B-cell depletion with obinutuzumab for the treatment of proliferative lupus nephritis: a randomised, double-blind, placebo-controlled trial

Abstract

Objective: Randomised trials of type I anti-CD20 antibodies rituximab and ocrelizumab failed to show benefit in proliferative lupus nephritis (LN). We compared obinutuzumab, a humanised type II anti-CD20 monoclonal antibody that induces potent B-cell depletion, with placebo for the treatment of LN in combination with standard therapies.

Methods: Patients with LN receiving mycophenolate and corticosteroids were randomised to obinutuzumab 1000 mg or placebo on day 1 and weeks 2, 24 and 26, and followed through week 104. The primary endpoint was complete renal response (CRR) at week 52. Exploratory analyses through week 104 were conducted. The prespecified alpha level was 0.2.

Results: A total of 125 patients were randomised and received blinded infusions. Achievement of CRR was greater with obinutuzumab at week 52 (primary endpoint, 22 (35%) vs 14 (23%) with placebo; percentage difference, 12% (95% CI -3.4% to 28%), p=0.115) and at week 104 (26 (41%) vs 14 (23%); percentage difference, 19% (95% CI 2.7% to 35%), p=0.026). Improvements in other renal response measures, serologies, estimated glomerular filtration rate and proteinuria were greater with obinutuzumab. Obinutuzumab was not associated with increases in serious adverse events, serious infections or deaths. Non-serious infusion-related reactions occurred more frequently with obinutuzumab.

Conclusions: Improved renal responses through week 104 were observed in patients with LN who received obinutuzumab plus standard therapies compared with standard therapies alone. Obinutuzumab was well tolerated and no new safety signals were identified.

Trial registration number: NCT02550652.

Keywords: lupus erythematosus; lupus nephritis; rituximab; systemic.

Conflict of interest statement

Competing interests: RAF reports personal fees from Genentech/Roche during the conduct of the study and outside the submitted work and grants from Genentech/Roche. MDC and JPG are employees and shareholders of Genentech/Roche. BHR reports personal fees from Genentech, during the conduct of the study; personal fees from Aurinia, personal fees from Bristol Myers Squibb, personal fees from Biogen, personal fees from Pfizer, personal fees from Lilly, personal fees from GlaxoSmithKline, personal fees from Mallinckrodt, personal fees from EMD Serono, personal fees from Omeros, personal fees from Calliditas, personal fees from Retrophin, personal fees from BioMarin, outside the submitted work. PB was an employee and shareholder of Genentech during the design and enrolment period. TS and IH are employees and shareholders of Roche. GA, AA, HF-L, EZ-S and AM have nothing to disclose.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Patient flow diagram.

Figure 2

Renal responses over time. CRR, complete renal response; mCRR, modified CRR; MMF, mycophenolate mofetil; ORR, overall renal response.

Figure 3

Change from baseline in laboratory parameters. Mean change from baseline was calculated with the last observation carried forward for missing data. If treatment failure occurred, the last measurement prior to treatment failure was used. eGFR, estimated glomerular filtration rate; MMF, mycophenolate mofetil; UPCR, urine protein-to-creatinine ratio.

Figure 4

Proportions of patients with B-cell depletion over time. B-cell depletion is defined as an absolute CD19 count ≤5 cells/µL. MMF, mycophenolate mofetil.