti-dsDNA antibody levels at week 76 (Table 1). Conclusion Obinutuzumab induced rapid and sustained depletion of total peripheral CD19+ B cells and B-cell subsets in patients with LN. Obinutuzumab demonstrated increases in serum C3 and C4 levels and reduced anti-dsDNA antibody levels over placebo in all patients. Among patients with abnormal baseline values, obinutuzumab led to earlier and greater normalisation rates vs placebo. These data suggest that deep B-cell depletion with obinutuzumab contributes to the observed improved clinical responses. Disclosure R.A. Furie: Other; R.A.F. has received research support and consulting fees from Chugai Pharmaceutical Co., Ltd., F. Hoffmann-La Roche Ltd, Genentech, Inc. and GlaxoSmithKline. I. Parodis: Other; I.P. has received research support and/or reports consulting services from Amgen, AstraZeneca, Aurinia, BMS, Eli Lilly, F. Hoffmann-La Roche Ltd, Gilead, GSK, Janssen, Novartis, Otsuka and UCB. R. Jones: Other; R.J. has received research support and reports consulting services from F. Hoffmann-La Roche Ltd, GSK and CSL Vifor. L. Lightstone: Other; L.L. reports consulting fees and/or services for Alexion, Argenx, AstraZeneca, Boehringer Ingelheim, Carna Health, F. Hoffmann-La Roche Ltd, GSK, Kezar, Nkarta, Novartis, Otsuka and Pfizer. O. Hwang: Other; O.H. is an employee of Genentech, Inc. and shareholder of F. Hoffmann-La Roche Ltd. A. Au-Yeung: Other; A.AY. is an employee of Genentech, Inc. and shareholder of F. Hoffmann-La Roche Ltd. I. Hassan: Other; I.H. is an employee of F. Hoffmann-La Roche Ltd. H. Mao: Other; H.A.M. is an employee and shareholder of F. Hoffmann-La Roche Ltd. W.F. Pendergraft: Other; W.F.P. is an employee of Genentech, Inc. and shareholder of F. Hoffmann-La Roche Ltd. J.P. Garg: Other; J.P.G. is an employee of Genentech, Inc. and shareholder of F. Hoffmann-La Roche Ltd. H. Raghu: Other; H.R. is an employee of Genentech, Inc. and shareholder of F. Hoffmann-La Roche Ltd. B.H. Rovin: Other; B.H.R. reports consulting services from F. Hoffmann-La Roche Ltd/Genentech, Inc.