Results from Longer Follow-Up with Povetacicept, an Enhanced Dual BAFF/APRIL Antagonist, in IgA Nephropathy (RUBY-3 Study)

Background: BAFF and/or APRIL inhibition has shown promise in IgAN, lupus, LN, and pMN, with the potential to exert a disease-modifying effect. Povetacicept (ALPN-303) is an Fc fusion protein of a variant TACI domain engineered for more potent dual BAFF/APRIL inhibition vs WT TACI or anti-BAFF/-APRIL Abs. In healthy volunteers, povetacicept mediated on-target reductions in Ab-secreting cells and levels of Ig, including the IgAN-specific biomarker Gd-IgA1. Earlier results from the ongoing RUBY-3 study of povetacicept (NCT05732402) showed good tolerability and promising improvements in IgAN disease activity, including UPCR reductions and stable renal function, accompanied by Gd-IgA1 reductions (Tumlin J, et al. Poster MON-304 presented at WCN 2024). Methods: RUBY-3 is an open-label, multiple ascending dose, ph 1b/2a study of povetacicept 80 or 240 mg SC Q4W for 24 wk, followed by a 28-wk extension; participants (pts) meeting prespecified criteria at 48 wk may enter an optional 52-wk extension. Eligible pts are aged ≥18 y with IgAN, pMN, LN, or ANCA-associated vasculitis (biopsy-confirmed diagnosis required for IgAN, pMN, and LN). Pts must be on maximally tolerated ACEi/ARB therapy, with well-controlled BP, and disease-specific immunosuppressive therapy where applicable. Primary objective: safety; secondary objectives: PK, PD, immunogenicity, biomarkers, efficacy. Results: As of 1 Mar 2024, 41 pts with IgAN have enrolled, with 12 and 29, respectively, at the povetacicept dose levels of 80 and 240 mg SC Q4W. Povetacicept was well tolerated at both dose levels. At 9 mo (n=6), a 64% reduction in UPCR and 69% reduction in Gd-IgA1 were achieved with povetacicept 80 mg; 67% of pts achieved remission, all pts with hematuria at BL had hematuria resolution, and stable renal function was observed. At the time of presentation, ≥20 pts are expected to have completed 36 wk across both dose levels and updated findings will be reported. Conclusion: Experience with povetacicept to date strongly supports its further development in glomerulonephritis and particularly in IgAN, for which a pivotal trial (RAINIER) is in preparation and planned for initiation later this year. Funding: Commercial Support - Alpine Immune Sciences, Inc.