Background: Lupus nephritis (LN) is the most common severe organ-threatening manifestation of systemic lupus erythematosus. The randomized, placebo-controlled, Phase II NOBILITY trial (NCT02550652) demonstrated superiority of obinutuzumab over placebo for achievement of complete and overall renal responses at Week 52 when added to standard-of-care mycophenolate mofetil and corticosteroids in patients with proliferative LN.1 Recent and ongoing registrational clinical trials in LN use composite primary endpoints driven primarily by reduction in proteinuria. Resolution of proteinuria after new-onset LN or LN flare positively influences long-term kidney health. Objectives: To assess the achievement of complete renal response (CRR) in participants from the NOBILITY trial using primary endpoint definitions from the ongoing REGENCY and completed BLISS-LN2 trials and to evaluate effect of proteinuria at baseline on achieving the REGENCY CRR. Methods: Primary and modified primary endpoints from the Phase III REGENCY trial (NCT04221477) and a modified primary endpoint from the Phase III BLISS-LN trial2 (NCT01639339) were used for this analysis at Weeks 52, 76 and 104. Endpoint measures were defined as follows: REGENCY CRR (estimated glomerular filtration rate [eGFR] ≥85% of baseline, urine protein-creatinine ratio [UPCR] ≤0.5 g/g and no treatment failure or rescue therapy), modified REGENCY CRR (eGFR ≥85% of baseline eGFR, UPCR ≤0.7 g/g and no treatment failure or rescue therapy) and modified BLISS-LN primary efficacy renal response (PERR; eGFR ≥80% of baseline eGFR or eGFR ≥60 mL/min, UPCR ≤0.7 g/g and no treatment failure or rescue therapy). Subgroup efficacy analyses were performed by baseline UPCR <2 vs ≥2 g/g and <3 vs ≥3 g/g. Cochran-Mantel-Haenszel test stratified for region (US vs non-US) and race (Afro-Caribbean/African American vs others) was used to compare the CRRs between the treatment arms. All patients met the American College of Rheumatology classification criteria for systemic lupus erythematosus and had biopsy-proven proliferative LN. Results: Obinutuzumab with standard-of-care therapy was significantly superior compared with placebo with standard-of-care therapy when using the REGENCY CRR definition with the existing UPCR ≤0.5 g/g or with the modified UPCR cutoff of ≤0.7 g/g at Weeks 76 and 104 as well as the BLISS-LN PERR definition at Week 104 (Figure 1). In addition, the statistically significant effect of obinutuzumab with standard-of-care therapy compared with placebo with standard-of-care therapy was observed irrespective of baseline proteinuria levels (Figure 2). Conclusion: Obinutuzumab effects, in combination with standard-of-care therapy, persisted using the REGENCY and BLISS-LN primary endpoint definitions and may also positively impact patients with LN irrespective of baseline proteinuria levels. Obinutuzumab is currently undergoing further evaluation in patients with active proliferative LN in the global, registrational, Phase III REGENCY trial (NCT04221477). REFERENCES: [1] Furie RA, et al. Ann Rheum Dis. 2022;81:100-107. [2] Furie RA, et al. N Engl J Med. 2020;383(12):1117-1128. Acknowledgements: Funding provided by F. Hoffmann-La Roche Ltd. Editorial assistance was provided by Nucleus Global and funded by F. Hoffmann-La Roche Ltd. Disclosure of Interests: Richard A. Furie has received consulting fees from Genentech, Inc, and research support from Genentech, Inc, Jorge A. Ross Terres is a shareholder of F. Hoffmann-La Roche Ltd, and an employee of Genentech, Inc., Elsa Martins is an employee of F. Hoffmann-La Roche Ltd, Imran Hassan is a shareholder of F. Hoffmann-La Roche Ltd, and an employee of F. Hoffmann-La Roche Ltd, Thomas Schindler is a shareholder of F. Hoffmann-La Roche Ltd, and an employee of F. Hoffmann-La Roche Ltd, Jay P. Garg is a shareholder of F. Hoffmann-La Roche Ltd, and an employee of Genentech, Inc., William F. Pendergraft III is a shareholder of F. Hoffmann-La Roche Ltd, and an employee of Genentech, Inc., Ana Malvar has received consulting fees from Genentech, Inc., and F. Hoffmann-La Roche Ltd, Brad H. Rovin has received consulting fees from Genentech, Inc., and F. Hoffmann-La Roche Ltd.

