Atacicept Shot Significantly Reduces Proteinuria in IgA Nephropathy: NEJM
USA: A novel self-administered drug, Atacicept, which inhibits two key immunoregulatory cytokines, showed a 45.7% reduction in proteinuria among patients with IgA nephropathy in the phase III ORIGIN 3 trial, compared to only a 6.8% reduction with placebo by week 36. The effect was clinically meaningful and consistent across subgroups.
Adverse events were mostly mild or moderate, reported in 59.3% of the atacicept group and 50% of the placebo group. Results were published in the New England Journal of Medicine and presented at the American Society of Nephrology Kidney Week meeting.
IgA nephropathy, the most common form of primary glomerulopathy globally, is a kidney disease caused by the deposition of IgA-containing immune complexes in the glomeruli. Originating from B-cell dysfunction, the condition progressively damages the kidneys, with nearly half of the affected individuals developing kidney failure or facing mortality within two decades of diagnosis.
Atacicept, developed to target the underlying disease mechanism, is a fully human fusion protein that binds and neutralizes two B-cell survival factors—B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL). Both these cytokines play a central role in driving the abnormal immune activity that leads to the buildup of IgA complexes in kidney tissues.
In the ongoing phase III, multicenter, double-blind, randomized, placebo-controlled ORIGIN 3 trial, researchers enrolled patients with biopsy-confirmed IgA nephropathy. Participants were randomly assigned in a 1:1 ratio to receive either weekly subcutaneous injections of atacicept (150 mg) for self-administration at home or a matching placebo. The primary endpoint was the percentage change from baseline in the 24-hour urinary protein-to-creatinine ratio (UPCR) at week 36, a key marker of kidney function. Safety and tolerability were also assessed throughout the study.
Key Findings:
- The interim analysis involved 203 patients, with 106 receiving atacicept and 97 assigned to placebo.
- At week 36, patients treated with atacicept showed a 45.7% reduction in urinary protein-to-creatinine ratio (UPCR) from baseline.
- The placebo group demonstrated only a 6.8% reduction in UPCR during the same period.
- The adjusted geometric mean difference between the two groups was 41.8 percentage points.
- The reduction in proteinuria with atacicept was statistically significant and clinically meaningful.
- Adverse events were reported in 59.3% of patients in the atacicept arm and 50% in the placebo arm.
- Most adverse events were mild or moderate in nature.
- The therapy was generally well-tolerated, with no unexpected safety issues identified during the interim analysis.
The investigators concluded that atacicept offers a promising new therapeutic approach for IgA nephropathy by addressing the disease’s root immunologic drivers rather than only managing symptoms. The trial results highlight its potential to slow disease progression and preserve kidney function in patients with limited existing treatment options. Further data from the ongoing study will provide additional insights into the long-term efficacy and safety of atacicept in this patient population.
Reference:
DOI: 10.1056/NEJMoa2510198
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