Prospective Cohort Study of Felzartamab in Rituximab-Resistant Primary Membranous Nephropathy

Introduction.Approximately 30% of patients with primary membranous nephropathy (MN) and nephrotic syndrome (NS) fail rituximab treatment through mechanisms that could be overcome by the human IgG1 monoclonal anti-CD38 antibody felzartamab. Methods.In this prospective, single-arm, single-center, open-label trial, ten consenting Caucasian adult patients with MN, rituximab-resistant NS and eGFR >30 ml/min/1.73m 2 received a five-month, nine-dose course of 16 mg/kg felzartamab infusions at the Nephrology Unit of Bergamo Hospital (Italy) between November 9 th 2021 and February 1 th 2023 and were followed-up for 24-months.Clinical and laboratory parameters were evaluated at baseline, 1, 2, 5, 6, 9, 18 and 24 months, whereas GFR and albumin and IgG fractional clearances were measured at baseline and at 6, 9, 12, 18, and 24 months post-treatment.The primary outcome was 24-hour proteinuria (median of three consecutive measurements) at 12 months.Results.Twelve-month 24-hour proteinuria was similar to baseline.Linear-mixed-model analyses showed no significant time-dependent changes in 24-hour proteinuria and albuminuria; serum totalprotein, albumin, creatinine and lipid levels, GFR and albumin fractional clearances.Circulating anti-PLA2R antibodies transiently decreased but were never depleted.All considered immunoglobulins transiently decreased up to month 12, and recovered to baseline thereafter.Felzartamab deeply and persistently decreased NK B-cell and antigen-inexperienced transitional B-cells, whereas did not affect CD20-expressing memory B-cells, plasmablasts and plasma cells.Treatment was safe and well tolerated.Conclusions.One course of felzartamab was safe and well tolerated, but ineffective in patients with MN and rituximab-resistant NS, possibly because of inability to persistently deplete nephritogenic autoantibody producing CD38-expressing B-cells.