BACKGROUND Obinutuzumab, a humanized type II anti-CD20 monoclonal antibody, provided significantly better renal responses than placebo in a phase 2 trial involving patients with lupus nephritis receiving standard therapy. METHODS In a phase 3, randomized, controlled trial, we assigned adults with biopsy-proven active lupus nephritis in a 1:1 ratio to receive obinutuzumab in one of two dose schedules (1000 mg on day 1 and at weeks 2, 24, 26, and 52, with or without a dose at week 50) or placebo. All patients received standard therapy with mycophenolate mofetil, along with oral prednisone at a target dose of 7.5 mg per day by week 12 and 5 mg per day by week 24. The primary end point was a complete renal response at week 76, defined by a urinary protein-to-creatinine ratio of less than 0.5 (with protein and creatinine both measured in milligrams), an estimated glomerular filtration rate of at least 85% of the baseline value, and no intercurrent event (i.e., rescue therapy, treatment failure, death, or early trial withdrawal). Key secondary end points at week 76 included a complete renal response with a prednisone dose of 7.5 mg per day or lower between weeks 64 and 76 and a urinary protein-to-creatinine ratio lower than 0.8 without an intercurrent event. RESULTS A total of 271 patients underwent randomization; 135 were assigned to the obinutuzumab group (combined dose schedules) and 136 to the placebo group. A complete renal response at week 76 was observed in 46.4% of the patients in the obinutuzumab group and 33.1% of those in the placebo group (adjusted difference, 13.4 percentage points; 95% confidence interval [CI], 2.0 to 24.8; P=0.02). A complete renal response at week 76 with a prednisone dose of 7.5 mg per day or lower between weeks 64 and 76 was observed in more patients in the obinutuzumab group than in the placebo group (42.7% vs. 30.9%; adjusted difference, 11.9 percentage points; 95% CI, 0.6 to 23.2; P=0.04), and a urinary protein-to-creatinine ratio lower than 0.8 without an intercurrent event was more common with obinutuzumab than with placebo (55.5% vs. 41.9%; adjusted difference, 13.7 percentage points; 95% CI, 2.0 to 25.4; P=0.02). No unexpected safety signals were identified. More serious adverse events, mainly infections and events related to coronavirus disease 2019, occurred with obinutuzumab than with placebo. CONCLUSIONS Among adults with active lupus nephritis, obinutuzumab plus standard therapy was more efficacious than standard therapy alone in providing a complete renal response.

O025 / #750 Topic:AS15 - Lupus Nephritis-Clinical Late-Breaking Abstract ABSTRACT CONCURRENT SESSION 04: ADVANCING LUPUS THERAPIES AND INSIGHTS 22-05-2025 1:40 PM - 2:40 PM Obinutuzumab, a humanized type II anti-CD20 monoclonal antibody, is approved for B cell malignancies. In the Phase II NOBILITY trial of patients with active lupus nephritis (LN;NCT02550652), study participants receiving obinutuzumab in addition to standard therapy were significantly more likely to achieve complete renal response than those receiving placebo in addition to standard therapy. The results of the Phase III REGENCY trial (NCT04221477), performed to verify NOBILITY, are presented here. REGENCY, a Phase III, double-blind placebo-controlled trial, randomized adults with biopsy-proven active proliferative LN 1:1 to placebo or one of 2 intravenous obinutuzumab dosing schedules (1000 mg: Day 1, Weeks 2, 24, 26, ±50 and 52) in addition to standard therapy. The primary endpoint was complete renal response (CRR, defined as urine protein-to-creatinine ratio [UPCR] <0.5 g/g, estimated glomerular filtration rate [eGFR] ≥85% of baseline and no intercurrent events of rescue therapy, treatment failure, death or early study withdrawal) at Week 76 and assessed in the intention-to-treat population. Key secondary endpoints included CRR at Week 76 with successful prednisone taper to ≤7.5 mg/day between Weeks 64 and 76, and UPCR <0.8 g/g at Week 76 with no intercurrent events, change in eGFR from baseline to Week 76 and renal-related events or death through Week 76. Incidence and severity of adverse events through Week 76 were compiled. Of 271 patients randomized, 135 were randomized to obinutuzumab and 136 to placebo. At Week 76, 46.4% of patients in the obinutuzumab group and 33.1% in the placebo group achieved CRR (adjusted difference, 13.4%; 95% CI, 2.0% to 24.8%;P=0.0232). More patients in the obinutuzumab group achieved CRR at Week 76 with successful prednisone taper (42.7% vs 30.9%, adjusted difference, 11.9%; 95% CI, 0.6% to 23.2%;P=0.0421) and a proteinuric response (UPCR <0.8 g/g) with no intercurrent events at Week 76 (55.5% vs 41.9%; adjusted difference, 13.7%; 95% CI, 2.0% to 25.4%;P=0.0227). Numerical changes in eGFR from baseline to Week 76 favored obinutuzumab compared with placebo, and fewer patients in the obinutuzumab group experienced the composite outcome of death or renal-related events through Week 76. Prespecified subgroup analyses demonstrated numerically greater CRR rates with obinutuzumab in patients with potentially more active disease at enrollment, such as those with Class IV LN, concomitant class V disease, baseline UPCR ≥3 g/g or greater baseline serologic activity. No new safety signals were observed based on the established safety profile of obinutuzumab in oncology indications. More coronavirus disease 2019 (COVID-19) events were observed in the obinutuzumab group, which primarily occurred during the acute phase of the COVID-19 pandemic. There were 3 deaths in the obinutuzumab group and 1 in the placebo group, which were mainly complications of COVID-19. Obinutuzumab plus standard therapy was more effective than placebo plus standard therapy for achieving CRR, a clinically meaningful surrogate of kidney function, in patients with LN, while exhibiting an acceptable safety profile.

