#2936 Origin 3 study design: a global, randomized, controlled, Phase 3 study of atacicept in IgA nephropathy
Bibliographic record
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.004 | 0.002 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.005 | 0.002 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.002 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.004 |
| Insufficient payload (model declined to judge) | 0.019 | 0.003 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".