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

Nephrology Dialysis Transplantation, vol. 40

Abstract

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.

Authors 11

1. Richard A. Lafayette

   Stanford Medicine · Stanford University

   Affiliation as printed

   Glomerular Disease Center, Stanford University, Stanford, CA, USA

2. Bart Maes

   AZ Delta

   Affiliation as printed

   AZ Delta, Roeselare, Belgium

3. Zeeshan Khawaja

   Brisbane City Council

   Affiliation as printed

   Vera Therapeutics, Inc., Brisbane, CA, USA

4. Jürgen Floege Aachen

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Rheinisch-Westfälische Technische Hochschule, Aachen University Hospital, Aachen, Germany

5. Vivekanand Jha

   Manipal Academy of Higher Education · George Institute for Global Health · Imperial College London

   Affiliation as printed

   Prasanna School of Public Health, Manipal Academy of Higher Education, Manipal, India

   School of Public Health, Imperial College, London, UK

   The George Institute for Global Health India, Delhi, India

6. Vladimı́r Tesař

   Charles University

   Affiliation as printed

   General University Hospital, Charles University, Prague, Czech Republic

7. Hong Zhang

   Peking University First Hospital

   Affiliation as printed

   Peking University First Hospital, Peking, P.R. China Department of Medicine,

8. Sean J. Barbour

   University of British Columbia

   Affiliation as printed

   The University of British Columbia, Vancouver, Canada

9. Hitoshi Suzuki

   Juntendo University Urayasu Hospital

   Affiliation as printed

   Juntendo University Urayasu Hospital, Chiba, Japan Department of Nephrology,

10. Hernán Trimarchi

    Hospital Británico de Buenos Aires

    Affiliation as printed

    Hospital Británico de Buenos Aires, Buenos Aires, Argentina

11. Jonathan Barratt

    University of Leicester

    Affiliation as printed

    College of Medicine Biological Sciences and Psychology, University of Leicester, Leicester, UK