Obinutuzumab Induces Histologic Remission and Deep Kidney Parenchymal B-Cell Depletion in Participants With Lupus Nephritis: Exploratory Analyses of the Phase III REGENCY Trial

Author(s):

Brad H. Rovin,¹ Elsa Martins,² Cary D. Austin,³ Harini Raghu,³ Caleb Chan,³ Patrick S. Chang,³ Jay P. Garg,³ Valeria Alberton,⁴ Mittermayer B. Santiago,⁵ Gustavo Aroca-Martínez,⁶ Fedra I. Palazuelos,⁷ Teresa Baczkowska,⁸ Jose Alfaro,⁹ Jorge Ravelo-Hernández,¹⁰ Richard A. Furie,¹¹ Luis F. Pinto,¹² Eduardo H. Albiero,¹³ Christopher Larsen,¹⁴ Bongin Yoo,³ Jennifer Pulley,¹⁵ Andrew Thorley,³ Thomas Schindler,² Theodore A. Omachi,³ William F. Pendergraft,³Ana Malvar¹⁶
 

¹Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, USA; ² F. Hoffmann-La Roche Ltd, Basel, Switzerland; ³ Genentech, Inc., South San Francisco, CA, USA; ⁴ Pathology Unit, Fernandez Hospital, Buenos Aires, Argentina; ⁵ Bahiana School of Medicine and Public Health and UFBA, Federal University of Bahia, and Clínica SER da Bahia, Salvador, Brazil; ⁶ Universidad Simon Bolivar, Barranquilla, Colombia y Clínica de la Costa, Barranquilla, Colombia; ⁷ Centro de Investigación y Tratamiento Reumatológico S.C., Mexico City, Mexico; ⁸ Department of Transplantation Medicine, Nephrology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland; ⁹ Instituto Peruano del Hueso y la Articulación, Lima, Peru; ¹⁰Clinica San Juan Bautista, Unidad de Investigacion en Reumatologia e Inmunologia, Lima, Peru; ¹¹Division of Rheumatology, Northwell Health, Great Neck, NY, USA; ¹²Internal Medicine and Rheumatology, Hospital Pablo Tobón Uribe, Medellín, Colombia; ¹³Sanatorio Allende, Córdoba, Argentina; ¹⁴Arkana Laboratories, Little Rock, AK, USA; ¹⁵Roche Products Ltd, Welwyn Garden City, UK; ¹⁶Organización Médica de Investigación, Buenos Aires, Argentina

Disclosures:
B.H.R. has received consulting fees from F. Hoffmann-La Roche Ltd/Genentech Inc.
E.M. and T.S. are employees and shareholders of F. Hoffmann-La Roche Ltd.
C.D.A., H.R., C.C., P.S.C., J.P.G., B.Y., A.T., T.A.O. and W.F.P. are employees of Genentech, Inc. and shareholders of F. Hoffmann-La Roche Ltd.
V.A. has received consulting fees and/or reported professional services for F. Hoffmann-La Roche Ltd, GlaxoSmithKline and Novartis.
M.B.S., G.A., T.B., L.F.P. and E.H.A. have nothing to disclose.
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.
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.R. has received consulting fees and/or reported professional services for AstraZeneca, Bristol Myers Squibb, F. Hoffmann-La Roche Ltd and Horizon Therapeutics.
R.A.F. has received research support and consulting fees from Chugai Pharmaceutical Co., Ltd., F. Hoffmann-La Roche Ltd, Genentech, Inc. and GlaxoSmithKline; is a consultant for AstraZeneca, EMD Serono, Novartis, Biogen, and BMS; is an investigator for AstraZeneca, Novartis, Biogen, BMS, and Kyverna; and is a speaker for AstraZeneca.
C.L. has received support and/or consulting fees from Calliditas Therapeutics AB and Novartis.
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.

Abstract or description:

Background
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 histologic remission and kidney tissue-level B-cell depletion at W76 in participants treated with OBI+ST vs PBO+ST.
 

Methods
Paired baseline and W76 kidney biopsies were analyzed. Histologic 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 participants achieving histologic or near-histologic 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. At W76, significantly more participants achieved AI=0 or ≤1 with OBI+ST vs PBO+ST. Among participants 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. Almost every participant in the OBI+ST group had a drop in their tissue B-cell count by W76. 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; P<0.0001).
 

Conclusions
In the largest longitudinal kidney biopsy cohort ever reported for a registrational LN clinical trial, significantly more participants achieved complete/near-complete histologic remission with OBI+ST vs PBO+ST. Obinutuzumab’s potent B-cell clearance from kidney tissue may drive kidney function improvement and LN flare reduction.

Additional abstract information
Acknowledgements: We thank all study participants, the staff and the study investigators. This study was funded by F. Hoffmann-La Roche Ltd. Editorial assistance was provided by Nucleus Global and funded by F. Hoffmann-La Roche Ltd.