A Phase 3 Trial of Atacicept in Patients with IgA Nephropathy
In a prespecified interim analysis of the phase 3 ORIGIN 3 trial, the dual BAFF/APRIL inhibitor atacicept produced a markedly greater reduction in proteinuria than placebo at week 36 in patients with IgA nephropathy, with most adverse events mild or moderate.
Background
IgA nephropathy is the most common primary glomerulopathy worldwide and a B-cell-mediated disease in which at least 50% of patients progress to kidney failure or death within 10 to 20 years. Atacicept is a TACI-Fc fusion protein that inhibits BAFF (B-cell activating factor) and APRIL (a proliferation-inducing ligand), two cytokines thought central to the production of pathogenic galactose-deficient IgA1 driving the disease.
Study design
ORIGIN 3 is an ongoing phase 3, multicenter, double-blind, randomized, placebo-controlled trial that assigned patients with biopsy-proven IgA nephropathy 1:1 to atacicept 150 mg once weekly, self-administered subcutaneously at home, or matching placebo. The primary endpoint was the percentage change from baseline in the 24-hour urinary protein-to-creatinine ratio at week 36, with safety also evaluated. A total of 203 patients (106 atacicept, 97 placebo) were included in the prespecified interim analysis.
Key findings
At week 36, the urinary protein-to-creatinine ratio fell by 45.7% in the atacicept group versus 6.8% in the placebo group, a geometric mean between-group difference of 41.8 percentage points (95% CI 28.9 to 52.3; P<0.001). Adverse events occurred in 59.3% of atacicept patients and 50.0% of placebo patients, most of which were mild or moderate in severity. The proteinuria reduction is consistent with the disease-modifying signals seen in earlier ORIGIN phase 2 data.
Clinical implications
These interim phase 3 results support atacicept as a potential disease-modifying treatment for IgA nephropathy, achieving a clinically meaningful reduction in proteinuria, a validated surrogate for progression, on top of standard renin-angiotensin system blockade. Longer-term data on eGFR preservation from the ongoing trial will be needed to confirm durable kidney protection.
Category
Research
Source
The New England Journal of Medicine
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