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IgA nephropathy (IgAN) is the most common primary glomerulonephritis and a significant contributor to ESKD worldwide. Hematuria is an indicator of IgAN activity representing active glomerulonephritis and resolution is associated with improved renal outcomes. IgAN is characterized by elevated serum levels of galactose-deficient IgA1 (Gd-IgA1). High Gd-IgA1 levels are associated with greater risk of renal function deterioration, ESKD, and death, and Gd-IgA1 reduction has been correlated with hematuria remission. Gd-IgA1 production is driven by the B-cell activating factor (BAFF)–A PRoliferation-Inducing Ligand (APRIL) signaling pathway, and atacicept is a dual anti-BAFF/APRIL fusion protein in clinical development for IgAN. The Phase 2b ORIGIN study met the primary endpoint with statistically significant UPCR reduction at 24 weeks for atacicept vs placebo. At 36 weeks, atacicept 150 mg achieved statistically and clinically meaningful UPCR reduction, eGFR stabilization, and Gd-IgA1 reduction vs placebo. This analysis evaluates changes in hematuria and serum Gd-IgA1 quartiles with atacicept 150 mg vs placebo over 36 weeks.
The randomized, double-blind, placebo-controlled Phase 2b ORIGIN study included 116 participants with biopsy-proven IgAN, 24h urine protein >0.75 g/day or UPCR >0.75 g/g, and eGFR ≥30 mL/min/1.73m2 despite optimized renin–angiotensin system blockade. Participants were randomized to atacicept 150, 75, or 25 mg, self-administered by subcutaneous injection once weekly vs placebo (2:2:1:2) for up to 36 weeks. Microscopic hematuria was evaluated on urine dipstick and participants with hematuria grade 1+ or higher at baseline were evaluated for improvement at 36 wk. Gd-IgA1 values assessed at baseline and weeks 4, 12, 24, and 36 were classified into quartiles using cutoffs derived from baseline Gd-IgA1 values. The relationship between Gd-IgA1 % change from baseline and hematuria grade at 36 weeks was evaluated with Spearman’s correlation method.
33 participants received atacicept 150 mg and 34 received placebo in the intent-to-treat population. Hematuria improved for more participants on atacicept than placebo, with 80% on atacicept 150 mg achieving resolution vs 5% on placebo. Atacicept 150 mg led to steady Gd-IgA1 reduction to the lowest quartile 1 at 36 weeks in 27/33 (82%) participants while most on placebo transiently increased or decreased by 1 quartile. All 8 participants on atacicept 150 mg with the highest baseline quartile 4 had reductions to quartile 1 or 2 at their last visits; all 9 participants on placebo with baseline quartile 4 remained in quartile 3 or 4 at their last visits. Gd-IgA1 reduction was correlated with lower hematuria at 36 weeks (r=0.35; p=0.0003).
In addition to clinically and statistically significant effects on renal function, atacicept 150 mg achieved improvement in hematuria and durable and significant Gd-IgA1 reduction over 36 weeks. Gd-IgA1 reduction correlated with lower hematuria at 36 weeks. These results support atacicept 150 mg as a potential disease-modifying treatment for patients with IgA nephropathy.
This abstract was presented at ASN Kidney Week 2023. By submitting the abstract to WCN’24, abstract authors declare that re-submitting the abstract is permitted by the organizers of the previous meeting.