ORIGIN Study of Atacicept for IgA Nephropathy

The phase 2b ORIGIN study compared randomized groups of patients with IgA nephropathy (IgAN) receiving either atacicept or placebo. Richard Lafayette and others shared interim analysis results at the 61st European Renal Association Congress.

Atacicept targets B-cell activating factor and a proliferation-inducing ligand (APRIL), both of which drive production of galactose-deficient IgA1 (Gd-IgA1) and its antibodies. Elevated Gd-IgA1 is the hallmark of IgAN.

ORIGIN included 116 participants with 24-hour urine protein >0.75 g/day or urine protein-to-creatine ratio (UPCR) >0.75 g/g and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m² despite optimized treatment with renin-angiotensin system (RAS) blockade. The double-blind study randomized them to receive atacicept 150, 75, or 25 mg versus placebo (2:2:1:2) for up to 36 weeks. During a subsequent open-label extension period, participants could receive atacicept 150 mg for up to 60 additional weeks.

Of the 116 participants, 106 (91%) finished 72 weeks of treatment. At 72 weeks, atacicept achieved statistically significant eGFR stability and reduction in UPCR and Gd-IgA1 compared with placebo.

The eGFR change from baseline at 72 weeks was 0 mL/min/1.73 m² in all participants originally randomized to atacicept (all-atacicept group; n=82). After the placebo group switched to atacicept 150 mg, individuals in that group showed eGFR stabilization with −3.2 mL/min/1.73 m² change from baseline at 72 weeks compared with −4.9 mL/min/1.73 m² at 36 weeks. Atacicept 150 mg was also associated with quick Gd-IgA1 reduction in the group that switched from placebo at 48 weeks, and the reduction was sustained through 72 weeks.

At 72 weeks, UPCR change from baseline was −45% in the all-atacicept group, while the placebo switch group demonstrated a −47% UPCR change from baseline at 72 weeks versus +3% at 36 weeks. Hematuria resolution occurred in 81% (35/43) of participants in the all-atacicept group at 72 weeks and 59% (10/17) in the placebo switch group.

In addition to the clinical benefits observed, atacicept was well-tolerated and demonstrated safety comparable with the placebo.

Source: Lafayette R, Maes R, Israni R, et al. Phase 2b ORIGIN study open label extension with atacicept in patients with IgA nephropathy and persistent proteinuria: week 72 interim analysis. Abstract #812. Presented at the 61st European Renal Association Congress; May 23-26, 2024; Stockholm, Sweden.