Presenter: James A. Tumlin, MD, Emory University School of Medicine, Atlanta, GA.
Efficacy and safety of povetacicept in patients with IgAN and primary membranous nephropathy (pMN) at 48 Weeks of treatment: the RUBY-3 study. Abstract SA-OR091. Presented November 8, 2025.
Povetacicept, a dual inhibitor of the cytokines B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL), has demonstrated early evidence of safety and efficacy in patients with autoimmune glomerular diseases, an investigator reported at American Society of Nephrology Kidney Week 2025.
Treatment with povetacicept produced early and sustained improvements in kidney function and disease activity in patients with IgA nephropathy and primary membranous nephropathy, according to James A. Tumlin, MD, of Emory University School of Medicine.
Dr. Tumlin presented findings from an ongoing open-label, phase 1/2 study of povetacicept during a late-breaking research session at the conference.
“By directly targeting both BAFF and APRIL, povetacicept interdicts the causal biology of IgA nephropathy and primary membranous nephropathy, with potential to be a best-in-class, transformative, disease-modifying treatment,” Dr. Tumlin and co-authors wrote in a conference abstract describing the study results.
In efficacy findings reported to date, povetacicept treatment reduced proteinuria, stabilized the estimated glomerular filtration rate, and was associated with high levels of clinical remission in IgA nephropathy and primary membranous nephropathy, two autoimmune, B-cell mediated glomerular diseases.
Treatment with povetacicept was well tolerated, with low rates of serious adverse events, severe infection, hypogammaglobulinemia, and injection site reactions, according to results also described in a journal pre-proof released in Kidney International Reports.
Povetacicept targets BAFF and APRIL, which drive the pathogenesis of autoimmune glomerulonephritis. These cytokines promote the survival and function of B cells and plasma cells that generate galactose-deficient IgA1 and corresponding anti-galactose-deficient-IgA1 autoantibodies.
The ongoing, open-label phase 1/2 study of povetacicept includes adults with IgA nephropathy or primary membranous nephropathy, all with estimated glomerular filtration rates of at least 30 mL/min/1.73 m2. The primary objective was safety. Secondary objectives included change from baseline in urine protein-to-creatinine ratio, estimated glomerular filtration rate, galactose-deficient-IgA1 (for IgA nephropathy), anti-phospholipase A2 receptor autoantibody (for primary membranous nephropathy), and clinical remission.
The interim analysis of the phase 1/2 study includes a total of 54 participants with IgA nephropathy and 10 with primary membranous nephropathy, all of whom received povetacicept administered subcutaneously every 4 weeks. Patients with IgA nephropathy received either 80 mg or 240 mg, while primary membranous nephropathy patients all received 80 mg.
Among participants with IgA nephropathy, treated at 80 mg, there was a 64% decrease in mean 24-hour urine protein-to-creatinine ratio from baseline (1.3 g/g) to week 48 (0.5 g/g), and 65% of these participants achieved ratio below 0.5 g/g, while estimated glomerular filtration rate remained stable during treatment.
Also in the IgA nephropathy 80-mg cohort, galactose-deficient-IgA1 levels declined in 57% of subjects at week 12, and 77% at week 48. Hematuria resolved in approximately 90% of participants, and clinical remission was observed in 53%.
Efficacy outcomes in IgA nephropathy with the 240-mg dose of povetacicept were comparable to those with the 80-mg dose, according to investigators.
In participants with primary membranous nephropathy, there was an 82% decrease in mean 24-hour urine protein-to-creatinine ratio from baseline (3.8 g/g) to week 48 (0.7 g/g), again with stable estimated glomerular filtration rates.
An early decline in anti-PLA2R autoantibodies was observed in 73% of subjects at week 12 and 83% at week 48, with 100% in immunologic remission, including 40% achieving complete remission.
In both IgA nephropathy and primary membranous nephropathy, povetacicept was generally safe and well tolerated, investigators reported.
Taken together, these data demonstrate the viability of inhibiting BAFF and APRIL in the treatment of IgA nephropathy and primary membranous nephropathy, both serious kidney diseases with high unmet need, Dr. Tumlin said in a news release describing the study.
“In IgA nephropathy, it is especially encouraging to see that at 48 weeks of follow-up, a full two-thirds of the participants treated with povetacicept achieved a complete response as defined by urine protein-to-creatinine ratio less than 0.5 g/g, which is in line with the most recent Kidney Disease: Improving Global Outcomes guidelines,” he said.
Phase 3 studies of povetacicept in IgA nephropathy and primary membranous nephropathy are underway.
Disclosures
James A. Tumlin, MD, and co-authors reported commercial support from Vertex Pharmaceuticals, Inc.
References
Tumlin JA, Yalavarthy R, Kim DK, et al. Efficacy and safety of povetacicept in patients with IgAN and primary membranous nephropathy (pMN) at 48 weeks of treatment: the RUBY-3 study [abstract]. Presented at: American Society of Nephrology Kidney Week 2025; November 6–9, 2025; Houston, TX.
Madan A, Yalavarthy R, Kim DK, et al, for the AISD03 RUBY-3 Study Group, Povetacicept for IgA nephropathy and primary membranous nephropathy. Kidney International Reports 2025. doi:https://doi.org/10.1016/j.ekir.2025.10.029