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.

Background. The THEORY study evaluated the effects of single and multiple doses of obinutuzumab, a type 2 anti-CD20 antibody that induces antibody-dependent cell-mediated cytotoxicity and direct cell death, in combination with standard of care in patients with end-stage renal disease. Methods. We measured B-cell subsets and protein biomarkers of B-cell activity in peripheral blood before and after obinutuzumab administration in THEORY patients, and B-cell subsets in lymph nodes in THEORY patients and an untreated comparator cohort. Results. Obinutuzumab treatment resulted in a rapid loss of B-cell subsets (including naive B, memory B, double-negative, immunoglobulin D + transitional cells, and plasmablasts/plasma cells) in peripheral blood and tissue. This loss of B cells was associated with increased B cell–activating factor and decreased CXCL13 levels in circulation. Conclusions. Our data further characterize the mechanistic profile of obinutuzumab and suggest that it may elicit greater efficacy in indications such as lupus where B-cell targeting therapeutics are limited by the resistance of pathogenic tissue B cells to depletion.

OBJECTIVE:To determine whether adding obinutuzumab to standard-of-care lupus nephritis (LN) therapy could improve the likelihood of long-term preservation of kidney function and do so with less glucocorticoids.METHODS:Post hoc analyses of the phase II NOBILITY trial were performed. Time to unfavorable kidney outcome (a composite of treatment failure, doubling of serum creatinine, or death), LN flare, first 30% and 40% declines in estimated glomerular filtration rate (eGFR) from baseline, and chronic eGFR slope during the trial were compared between patients with active LN who were randomized to take obinutuzumab (n = 63) or placebo (n = 62) in combination with mycophenolate mofetil and glucocorticoids. The number of patients who achieved complete renal response (CRR) on 7.5 mg or less per day of prednisone was also determined.RESULTS:Obinutuzumab reduced the risk of developing the composite kidney outcome by 60%, LN flare by 57%, and first eGFR decline of 30% or 40% by 80% and 91%, respectively. Patients receiving obinutuzumab had a significantly slower decline in eGFR than patients receiving placebo, with an annualized eGFR slope advantage of 4.1 ml/min/1.73 m2 /year (95% confidence interval 0.14-8.08). Overall, 38% of patients receiving obinutuzumab compared with 16% of patients receiving placebo achieved CRR at week 76 while receiving 7.5 mg or less per day of prednisone (P < 0.01); at week 104, the difference did not achieve significance (38% vs 22%; P = 0.06).CONCLUSION:Post hoc analyses of NOBILITY demonstrated that compared with standard-of-care therapy, obinutuzumab treatment resulted in superior preservation of kidney function and prevention of LN flares. More patients achieved CRR at week 76 with less glucocorticoid use in the obinutuzumab group.

