#2859 <b>ORIGIN 2b: changes in Gd-IgA1 and eGFR after discontinuation of atacicept treatment in IgA nephropathy</b>

Abstract Background and Aims IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide, with up to 50% of patients progressing to ESKD or death within 20 years. The cytokines B-cell Activating Factor (BAFF) and A Proliferation-Inducing Ligand (APRIL) play key roles in IgAN pathophysiology by binding to the TACI receptor on B cells and fueling production of galactose-deficient IgA1 (Gd-IgA1) and anti-Gd-IgA1 autoantibodies. Gd-IgA1 is recognized as an autoantigen by anti-Gd-IgA1 autoantibodies, forming the immune complexes which drive kidney pathology and clinical disease. Atacicept is a fully humanized TACI-Fc fusion protein that inhibits both BAFF and APRIL with nanomolar binding affinity, interrupting the immunopathogenesis of IgAN. Atacicept is self-administered at home by subcutaneous injection once weekly (QW). The ORIGIN 2b study evaluated the safety and efficacy of atacicept in IgAN and met the primary endpoint with a statistically significant and clinically meaningful UPCR reduction at 24 wk, with deepening efficacy through 36 wk as compared to placebo. In the open-label extension (OLE), atacicept demonstrated further Gd-IgA1 reductions, hematuria improvements, and UPCR reductions with eGFR stabilization at a rate of decline similar to the general population without kidney disease through 96 wk, suggesting atacicept offers a potentially safe, long-term, disease-modifying treatment for IgAN. Herein, we report the changes in Gd-IgA1 and eGFR during the 26-wk follow-up period after atacicept discontinuation. Method The randomized, double-blind, placebo-controlled Phase 2b ORIGIN study included 116 participants with biopsy-proven IgAN, 24 h urine protein >0.75 g/day or UPCR >0.75 g/g, and eGFR ≥30 mL/min/1.73 m2 despite optimized renin–angiotensin system blockade. Participants were randomized to atacicept or placebo QW for up to 36 wk. The double-blind, randomized treatment period was followed by an OLE in which participants received atacicept 150 mg QW for up to 60 wk, for a total of up to 96 wk of treatment. Participants were subsequently followed for a 26-wk follow-up period after completing atacicept treatment, with evaluations at 12 and 26 wk post-treatment. During this follow-up period, routine hematology, chemistry, and Gd-IgA1 levels were collected and analyzed; no urine samples were collected. This analysis includes participants treated with atacicept who had a last on-treatment Gd-IgA1 or eGFR value in the study wk 96 analysis window and ≥1 measure in the follow-up period, with the study wk 96 values reset as the new baseline and analyzed along with the follow-up 12 and 26 wk data. Gd-IgA1 and eGFR changes were analyzed using a MMRM model. Results There were 103 participants who received ≥1 atacicept dose for ≥60 wk and remained in the follow-up study period. Following completion of atacicept treatment, increases in serum Gd-IgA1 were observed at wk 12 and 26 of +90% and +117% respectively. In addition, changes in eGFR at wk 12 and 26 were −1.6 and −3.9 ml/min/1.73 m2, respectively. (Fig. 1) Conclusion IgAN is a chronic and progressive disease of B-cell origin, in which cytokines BAFF and APRIL are sustaining factors in its pathophysiology. Treatment with atacicept, a precision B-cell modulator inhibiting both BAFF and APRIL, demonstrated significant and sustained reductions in Gd-IgA1, improvements in hematuria, and reductions in UPCR, along with stabilization of eGFR over 96 wk. Following discontinuation of atacicept, an increase in Gd-IgA1 and decline in eGFR were observed, consistent with the typical clinical progression of IgAN in high-risk patients despite standard-of-care treatments. In light of these findings, participants may enroll in a new OLE study (ORIGIN Extend), which will provide insights into the effects of atacicept treatment reinitiation. The rapid impact on key markers of kidney function decline and disease progression after atacicept discontinuation underscores the potential therapeutic benefit of atacicept and supports the paradigm of sustained treatment with atacicept in IgAN patients.

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