Povetacicept, an Enhanced Dual BAFF/APRIL Antagonist, in Autoantibody-Associated Glomerulonephritis (GN)

Background: Inhibition of BAFF and/or APRIL has shown promise in IgA nephropathy (IgAN), primary membranous nephropathy (pMN), and lupus nephritis (LN), with the potential to exert a disease-modifying effect. Povetacicept (ALPN-303) is an Fc fusion of a variant TACI domain engineered for more potent dual BAFF/APRIL inhibition vs WT TACI or anti-BAFF or -APRIL Abs. In healthy volunteers, povetacicept was well tolerated and reduced Ig (including Gd-IgA1) levels and Ab-secreting cells. This is a report of an open-label, multiple ascending dose experience with povetacicept in GN. Methods: RUBY-3 (NCT05732402) is a ph 1b/2a study of povetacicept 80 or 240 mg SC Q4W for 24 wk, with an optional 24-wk extension. Eligible participants (pts) are aged ≥18 y with biopsy-confirmed IgAN, pMN, or LN, and on maximally tolerated ACEi/ARB therapy, with well-controlled BP, and disease-specific immunosuppressive therapy where applicable. Primary objective is safety; secondary objectives include PK, PD, immunogenicity, biomarkers, and efficacy. Results: As of 1Sep23, 12 pts with IgAN and 1 with pMN have enrolled at the lower povetacicept dose level of 80 mg; 6 and 1 pts, respectively, have completed ≥12 wk. The 240-mg IgAN cohort has also begun enrolling. Povetacicept has been well tolerated, with no serious or severe TEAEs, IgG <3 g/L, or administration-related reactions. In IgAN, UPCR was reduced by 30% at 12 wk (n=6) and expected decreases in Ig levels were seen (Fig). The first enrolled pt achieved a urinary protein excretion level below the threshold of detection (<0.56 g/g) by 24 wk, preceded by a 43% reduction in Gd-IgA1 at 4 wk. In pMN (n=1), a 39% UPCR reduction (Fig) and 77% reduction in anti-PLA2R were seen at 12 wk. Updated data will be presented.Conclusions: Initial experience indicates povetacicept is well tolerated during multiple-dose administration in GN, with highly encouraging early reductions in UPCR and disease-specific biomarkers in pts with IgAN and pMN. Funding: Commercial Support - Alpine Immune Sciences, Inc.