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.

O35 Table 1 Renal responses at week 76 by depletion status Abstracts Lupus Science & Medicine 2020;7(Suppl 1):A1–A131 A27 on M arch 3, 2021 by gest. P rocted by coright. httpupus.bm jcom / Lpus S ci M d: frst pulished as 10.1136/lu020-eurolupus.45 on 23 M arch 220. D ow nladed fom

Background:Incomplete B-cell and plasmablast depletion, as measured using highly sensitive flow cytometry (HSFC), is associated with lower response rates following rituximab in SLE [1]. Enhanced B-cell depletion with the type II anti-CD20 mAb obinutuzumab resulted in increased renal responses in proliferative lupus nephritis (LN) in the NOBILITY trial (NCT02550652) and will be further evaluated in the Phase 3 REGENCY trial (NCT04221477).Objectives:To measure peripheral B-cells, B-cell subsets (naïve, memory and plasmablast) and B-cell activating factor (BAFF) levels and to assess associations between B-cell depletion and renal response in LN patients in a clinical trial of obinutuzumab.Methods:126 patients with active Class III/IV LN were randomized to obinutuzumab or placebo infusions in combination with mycophenolate and glucocorticoids. Peripheral B-cells were measured using a HSFC method with a lower limit of quantitation of 0.441 cells/μL. Serum levels of BAFF were evaluated using ELISA. Sustained depletion was defined by total B-cells below the limit of detection at both weeks 24 and 52. Renal response definitions from Phase 2 NOBILITY and Phase 3 REGENCY trials were used.Results:Obinutuzumab resulted in rapid and complete depletion of total B-cells, memory and naïve B-cells, and plasmablasts from peripheral blood, with 88% of obinutuzumab patients depleted to < 0.441 total B-cells/μL at week 2 (Figure). Mean serum BAFF increased from 4,585 pg/mL at baseline to 14,601 pg/mL at week 52 in the obinutuzumab group. Sustained B-cell depletion was achieved in 32/52 (62%) of patients with complete data and was associated with higher renal response rate at week 76 (Table), although patients who achieved sustained depletion also had lower baseline proteinuria and serum creatinine.Conclusion:Obinutuzumab, a type II anti-CD20 mAb, mediated rapid, complete and sustained depletion of peripheral B-cells and plasmablasts and large increases in serum BAFF. Similar to previous reports, sustained B-cell depletion was associated with increased renal response though there may be confounding factors. REGENCY is being conducted to further evaluate the therapeutic hypothesis with obinutuzumab in LN.References:[1]Md Yusof MY et al.Ann Rheum Dis. 2017;76:1829-36.Table.Data from NOBILITY at week 76 by depletion status at weeks 24 and 52Definition of responseObinutuzumab sustained depletion (N = 32)aObinutuzumab detectable B-cells (N = 20)aPlacebo group detectable B-cells (N = 62)NOBILITY complete responseUPCR < 0.5, SCr ≤ ULN and not increased > 15% from baseline SCr, and < 10 RBC/hpf without casts50%**35%*18%NOBILITY overall responseCRR or ≥ 50% reduction in UPCRb with SCr not increased > 15% from baseline and urinary RBCs not increased > 50% from baseline66%***45%*29%REGENCY complete responseUPCR < 0.5, SCr ≤ ULN and not increased > 25% from baseline SCr69%**45%31%REGENCY overall responseCRR or ≥ 50% reduction in UPCRb with SCr not increased > 25% from baseline84%***55%50%* P < 0.2 vs. placebo group.** P < 0.05 vs. placebo group.*** P < 0.001 vs. placebo group.aEleven patients in the obinutuzumab group with insufficient data to determine depletion status were excluded.b≥ 50% reduction in UPCR to a value < 1 (< 3 if the baseline UPCR was ≥ 3).Acknowledgments :This study was funded by F. Hoffmann-La Roche.Disclosure of Interests: :Edward Vital Grant/research support from: AstraZeneca, Roche/Genentech, and Sandoz, Consultant of: AstraZeneca, GSK, Roche/Genentech, and Sandoz, Speakers bureau: Becton Dickinson and GSK, Philippe Rémy: None declared, Luis Fernando Quintana Porras: None declared, Laurent Chiche: None declared, Dominique Chauveau: None declared, Richard Furie Grant/research support from: AstraZeneca, Biogen, Consultant of: AstraZeneca, Biogen, Thomas Schindler Employee of: F. Hoffmann-La Roche, Jay Garg Employee of: Genentech, Matthew D. Cascino Employee of: Genentech, Zahir Amoura Grant/research support from: GSK, Roche, Consultant of: GSK, Astra Zeneca, Amgen, Andrea Doria Consultant of: GSK, Pfizer, Abbvie, Novartis, Ely Lilly, Speakers bureau: UCB pharma, GSK, Pfizer, Janssen, Abbvie, Novartis, Ely Lilly, BMS, Cary Michael Donna Looney Employee of: Genentech, Dario Roccatello: None declared

