LONGITUDINAL ASSESSMENT OF BIOMARKERS IN NOBILITY, A RANDOMIZED, PHASE II CLINICAL TRIAL OF OBINUTUZUMAB FOR TREATMENT OF PROLIFERATIVE LUPUS NEPHRITIS.
No Thumbnail Available
All Authors
Furie, R.A.
Tas S.W.
Malvar A.
Looney C.M.
Raghu H.
Anania V.G.
Mao A.
Schindler T.
Martins E.
Ross Terres J.A.
LTHT Author
Vital, Edward
LTHT Department
NIHR Leeds Biomedical Research Centre
Rheumatology
Rheumatology
Non Medic
Publication Date
2024
Item Type
Conference Abstract
Language
Subject
Subject Headings
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/m L) 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 obinutuzumabtreated 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/mL), whereas mean naive B cells were repleted (127 vs 229 cells/mL; 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 obinutuzumabtreated 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.
Journal
Lupus Science and Medicine