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The cytokines BAFF and APRIL are clinically validated targets in multiple autoantibody-associated diseases. Their inhibition has shown promise in IgA nephropathy (IgAN), lupus nephritis (LN), and primary membranous nephropathy (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 than wild-type TACI or anti-BAFF or anti-APRIL antibodies. In healthy volunteers, povetacicept has been associated with on-target reductions in levels of immunoglobulin, including galactose-deficient IgA1 (Gd-IgA1), and antibody-secreting cells. This is a report of an open-label, multiple ascending dose experience with povetacicept in glomerulonephritis.
RUBY-3 (NCT05732402) is a phase 1b/2a study of povetacicept 80 or 240 mg administered subcutaneously once every 4 weeks for 24 weeks, with an optional 24-week extension. 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.
As of 25 Oct 2023, 12 participants with IgAN and 1 with pMN have enrolled at the lower povetacicept dose level of 80 mg; enrollment in the 240-mg IgAN cohort is also in progress. Povetacicept has been well tolerated, with no severe treatment-emergent adverse events, severe hypogammaglobulinemia (IgG <3 g/L), severe infections, or administration-related reactions (data cutoff 20 Oct 2023). In the IgAN cohort, low-dose povetacicept (80 mg) has been associated with a 53.5% reduction in urine protein to creatinine ratio (UPCR) at 24 weeks (n=5) as well as a significant reduction in Gd-IgA1 and pharmacodynamically expected decreases in immunoglobulin levels. The participant with pMN achieved immunological remission (anti-PLA2R1 levels reduced to below the limit of detection) at 22 weeks. Updated data will be reported at the time of the presentation.
Initial experience indicates that povetacicept is well tolerated during multiple-dose administration in glomerulonephritis, with very promising activity including reductions in disease-specific biomarkers in participants with IgAN and pMN. These results strongly support further study of povetacicept in IgAN as well as other glomerulonephritis and autoantibody-associated diseases.