Atacicept Reduces Proteinuria by 46% in Phase 3 IgA Nephropathy Trial, ORIGIN 3 Study Shows
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A major phase 3 clinical trial published in the New England Journal of Medicine found that atacicept, a dual BAFF/APRIL inhibitor, reduced proteinuria by 46% in patients with IgA nephropathy after 36 weeks of treatment, compared to only 4% in the placebo group. The ORIGIN 3 trial, conducted across 157 sites in 31 countries, also showed that atacicept nearly eliminated the galactose-deficient IgA1 antibodies that drive kidney damage in this disease. For patients with IgA nephropathy, these results represent a significant step toward treating the root immunological cause of the disease rather than just its downstream effects on the kidneys.
Abstract
IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide and a leading cause of end-stage kidney disease. Its pathogenesis involves elevated levels of galactose-deficient IgA1 (Gd-IgA1), which trigger an autoimmune cascade leading to complement activation and progressive kidney injury. Atacicept is a fusion protein that simultaneously inhibits two key cytokines driving IgA production: B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL).
ORIGIN 3 was a multicenter, double-blind, randomized, placebo-controlled phase 3 trial enrolling 431 adults with IgA nephropathy from 157 sites across 31 countries. Patients were randomized 1:1 to receive atacicept 150 mg or matching placebo by once-weekly subcutaneous self-injection. The primary endpoint was change from baseline in 24-hour urine protein-to-creatinine ratio (UPCR) at week 36.
Atacicept reduced UPCR by 46% from baseline, achieving a statistically significant and clinically meaningful 42% reduction compared to placebo (P less than 0.0001). Gd-IgA1 levels fell by 68.3% in the atacicept group versus 2.9% in the placebo group. Among patients with baseline hematuria, 81% in the atacicept group achieved resolution versus 20.7% in the placebo group. Serious adverse events were notably lower in the atacicept arm (0.5%) compared to placebo (5.1%), and the drug was well tolerated overall.