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Abstract
Objective To investigate changes in peripheral B cells, B-cell subsets and biomarkers in NOBILITY.
Methods In the randomized Phase II NOBILITY trial (NCT02550652), patients with lupus nephritis received standard care (MMF) plus obinutuzumab 1000 mg or placebo on Weeks 0, 2, 24 and 26. We analyzed autoantibodies, complement C3/C4, total CD19+ B cells and B-cell subsets using high-sensitivity flow cytometry at Weeks 4, 12, 24, 52, 76 and 104. Sustained B-cell depletion was defined as total B cells below the lower limit of quantitation (LLOQ; 0.4 cells/μL) at Weeks 24 and 52. Detectable B cells were defined as total B cells above LLOQ.
Results Baseline biomarker levels were similar between treatment groups. By Week 4, 89.3% (50/56) of obinutuzumab-treated patients had total and all B-cell subsets below LLOQ; by Week 104, 91.8% (45/49) had total B cells above LLOQ. At Week 104, mean memory B cells remained low compared with baseline in obinutuzumab-treated patients (3.5 vs 65 cells/µL), whereas mean naïve B cells were repleted (127 vs 229 cells/µL; figure 1). Of 52 obinutuzumab-treated patients with B-cell measurements at Weeks 24 and 52, 61.5% had sustained B-cell depletion. A trend towards higher renal response rates at Week 76 were observed in obinutuzumab-treated patients with sustained B-cell depletion and those with detectable B cells compared with placebo-treated patients (figure 2). In patients positive for anti-dsDNA antibodies at baseline (>30 IU/mL), median anti-dsDNA antibodies at Week 104 were reduced by 84% and 39% in the obinutuzumab and placebo groups, respectively; anti-C1q antibodies were reduced by 61% and 7%, respectively. Among patients who were hypocomplementemic at baseline (C3 <90 mg/dL or C4 <16 mg/dL), more patients who received obinutuzumab than placebo had normal C3 (75% vs 38%) and C4 (82% vs 31%) levels at Week 52.
Conclusion In patients with lupus nephritis, obinutuzumab treatment resulted in robust and sustained reductions in B cells, greater renal response in patients with sustained B-cell depletion and greater improvements in autoantibodies and C3/C4 compared with placebo. These data support the superiority of obinutuzumab plus MMF at inducing renal response.
Acknowledgements Funded by F. Hoffmann-La Roche Ltd. Editorial assistance was provided by Health Interactions, Inc., and funded by F. Hoffmann-La Roche Ltd.
Disclosures
R.A. Furie has received research support and consulting fees from Genentech, Inc.
S.W. Tas has received research support from F. Hoffmann-La Roche Ltd/Genentech, Inc.
A. Malvar has received consulting fees from Genentech, Inc., and F. Hoffmann-La Roche Ltd.
C.M. Looney, E. Martins, A. Mao and T. Schindler are employees and shareholders of F. Hoffmann-La Roche Ltd.
H. Raghu, V.G. Anania and J.A. Ross Terres are employees of Genentech, Inc., and shareholders of F. Hoffmann-LaRoche Ltd.
E.M. Vital has received consulting fees from F. Hoffmann-La Roche Ltd/Genentech, Inc.
Depletion of B cells and B-cell subsets over time in patients with lupus nephritis in NOBILITYCD, cluster of differentiation; MMF, mycophenolate mofetil.
Renal response at week 76 by B-cell depletion status at weeks 24 and 52. HPF, high-powered field; RBC, red blood cell; LLOQ, lower limit of quantitation; ULN, upper limit of normal; UPCR, urine protein-to-creatinine ratio. †Total B cells below LLOQ (0.4 cells/μL). ‡Total B cells above LLOQ (0.4 cells/μL). §A composite measure requiring UPCR of <0.5, normal renal function (serum creatinine ≤ ULN) without worsening of baseline serum creatinine by >15% and inactive urinary sediment (<10 RBCs/HPF without RBC casts). ║A composite measure requiring serum creatinine of ≤15% above baseline value, no urinary RBC casts and either RBCs/HPF of ≤50% above baseline or <10 RBCs/HPF, 50% UPCR improvement, with 1 of the following conditions met (1) if the baseline UPCR is ≤3.0, then UPCR of <1.0 or (2) if the baseline UPCR is >3.0, then UPCR of <3.0. * P<0.2 vs placebo group. ** P<0.05 vs placebo group. *** P<0.001 vs placebo group.
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