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Abstract Background and Aims IgA nephropathy (IgAN), the most common primary glomerulonephritis and a significant contributor to ESKD worldwide, is characterized by elevated serum levels of galactose-deficient IgA1 (Gd-IgA1). The production of Gd-IgA1 and its autoantibodies is driven by both the B-cell Activating Factor (BAFF) and A PRoliferation-Inducing Ligand (APRIL) signaling pathways that stimulate maturation, differentiation, and effector function of B cells and plasma cells. Atacicept is a fusion protein targeting both BAFF and APRIL in clinical development for IgAN treatment. The Phase 2b ORIGIN study met the primary endpoint with statistically significant urine protein:creatinine ratio (UPCR) reduction at 24 weeks vs placebo. At 36 weeks, atacicept 150 mg achieved statistically significant and clinically meaningful UPCR reduction, eGFR stabilization, and Gd-IgA1 reduction vs placebo, with similar safety to placebo. This interim analysis reports 72-week results from the open-label extension period. Method The randomized, double-blind, placebo-controlled Phase 2b ORIGIN study included 116 participants with biopsy-proven IgAN, 24 h urine protein 0.75 g/day or UPCR 0.75 g/g, and eGFR ≥30 mL/min/1.73 m2 despite optimized renin–angiotensin system blockade. Participants were randomized to atacicept 150, 75, or 25 mg, vs placebo (2:2:1:2), self-administered by subcutaneous injection once weekly for up to 36 weeks. The double-blind randomized treatment period was followed by an open-label extension in which participants could receive atacicept 150 mg for up to 60 additional weeks, for a total of 96 weeks. For this interim analysis, changes from baseline in eGFR, natural log transformed UPCR, and Gd-IgA1 through 72 weeks were analyzed using a mixed-effects model for repeated measurements. Microscopic hematuria was evaluated on urine dipstick and participants with hematuria grade 1+ or higher at baseline were evaluated for resolution, defined as a decrease to negative/trace, at 72 weeks. Results Of 116 randomized participants in the double-blind period, 106 participants (91%) completed 72 weeks of treatment. At 72 weeks, eGFR total slope estimate was 0.0 mL/min/1.73m2/year and eGFR change from baseline was 0 mL/min/1.73m2 in all participants originally randomized to atacicept (all-atacicept group; n = 82). After switching to open-label atacicept 150 mg, the original placebo group showed eGFR stabilization with −3.2 mL/min/1.73m2 change from baseline at 72 weeks vs −4.9 mL/min/1.73m2 at 36 weeks (Figure 1). At 72 weeks, UPCR change from baseline was −45% in the all-atacicept group and the placebo switch group showed a −47% UPCR change from baseline at 72 weeks vs +3% at 36 weeks (Figure 2). Open-label atacicept 150 mg was also associated with rapid Gd-IgA1 reduction in the placebo switch group at 48 weeks that was sustained through 72 weeks. Hematuria resolution was observed at 72 weeks in 81% (35/43) of participants in the all-atacicept group and 59% (10/17) in the placebo switch group. Atacicept was generally well tolerated during the open-label extension, with a similar rate of infections compared to the double-blind period and one study drug-related serious adverse event. Conclusion At 72 weeks, treatment with atacicept 150 mg was associated with sustained eGFR stability and deepening UPCR reductions, as well as a reversal of the downward eGFR decline in the placebo switch group. Sustained reductions in hematuria were also observed. The open-label extension showed a favorable safety profile similar to the double-blind period. These results support atacicept 150 mg as a potential disease-modifying treatment for IgAN.
Lafayette et al. (Wed,) studied this question.