Background Previous analyses identified associations between the degree of B-cell depletion and response in lupus nephritis (LN). NOBILITY tested whether enhanced B-cell depletion with the type II anti-CD20 mAb obinutuzumab could improve responses in LN. Methods 126 patients with active Class III/IV LN were randomized to obinutuzumab or placebo infusions in combination with mycophenolate and corticosteroids. Peripheral B-cells were measured using a flow cytometry method with a lower limit of 0.441 cells/μL. Sustained depletion was assessed by flow cytometry measurements at weeks 24 and 52. Results Obinutuzumab was associated with increased CRR (40% vs. 18%, P=0.007) and ORR (51% vs. 29%, P =0.015) at week 76. Obinutuzumab resulted in rapid and complete depletion of peripheral B-cells, memory and naïve B-cell subsets, and plasmablasts, with 89% of obinutuzumab patients depleted to <0.441 CD19+ cells/μL at week 4. Among obinutuzumab patients, sustained B-cell depletion was associated with greater renal response at week 76 (table 1), although patients who achieved sustained depletion also had lower baseline proteinuria and serum creatinine. Conclusions Obinutuzumab, a type II anti-CD20 mAb, induced rapid and complete depletion of peripheral B-cells and B-cell subsets. Similar to previous reports, sustained B-cell depletion was associated with increased renal response. Further evaluation is ongoing to understand the factors associated with achievement of sustained B-cell depletion and renal response. Acknowledgements This study was funded by F. Hoffmann-La Roche.

