#2936 Origin 3 study design: a global, randomized, controlled, Phase 3 study of atacicept in IgA nephropathy

Abstract Background and Aims IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide, with up to 50% of patients progressing to end-stage kidney disease or death within 20 years [1, 2]. B-cell Activating Factor (BAFF) and A PRoliferation-Inducing Ligand (APRIL) bind to the TACI receptor on B cells and play key roles in IgAN pathophysiology by fueling B cells to produce both 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 binds BAFF and APRIL with nanomolar binding affinity to modulate the activity of dysregulated B cells and has been shown to reduce circulating levels of Gd-IgA1, anti-Gd-IgA1, and immune complexes. The ORIGIN 2b study evaluated the safety and efficacy of atacicept in patients with biopsy-proven IgAN and met the primary endpoint with a statistically significant and clinically meaningful UPCR reduction at 24 weeks, with deepening efficacy through 36 weeks as compared to placebo. In the open-label extension, atacicept demonstrated further Gd-IgA1 reductions, hematuria improvement, and UPCR reduction with eGFR stabilization at a rate of decline similar to the general population without kidney disease through 96 weeks, suggesting atacicept offers a potentially safe, long-term, disease-modifying treatment for IgAN [3]. Method ORIGIN 3 is a global, randomized, double-blind, placebo-controlled Phase 3 study evaluating safety and efficacy of atacicept 150 mg for treatment of IgAN (Fig. 1). Eligible patients are adults with biopsy-proven IgAN and persistent proteinuria despite stable and maximum-tolerated RASi regimen for ≥12 weeks (see Fig. 1 for key entry criteria). 376 patients globally will be randomized 1:1 to at-home self-administered weekly subcutaneous atacicept 150 mg or placebo for a 104-week double-blind treatment period, followed by a 52-week open-label extension. Results The primary endpoint is UPCR % change from baseline at 36 weeks analyzed using a mixed-effects model with repeated measurement. The key secondary endpoint is eGFR annualized rate of change through 104 weeks. Conclusion This pivotal Phase 3 study has a consistent design, patient population and atacicept dose and subcutaneous formulation with that of the completed ORIGIN Phase 2b study, which demonstrated the efficacy of atacicept in reducing Gd-IgA1, improving hematuria, reducing proteinuria, and stabilizing eGFR. This Phase 3 study will further evaluate atacicept's disease-modifying potential as a treatment for IgAN.