Abstract Background/Aims The REGENCY trial (NCT04221477) demonstrated superiority of obinutuzumab (OBI) plus standard therapy (+ST) vs placebo (PBO) +ST in achieving complete renal response (CRR) at week 76 (W76) in adults with active lupus nephritis (LN). These exploratory analyses aimed to evaluate histological remission and kidney tissue-level B-cell depletion at W76 in patients treated with OBI+ST vs PBO+ST. Methods Paired baseline and W76 kidney biopsies from REGENCY participants with biopsy-proven proliferative LN were analysed. Histological analysis: 64 biopsies (32 OBI+ST, 32 PBO+ST) were evaluated using the 2018 ISN/RPS LN classification, along with the NIH activity (AI) and chronicity indices. The proportion of patients achieving histological or near-histological remission (AI = 0 or ≤ 1) was determined. B-cell analysis: 29 participants (14 OBI+ST, 15 PBO+ST) were assessed. CD79a+/CD138− B cells were quantified by immunofluorescence microscopy and digital whole-slide analysis. Changes in B-cell counts at W76 were compared using an ANCOVA model, adjusting for baseline B-cell counts and stratification factors. Results Baseline characteristics were balanced, despite higher tissue B-cell levels in the OBI+ST group (Table 1). At W76, significantly more patients achieved AI = 0 or ≤ 1 with OBI+ST vs PBO+ST. Among patients not achieving CRR, 52.6% (10/19) in the OBI+ST group had an AI = 0 at W76, vs 8.3% (2/24) in the PBO+ST group. Most patients in the OBI+ST group had substantial drops in kidney tissue B-cell counts by W76. The adjusted mean change in B-cell counts from baseline to W76 was −28.5 (95% CI, −33.3 to − 23.6) for OBI+ST vs − 11.9 (95% CI, −16.6 to − 7.2) for PBO+ST, a significant difference of − 16.6 (95% CI, −23.4 to − 9.7; P0.0001). Conclusion In the largest longitudinal kidney biopsy cohort ever reported for a registrational LN clinical trial, significantly more patients achieved complete or near-complete histological remission with OBI+ST vs PBO+ST. This is the first demonstration of deep kidney tissue B-cell depletion by any anti-CD20 agent, in any glomerular disease. Obinutuzumab’s potent B-cell clearance from kidney tissue may drive kidney function improvement and LN flare reduction. These findings support assessment of histological outcomes in future LN trials and highlight a potential mechanism for obinutuzumab in preserving long-term kidney health. Disclosure B.H. Rovin: Other; B.H.R. has received consulting fees from F. Hoffmann-La Roche Ltd/Genentech Inc. E. Martins: Other; E.M. is an employee and shareholder of F. Hoffmann-La Roche Ltd. C.D. Austin: Other; C.D.A. 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. C. Chan: Other; C.C. is an employee of Genentech, Inc. and shareholder of F. Hoffmann-La Roche Ltd. P.S. Chang: Other; P.S.C. 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. V. Alberton: Other; V.A. has received consulting fees and/or reports professional services for F. Hoffmann-La Roche Ltd, GlaxoSmithKline and Novartis. M.B. Santiago: None. G. Aroca-Martínez: None. F.I. Palazuelos: Other; F.I.P. has received consulting fees and/or research support from AbbVie, Amgen, Eli Lilly, F. Hoffmann-La Roche Ltd, Janssen, Novartis, Pfizer and Takeda. T. Baczkowska: None. J. Alfaro: Other; J.A. has received consulting fees and/or reports professional services for AstraZeneca, Bristol Myers Squibb, F. Hoffmann-La Roche Ltd, Horizon Therapeutics and Kezar. J. Ravelo-Hernández: Other; J.R. has received consulting fees and/or reports professional services for AstraZeneca, Bristol Myers Squibb, F. Hoffmann-La Roche Ltd and Horizon Therapeutics. 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. L.F. Pinto: None. E.H. Albiero: None. C. Larsen: Other; C.L. has received support and/or consulting fees from Calliditas Therapeutics AB and Novartis. B. Yoo: Other; B.Y. is an employee of Genentech, Inc. and shareholder of F. Hoffmann-La Roche Ltd. J. Pulley: Other; J.P. is an employee and shareholder of F. Hoffmann-La Roche Ltd. A. Thorley: Other; A.T. is an employee of Genentech, Inc. and shareholder of F. Hoffmann-La Roche Ltd. T. Schindler: Other; T.S. is an employee and shareholder of F. Hoffmann-La Roche Ltd. T.A. Omachi: Other; T.A.O. is an employee of Genentech, Inc. 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. A. Malvar: Other; A.M. has received consulting fees and/or reports professional services for Bristol Myers Squibb, F. Hoffmann-La Roche Ltd, GlaxoSmithKline, Kezar, Novartis and Pfizer.
Rovin et al. (Wed,) studied this question.