Background:Obinutuzumab, a type II anti-CD20 mAb, resulted in rapid and complete B-cell depletion and improved renal responses in proliferative lupus nephritis (LN) in the Phase 2 NOBILITY trial and will be further evaluated in the Phase 3 REGENCY trial. Recent analyses suggest alternative urinary sediment, serum creatinine (SCr), and urine protein/creatinine ratio (UPCR) requirements may be better measures of response in LN than those used in NOBILITY [1,2].Objectives:To evaluate the NOBILITY response definitions and to report the results of NOBILITY using alternative definitions of renal response.Methods:126 patients with active Class III/IV LN were randomized to obinutuzumab or placebo in combination with mycophenolate and glucocorticoids. NOBILITY complete renal response (CRR) required UPCR < 0.5, SCr ≤ the upper limit of normal (ULN) of the reference laboratory and not increased > 15% from baseline SCr, and inactive urinary sediment. Exploratory analyses were conducted, and alternative response definitions were evaluated post hoc.Results:NOBILITY CRR was increased with obinutuzumab over placebo at Week 52 (35% vs. 23%, P = 0.11) and Week 76 (40% vs. 18%, P = 0.007). Response rates were low among patients with baseline SCr < 0.65 mg/dL (n = 45) due to the requirement that SCr not increase > 15% from baseline; increasing this threshold to 25% increased the response rate to a level similar to other groups (Figure). Alternative response definitions demonstrated increased rates of response in both treatment groups and similar benefits of obinutuzumab over placebo at Weeks 52 and 76 (Table).Conclusion:Obinutuzumab resulted in consistent treatment benefits across a range of renal response definitions in NOBILITY and will be further evaluated in REGENCY. A requirement that SCr not increase > 15% from baseline may be overly restrictive in patients with low baseline SCr (< 0.65 mg/dL), where a change of 15% represents < 0.1 mg/dL and is of questionable clinical relevance. These findings may inform LN clinical trial design and more accurately reflect clinical practice.References:[1]Dall’era M et al.Arthritis Rheumatol. 2015;67:1305-13.[2]Almaani S et al.J Am Soc Nephrol. 2019;30:669 [abstract].Table.Data from NOBILITY at weeks 52 and 76 using several response definitionsDefinition of responseWeek 52Week 76OBI (n = 63)PBO (n = 62)Diff.OBI (n = 63)PBO (n = 62)Diff.NOBILITY complete responseUPCR < 0.5, SCr ≤ ULN and not increased > 15% from baseline SCr, and < 10 RBC/hpf without casts35%23%12%*40%18%22%**REGENCY complete responseUPCR < 0.5, SCr ≤ ULN and not increased > 25% from baseline SCr43%29%14%*54%31%23%**UPCR < 0.8 only64%48%15%*64%47%17%*UPCR < 0.8 with SCr requirementUPCR < 0.8 and SCr ≤ ULNornot increased > 15% from baseline SCr60%48%12%*64%45%18%**NOBILITY overall responseCRR or ≥ 50% reduction in UPCRawith SCr not increased > 15% from baseline and urinary RBCs not increased > 50% from baseline56%36%20%**51%29%22%**REGENCY overall responseCRR or ≥ 50% reduction in UPCRawith SCr not increased > 25% from baseline68%45%23%**67%50%17%**OBI, obinutuzumab; PBO, placebo.* P < 0.2 vs. placebo group. ** P < 0.05 vs. placebo group.a≥ 50% reduction in UPCR to a value < 1 (< 3 if the baseline UPCR was ≥ 3). All response definitions required no use of rescue medications or early withdrawal.Acknowledgments:This study was funded by F. Hoffmann-La Roche.Disclosure of Interests:Zahir Amoura Grant/research support from: GSK, Roche, Consultant of: GSK, Astra Zeneca, Amgen, Philippe Rémy: None declared, Luis Fernando Quintana Porras: None declared, Laurent Chiche: None declared, Dominique Chauveau: None declared, Dario Roccatello: None declared, Richard Furie Grant/research support from: AstraZeneca, Biogen, Consultant of: AstraZeneca, Biogen, Thomas Schindler Employee of: F. Hoffmann-La Roche, Jay Garg Employee of: Genentech, Matthew D. Cascino Employee of: Genentech, Brad H Rovin Grant/research support from: GSK, Consultant of: GSK, Andrea Doria Consultant of: GSK, Pfizer, Abbvie, Novartis, Ely Lilly, Speakers bureau: UCB pharma, GSK, Pfizer, Janssen, Abbvie, Novartis, Ely Lilly, BMS

Objective The outcome of participants with nephrotic syndrome in clinical trials of lupus nephritis has not been studied in detail.Methods Collated data from two randomised controlled trials in lupus nephritis, Lupus Nephritis Assessment of Rituximab (LUNAR) and A Study to Evaluate Ocrelizumab in Patients With Nephritis due to Systemic Lupus Erythematosus (BELONG) were analysed. Nephrotic syndrome was defined as albumin <3 g/dL and urine protein/creatinine ratio ≥3.5 g/g at start of trial. Renal response was defined as a first morning urine protein/creatinine ratio ≤0.5 g/g in addition to ≤25% increase in creatinine from trial entry assessed at week 48. Logistic regression was used to evaluate the association of nephrotic syndrome with renal response while adjusting for treatment received and ACE inhibitor or angiotensin receptor blocker use.Results 28 (26%) participants with nephrotic syndrome achieved renal response as compared with 130 (52.5%) of those without (p<0.001). Having nephrotic syndrome at baseline significantly lowered the likelihood of achieving renal response (OR 0.32, 95 % CI 0.19 to 0.54, p<0.001). 125 (80%) participants achieved resolution of their nephrotic syndrome in a median time of 16 weeks.Conclusions Nephrotic syndrome at baseline decreases the likelihood of renal response at 1 year. Longer clinical trials or better short-term predictors of long-term outcomes may better assess the effect of novel therapeutic approaches on subjects with nephrotic syndrome.

