#1342 Updated results from the RUBY-3 study of povetacicept, an enhanced dual BAFF/APRIL antagonist, in autoantibody-associated glomerulonephritis

Abstract Background and Aims Inhibition of BAFF and/or APRIL has shown promise in IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), lupus nephritis (LN), and primary membranous nephropathy (pMN), and has 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 than wild-type TACI or anti-BAFF or anti-APRIL antibodies. In a previous report, povetacicept 80 mg every 4 weeks was initially well tolerated and demonstrated promising, clinically meaningful reductions in urine protein to creatinine ratio (UPCR) and Gd-IgA1 in participants with IgAN (Tumlin J, et al. Poster TH-PO1125 presented at ASN 2023). Updated data are reported here. Method RUBY-3 is an open-label, multiple ascending dose, phase 1b/2a study of povetacicept 80 or 240 mg administered subcutaneously once every 4 weeks. Eligible participants are aged ≥18 years with biopsy-confirmed IgAN, LN, or pMN and on maximally tolerated ACE inhibitor/ARB therapy, with well-controlled blood pressure, and disease-specific immunosuppressive therapy where applicable. The primary objective is safety; secondary objectives include pharmacokinetics, pharmacodynamics, immunogenicity, biomarkers, and efficacy. Results As of 1 Dec 2023, 12 participants with IgAN have enrolled and received povetacicept 80 mg, with 7 (58%) having received ≥24 weeks of treatment. Povetacicept continues to be well tolerated, with the majority of treatment-emergent adverse events being of low grade. There have been no incidences of severe hypogammaglobulinemia (IgG 3 g/L) or severe infections. Povetacicept 80 mg was associated with a UPCR reduction of 52.6% at 24 weeks (n = 7). Reductions in Gd-IgA1, stable renal function, and pharmacodynamically expected decreases in immunoglobulin levels were also observed. Additional results from the 80 mg cohort with longer duration of follow-up, as well as initial results from the 240 mg dosing cohort, are planned to be presented. Conclusion Povetacicept remains well tolerated with multiple dosing and continues to demonstrate very promising activity in IgAN, strongly supporting further study in IgAN as well as other glomerulonephritis and autoantibody-associated diseases.