Efficacy and Safety of Povetacicept in Patients with IgAN and Primary Membranous Nephropathy (pMN) at 48 Weeks of Treatment: The RUBY-3 Study

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Background: BAFF and APRIL are central to the pathogenesis of autoimmune glomerulonephritis (GN) by promoting B cell and plasma cell survival, which produce Gd-IgA1 and anti-Gd-IgA1 autoantibodies. APRIL is primarily limited to promoting plasma cell survival and activity, while BAFF also regulates early pathogenic B cell development, activates pathogenic T cells and innate immune cells, promotes aberrant IgA glycosylation leading to Gd-IgA1, and contributes to mesangial cell proliferation and podocyte injury. Povetacicept, a dual BAFF/APRIL inhibitor, is engineered for high inhibitory potency, target affinity, and tissue penetration, offering effective B cell control and a significant therapeutic advancement for autoimmune GN. Methods: This is an ongoing ph1/2, open-label study in adults with IgAN and pMN receiving povetacicept 80mg (IgAN:n=21 dosed; n=17,W48; pMN:n=10 dosed; n=5,W48) or 240mg (IgAN:n=33 dosed; n=30,W48) subcutaneously Q4W (13Jun2025 cutoff). Primary and secondary objectives were safety and efficacy. Results: IgAN 80mg at W48: Mean 24-hr UPCR decreased 64% (95%CI:-76,-48) from baseline (1.3g/g to 0.5g/g; 65% with UPCR <0.5g/g) with stable eGFR. Eary decline in Gd-IgA1 was seen at W12 (57%) and continued at W48 (77%). 90% achieved hematuria resolution and 53% achieved clinical remission. Efficacy outcomes were generally similar with 240mg. pMN 80mg at W48: Mean 24-hr UPCR decreased 82% (95%CI:-92,-60) from baseline (3.8g/g to 0.7g/g) and eGFR was stable. Early decline in anti-PLA2R autoantibodies was seen at W12 (73%) and continued at W48 (83%) with 100% in immunologic remission. 40% achieved complete remission; 100% achieved partial remission. Povetacicept was generally safe and well tolerated for IgAN (both doses) and pMN. Conclusion: Povetacicept led to substantial, sustained UPCR reductions with stable eGFR, significant Gd-IgA1 reductions, hematuria resolution, clinical remission, with favorable safety in IgAN. Similar results were seen in pMN. By directly targeting both BAFF and APRIL, povetacicept interdicts the causal biology of IgAN and pMN, with potential to be a best-in-class, transformative, disease-modifying treatment; ph3 studies in IgAN and pMN are underway. Funding: Commercial Support - Vertex Pharmaceuticals Inc

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