Povetacicept led to substantial, sustained UPCR reductions with stable eGFR, significant Gd-IgA1 reductions, hematuria resolution, clinical remission, with favorable safety in IgA nephropathy (IgAN) and primary membranous nephropathy (pMN).
These findings, from the phase 1/2 RUBY-3 trial, were presented at the American Society of Nephrology (ASN) Kidney Week 2025, held November 5-9, 2025, in Houston, Texas, by James Tumlin, MD, Adjunct Professor, Department of Medicine, Emory University School of Medicine.
Povetacicept is designed to simultaneously inhibit BAFF and APRIL, two central cytokines that regulate pathogenic B-cell maturation, immunoglobulin class switching, plasma-cell survival, and downstream autoantibody production. Unlike agents that act downstream on inflammation or proteinuria, this approach aims to directly interrupt the causal biology driving Gd-IgA1 generation in IgAN and anti-PLA2R autoantibody production in pMN. The 48-week analyses from RUBY-3 provide the clearest evidence to date that these upstream immunologic effects translate into meaningful reductions in proteinuria and support the potential for disease-modifying impact.
Patients with IgAN receiving povetacicept 80 mg experienced a 64% mean reduction in 24-hour UPCR at week 48, with 65% achieving UPCR
HCPLive spoke with Tumlin to discuss how dual BAFF/APRIL inhibition reshapes disease biology in IgAN and pMN, what the 48-week kinetics suggest about long-term remission potential, and how these findings may influence future treatment sequencing in immune-complex glomerular disease.
Across both diseases, povetacicept was generally well tolerated, with decreases in IgG monitored but not associated with serious infections or clinically significant immune compromise. Tumlin emphasized that these characteristics underscore its promise as a disease-modifying therapy, distinct from hemodynamic or anti-proteinuric approaches.
“I think, looking forward ahead, the APRIL/BAFFS may be able to induce a more long and sustained remission. Don’t know that yet, but that’s data that will be evolved and gleaned out over time,” Tumlin said.
Disclosures for Tumlin include Vera Therapeutics, Calliditas Therapeutics, Alexios Pharmaceuticals, and Vertex Pharmaceuticals.
Reference
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. Presented at: ASN Kidney Week. Houston, Texas. November 05-09, 2025. #SA-OR091
