BACKGROUND: B-cell activating factor (BAFF) and A proliferation-inducing ligand (APRIL) play key roles in the pathogenesis of IgA nephropathy. Atacicept is a novel fully humanized fusion protein, self-administered at home by subcutaneous injection, that binds and inhibits BAFF and APRIL. By inhibiting BAFF and APRIL, atacicept targets the underlying B-cell–mediated pathogenesis driving disease progression. This study evaluated the long-term efficacy and safety of atacicept in patients with IgA nephropathy over 96 weeks. METHODS: Participants with IgA nephropathy who received atacicept (25, 75, or 150 mg) or placebo in a 36-week phase 2b, randomized, blinded trial were enrolled in an open-label extension study and received atacicept 150 mg for an additional 60 weeks. Key efficacy outcomes were changes in galactose-deficient IgA1 (Gd-IgA1), percentage of participants with hematuria, urine protein-creatinine ratio (UPCR), and eGFR over 96 weeks. Long-term safety data were also evaluated. RESULTS: There were 113 participants (67 [59%] male; 46 [41%] female) who ranged in age from 18 to 67 years who received ≥1 atacicept dose. Over 96 weeks, safety data demonstrated that atacicept was generally well tolerated. There were also sustained reductions (mean±SEM) in Gd-IgA1 (−66%±2%), percentage of participants with hematuria (−75%; 95% confidence intervals, −87 to −59; in participants with baseline hematuria), and UPCR (−52%±5%). The mean annualized slope of eGFR was −0.6±0.5 ml/min per 1.73 m2 through 96 weeks. CONCLUSIONS: Atacicept was also well tolerated over the duration of the study. Atacicept treatment reduced Gd-IgA1, hematuria, and UPCR with stabilization of eGFR through 96 weeks. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Atacicept in Subjects with IgA Nephropathy (ORIGIN 3), NCT04716231.

• Publication type
• Journal Article MeSH

Glomerulonephritis (GN) encompasses a diverse group of immune-mediated diseases that damage the glomerular component of the nephron. While kidney biopsy remains the gold standard for diagnosis, it often fails to provide adequate insight into the underlying etiology of GN. Current classification systems have limited our understanding of the disease's pathophysiology and hinder the development of targeted therapies. Immunosuppressive treatments, such as glucocorticoids, calcineurin inhibitors, cyclophosphamide, and rituximab, remain the mainstay of therapy, though many patients fail to achieve remission or experience significant adverse effects. Moreover, the complex and multifactorial nature of GN pathogenesis calls for more refined therapeutic approaches. In recent years, multitarget therapies-combining different immunosuppressive agents targeting distinct immune pathways-have emerged as promising alternatives. Evidence suggests that multitarget therapy may offer superior outcomes compared to standard treatments. Despite early success, further studies are needed to optimize these regimens, reduce toxicity, and extend benefits to a broader range of GN patients. The development of personalized, biomarker-driven treatments, potentially leveraging innovative drug delivery systems and targeted biologics, holds promise for transforming GN care in the future.

• Keywords
• cyclophosphamide, glomerulonephritis, multitarget therapy, rituximab,
• Publication type
• Journal Article MeSH