#3280 B-CELL RECOVERY IN A RANDOMIZED CONTROLLED TRIAL OF B-CELL DEPLETION WITH OBINUTUZUMAB FOR THE TREATMENT OF PROLIFERATIVE LUPUS NEPHRITIS (NOBILITY)

Abstract Background and Aims B cells are central to the pathogenesis of systemic lupus erythematosus and lupus nephritis (LN). Obinutuzumab, a humanized type II anti-CD20 monoclonal antibody, induces more potent B-cell depletion than rituximab. Patients with LN who received obinutuzumab with standard-of-care (mycophenolate mofetil [MMF]) immunosuppression (Phase II NOBILITY study; NCT02550652) showed improved clinical responses through Week 104 compared with those who received MMF alone. Further, sustained as opposed to unsustained B-cell depletion up to Week 52 in those who received obinutuzumab was associated with a higher incidence of complete renal response (CRR) at Week 76.1,2 This analysis aims to characterize the kinetics of B-cell recovery after the last dose of obinutuzumab in NOBILITY and the impact of these kinetics on response and safety. Method A total of 125 patients with active Class III/IV LN receiving MMF and corticosteroids were randomized and received either obinutuzumab 1000 mg (n = 63) or placebo (n = 62) on Day 1 and Weeks 2, 24 and 26, and followed through Week 104 or to B-cell recovery, whichever was longer.1 B cells were measured using both a T and B natural killer cell (TBNK) assay with a lower limit of quantification (LLoQ) of 10 CD19+ cells/µL and a high-sensitivity minimal residual B-cell 1.1 (MRB1.1) assay with an LLoQ of 0.4 cells/µL. Peripheral B-cell depletion was defined as ≤0.4 cells/µL. Peripheral B-cell recovery was defined as ≥20 cells/µL or the patient's predose baseline, whichever was lower. Time to peripheral B-cell recovery after the last dose of obinutuzumab (Week 26 in 57 of 63 patients), the relationship of time to recovery to efficacy at Week 104 and safety throughout the main study and follow-up period were evaluated (severe adverse event [SAE] and infectious SAE rates, adjusted for patient-years [PY] at risk). Results Of 63 patients who received obinutuzumab, 4 did not achieve full B-cell depletion during the study. By Week 24, 59 patients (93.7%) achieved B-cell depletion (before obinutuzumab redosing); of those, 4 discontinued prior to B-cell recovery, and 4 completed the study at or after Week 104 but before achieving B-cell recovery. The remaining 51 patients constitute the population for this analysis. Based on the distribution of time to B-cell recovery, 93 weeks after the last obinutuzumab infusion was used to group patients (Figure 1). Of the 51 patients, 3 (5.9%) recovered B cells before redosing at Week 26; 1 of the 3 achieved CRR at Week 104. A total of 37 patients (72.5%) attained B-cell recovery within 93 weeks of their last dose of obinutuzumab (median time to B-cell recovery, 78.1 weeks), 18 of 37 (48.6%) and 23 of 37 (62.2%) achieved CRR and overall renal response (ORR) at Week 104, respectively. In these 37 patients, SAE and infectious SAE rates per 100 PY were 13 and 8, respectively. In 11 patients (21.6%), >93 weeks passed after their last dose to achieve B-cell recovery. Nine of 11 patients achieved B-cell recovery with a median time of 102 weeks, and 2 of 11 had not yet achieved B-cell recovery at the time of writing. Five of 11 patients (45.5%) achieved CRR, and 8/11 (72.7%) achieved ORR at Week 104. In these 11 patients, SAE and infectious SAE rates per 100 PY were 10 and 0, respectively. Conclusion Most patients in NOBILITY recovered peripheral B cells within 80 weeks after the last obinutuzumab dose. In 5.9% of patients, recovery occurred very rapidly, even before redosing at 26 weeks, whereas in ≈20%, recovery took >2 years (Figure 2). Renal response rates at Week 104 were similar among patients who recovered B cells within 2 years of their final obinutuzumab infusion, those who recovered later and those who are still depleted, suggesting a greater mechanistic effect of early sustained depletion vs duration of depletion. Within the limitation of small sample size, the SAE and infectious SAE rates appear to be similar regardless of duration of B-cell depletion.

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