Povetacicept for IgA Nephropathy and Primary Membranous Nephropathy.

Introduction: Povetacicept is an inhibitor of B-cell activating factor (BAFF) and A proliferation-inducing ligand (APRIL), 2 cytokines central to the pathogenesis of autoimmune glomerulonephritis. Both BAFF and APRIL promote B-cell and plasma cell survival and function. APRIL primarily supports plasma cell survival and function, whereas BAFF regulates early pathogenic B-cell development, activates pathogenic T cells and innate immune cells, and contributes to mesangial cell proliferation and podocyte injury. Methods: Our phase 1 and 2, open-label study evaluated povetacicept in adult participants with IgA nephropathy (IgAN) or primary membranous nephropathy (pMN), all with estimated glomerular filtration rate (eGFR) of ≥ 30 ml/min per 1.73 m Results: Povetacicept was administered subcutaneously every 4 weeks (Q4W) to 54 participants with IgAN (21 received 80 mg, 33 received 240 mg) and 10 with pMN (all received 80 mg). In this interim analysis, participants with IgAN on 80 mg had a 64% mean 24-hour UPCR decrease (95% confidence interval: -76 to -48) from baseline (1.3 g/g to 0.5 g/g; 65% with UPCR < 0.5 g/g) with stable eGFR at week 48. Early decline in Gd-IgA1 at week 12 (57%), continued at week 48 (77%). Approximately 90% achieved hematuria resolution and 53% achieved clinical remission. Efficacy outcomes were similar with 240 mg povetacicept. Participants with pMN had an 82% mean 24-hour UPCR decrease (95% confidence interval: -92 to -60) from baseline (3.8 g/g to 0.7 g/g) with stable eGFR. Early decline in aPLA2R at week 12 (73%), continued at week 48 (83%) with 100% in immunologic remission (40% achieved complete remission; 100% achieved partial remission). Povetacicept was generally safe and well-tolerated for IgAN and pMN. Conclusion: Povetacicept had substantial, sustained UPCR reductions with stable eGFR, significant Gd-IgA1 reductions, hematuria resolution, clinical remission, with favorable safety in IgAN. Similar results were observed in pMN. By inhibiting both BAFF and APRIL, povetacicept targets the underlying cause of disease and has potential to provide a significant therapeutic advancement for autoimmune glomerular diseases.