Targeting BAFF and APRIL in IgAN: Mechanisms and VISIONARY eGFR Data

Dr. Wadhwani asks Dr. Cheung for the rationale behind targeting the BAFF/APRIL axis. Dr. Cheung explains that both cytokines come from activated dendritic and myeloid cells in the mucosal microenvironment, where B-cell priming takes place, and that they drive production of pathogenic galactose-deficient IgA1. BAFF supports maturation of immature B cells and class switching to IgA-producing cells. APRIL also supports class switching and acts on later-stage cells, including survival of the plasma cells that make antibody. Unlike rituximab, these agents do not broadly deplete peripheral B cells.

Dr. Cheung then separates two approaches. Monoclonal antibodies, including approved sibeprenlimab and one still in trials, selectively block APRIL, which signals through BCMA on late-stage B cells. Fusion proteins such as atacicept combine a receptor with the Fc portion of IgG and suppress B-cell signaling more broadly. Dr. Wadhwani notes that Kidney Week featured a record three IgAN late-breakers in one plenary session, all on this class.

Dr. Geara reviews the VISIONARY trial of selective APRIL inhibition. Proteinuria fell about 50 percent with sibeprenlimab versus a 2.1 percent increase on placebo at nine months, and the effect was sustained through 24 months. Mean eGFR change at 24 months was 1.3 mL/min versus a loss of 7.9 with placebo. He stresses how poorly the placebo group fared, underscoring the need for therapy.

Dr. Wadhwani calls the result remarkable. Earlier phase 3 trials separated treatment from placebo but still showed negative slopes. Here the annualized slope was positive at 0.3 mL/min per year, against a placebo decline above 4, which she says gives patients and clinicians real hope.

Our next episode, "Dual BAFF/APRIL Inhibition in IgAN: ORIGIN 3 Data and Open Questions," turns to the ORIGIN 3 results for dual inhibition and what the panel still wants to learn about durability.