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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. Povetacicept administration has been associated with on-target reductions in circulating immunoglobulins, including galactose-deficient IgA1 (Gd-IgA1), and antibody-secreting cells in healthy volunteers. In initial results from the ongoing RUBY-3 study (NCT05732402), povetacicept 80 mg administered subcutaneously once every 4 weeks demonstrated good tolerability with multiple dosing and promising 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 based on longer follow-up are reported here.
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.
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 has been well tolerated, with the majority of treatment-emergent adverse events being of low grade and none leading to treatment discontinuation or dose reduction/interruption. 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 (based on estimated glomerular filtration rate), and pharmacodynamically expected decreases in immunoglobulin levels were also observed.
Povetacicept is 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.