#3848 ORIGIN TRIAL: 24-WK PRIMARY ANALYSIS OF A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED PH2B STUDY OF ATACICEPT IN PATIENTS WITH IGAN

Abstract Background and Aims IgA nephropathy (IgAN) is the most common primary glomerulonephritis in the world. Galactose-deficient IgA1 (Gd-IgA1), anti-Gd-IgA1 autoantibodies (anti-Gd-IgA1), and IgA-IgG-containing immune complexes (ICs) are central in the pathogenesis of IgAN, contributing to kidney damage. The potential of targeting these disease-causing species was demonstrated in the Phase 2a JANUS trial (NCT02808429), evaluating the safety and efficacy of atacicept in patients with IgAN. Atacicept is a fusion protein that binds B-lymphocyte stimulator (BlyS) and a proliferation-inducing ligand (APRIL) inhibiting maturation and class-switching of B-cells and plasma cells. In JANUS, patients treated with atacicept 25 mg or 75 mg experienced stabilization of estimated glomerular filtration rate (eGFR) compared with placebo over 72 weeks. Patients in the atacicept arms also experienced dose-dependent reductions in Gd-IgA1, anti-Gd-IgA1 and ICs during the treatment period compared with placebo. The Phase 2b ORIGIN trial (NCT04716231) is a dose-ranging study evaluating atacicept versus placebo in an IgAN population with significant proteinuria. Method ORIGIN is a double-blind, placebo-controlled Phase 2b clinical trial including 116 patients with biopsy-proven IgAN, 24-hour urine protein > 0.75 g per day or urine protein-to-creatinine ratio (UPCR) > 0.75 g/g, and eGFR > 30 mL/min/1.73 m2 despite optimized renin–angiotensin system blockade. Patients were randomized to atacicept 150 mg, 75 mg, or 25 mg, administered by subcutaneous injection once per week versus placebo (2:2:1:2) for up to 36 weeks followed by an open-label extension during which all patients may receive active atacicept 150 mg for an additional 60 weeks. The primary endpoint was the change in 24-hour UPCR at 24 weeks in the pooled atacicept 150 mg and 75 mg arms compared with placebo. Secondary objectives include UPCR at additional time points, the effect of atacicept on change in eGFR, safety and tolerability. Results Between May 2021 and June 2022, 232 patients were screened. Of these, 116 patients were randomized and included in the primary analysis (33, 33, and 16 receiving atacicept 150, 75, and 25 mg, respectively; and 34 receiving placebo) of the intent-to-treat (ITT) population. At 24 weeks, mean UPCR was reduced from baseline by 31% in the pooled atacicept 150 mg and 75 mg arms compared with a 7% reduction from baseline in the placebo (∆ = 25%, p = 0.037). The atacicept 150 mg arm achieved a 33% reduction from baseline at Week 24 and was the only individual treatment arm that showed a statistically significantly greater reduction than placebo (∆ = 28%, p = 0.047). Results of the ITT analysis are supported by a pre-specified per-protocol (PP) analysis (n = 27, 32, and 14 for atacicept 150, 75, and 25 mg, respectively; n = 29 placebo): the atacicept 150 mg arm showed a 41% reduction from baseline in UPCR at 24 weeks compared with a 10% reduction in the placebo arm ((∆ = 34%, p = 0.025). The secondary endpoint, eGFR, showed stability at 24 weeks. Gd-IgA1 reduction of 60% was achieved at Week 24 with atacicept 150 mg. The safety results indicated that atacicept was generally well-tolerated with no increased rate of infections compared to placebo, a low rate (2%) of serious AEs overall with none in the atacicept 150 mg group, and no study drug discontinuation or interruptions due to hypogammaglobulinemia. Conclusion The ORIGIN Ph2b study met its primary endpoint demonstrating a favorable impact on disease biomarkers and a clinically meaningful reduction in proteinuria and demonstrated a favorable safety profile. These promising results at Week 24 support atacicept 150 mg for further evaluation as a potential disease modifying treatment of patients with IgA nephropathy.

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