Peficitinib is a novel orally bioavailable, once-daily Janus kinase (JAK) inhibitor approved in Japan for the treatment of rheumatoid arthritis (RA). This 2-year extension study of two global phase IIb trials investigated the long-term safety and effectiveness of peficitinib. All eligible patients with moderate-to-severe RA including patients in the placebo group who participated in one of two global phase IIb trials (‘with methotrexate’ or ‘without methotrexate’) were included in this 2-year open-label extension study and were converted to peficitinib 100 mg once daily. The primary objective was to evaluate an additional 2 years of safety by assessing treatment-emergent adverse events (AEs) and clinical laboratory evaluations for 105 weeks. Evaluation of an additional 2 years of effectiveness using American College of Rheumatology (ACR) 20/50/70 responses was the exploratory objective. Overall, 611 patients were enrolled in the extension study: 319 (52.2%) patients completed the study and 292 (48%) discontinued treatment, including for withdrawal of patient consent (n = 96), failure to achieve low disease activity (n = 62), and AE not including death (n = 41). AEs were reported in 463 (76%) patients. The most common AEs (per 100 patient-years) were upper respiratory tract infections (9.9) and urinary tract infections (7.2). Serious AEs were reported in 80 (13%) patients, with incidences per 100 patient-years of serious infections 2.7, herpes zoster 1.5 (including one herpes zoster ophthalmic), and malignancies 0.6 (most frequently basal cell carcinoma). At week 105, 269 (44%) patients demonstrated an ACR20 response relative to their respective phase IIb trial baselines. Among 319 patients who completed this 2-year extension of two global phase IIb studies, peficitinib 100 mg once daily demonstrated a stable safety profile and sustained effectiveness in patients with moderate-to-severe RA. ClinicalTrials.gov identifier, NCT01711814. Registered 19 October 2012. Astellas Pharma Global Development, Inc.

BACKGROUND AND OBJECTIVES:Incomplete peripheral blood B cell depletion after rituximab in lupus nephritis might correlate with inability to reduce tubulointerstitial lymphoid aggregates in the kidney, which together could be responsible for inadequate response to treatment. We utilized data from the Lupus Nephritis Assessment with Rituximab (LUNAR) study to characterize the variability of peripheral blood B cell depletion after rituximab and assess its association with complete response in patients with lupus nephritis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:We analyzed 68 participants treated with rituximab. Peripheral blood B cell depletion was defined as 0 cells/µl, termed "complete peripheral depletion," assessed over 78 weeks. Logistic regression was used to estimate the association between characteristics of complete peripheral depletion and complete response (defined as urine protein-to-creatinine ratio <0.5 mg/mg, and normal serum creatinine or an increase in creatinine <15%, if normal at baseline), assessed at week 78. RESULTS:A total of 53 (78%) participants achieved complete peripheral depletion (0 cells/µl) in a median time of 182 days (interquartile range, 80-339).The median duration of complete peripheral depletion was 71 days (interquartile range, 14-158). Twenty-five (47%) participants with complete peripheral depletion achieved complete response, compared with two (13%) without. Complete peripheral depletion was associated with complete response (unadjusted odds ratio [OR], 5.8; 95% confidence interval [95% CI], 1.2 to 28; P=0.03). Longer time to achieving complete peripheral depletion was associated with a lower likelihood of complete response (unadjusted OR, 0.89; 95% CI, 0.81 to 0.98; P=0.02). Complete peripheral depletion lasting >71 days (the median) was associated with complete response (unadjusted OR, 4.1; 95% CI, 1.5 to 11; P=0.008). CONCLUSIONS:There was substantial variability in peripheral blood B cell depletion in patients with lupus nephritis treated with rituximab from the LUNAR trial. Achievement of complete peripheral depletion, as well as the rapidity and duration of complete peripheral depletion, were associated with complete response at week 78. PODCAST:This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018_09_06_CJASNPodcast_18_10_.mp3.

Kidney disease secondary to SLE can affects up to 50% of patients with SLE and largely mediated by deposition of immune complex in the kidneys (1) (2). The clinical diagnosis of lupus nephritis is usually made following a diagnostic kidney biopsy in the presence of proteinuria and/or hematouria,positive serology,and extrarenal manifestation of SLE. The presence of kidney disease is the most important predictor of morbidity and mortality in the patients with SLE. Several demographic,serologic,and genetic risk factors are associated with an increased risk for developing kidney disease. Patient with lupus nephritis are more likely than SLE patients without kidney involvement to have a family history of SLE,anemia,high antidsDNA antibody titer,and hypocomplementemia. Children with SLE develop nephritis more frequently than adults and so do males.