ORIGIN: 24-Week Results of Phase 2b Trial of Atacicept in Patients With IgAN

Worldwide, immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis. Central in the pathogenesis of IgAN are galactose-deficient IgA1 (GD-IgA1), anti-GD-IgA1 autoantibodies (anti-Gd-IgA1), and IgA-IgA-containing immune complexes (ICs), all contributing to kidney damage. The phase 2a JANUS trial (NCT02808429) evaluating the safety and efficacy of atacicept in patients with IgAN demonstrated the potential of targeting the disease-causing species.

During a late-breaking session at the ERA 60th Congress, Richard Lafayette, MD, and colleagues presented preliminary results of the phase 2b ORIGIN trial (NCT04716231) in a presentation titled ORIGIN Trial: 24-wk Primary Analysis of a Randomized, Double-Blind, Placebo-Controlled PH2B Study of Atacicept in Patients With IgAN. Atacicept is a fusion protein that binds B-lymphocyte stimulator and a proliferation inducing ligand to inhibit maturation and class-switching of B-cells and plasma cells.

The ORIGIN cohort includes 116 patients with biopsy-proven IgAN, 24-hour urine protein >0.75 g per day or urine protein-to-creatinine ratio (UPCR) >0.75 g/g, and estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m² despite treatment with optimized renin-angiotensin system blockade. Patients were randomized to atacicept 150 mg, 75 mg, or 25 mg administered via subcutaneous injection once per week versus placebo (2:2:1:2) for up to 36 weeks. The primary end point was the change in 24-hour UPCR at 24 weeks in the pooled atacicept 150 mg and 75 mg arms compared with placebo.

Of the 116 patients in the intent-to-treat (ITT) population, 33, 33, and 16 received atacicept 150, 75, and 25 mg, respectively, and 34 received placebo. In the pooled 75 and 150 mg atacicept arms, mean UPCR at 24 weeks was reduced from baseline by 31% compared with a 7% reduction from baseline in the placebo arm. Results of the ITT analysis are supported by a prespecified per-protocol analysis: the atacicept 150 mg arm showed a 41% reduction from baseline in UPCR at 24 weeks compared with a 10% reduction in the placebo arm.

For the secondary outcome, eGFR showed stability at week 24 in the atacicept 150 mg arm. Safety results demonstrated that atacicept was generally well tolerated, with no increased rates of infection compared with placebo and a low rate (2%) of serious adverse events overall, with no serious adverse events in the atacicept 150 mg arm.

“The ORIGIN Ph2b study met its primary end point, demonstrating a favorable impact on disease biomarkers and a clinically meaningful reduction in proteinuria and demonstrated a favorable safety profile,” the researchers said. “These promising results at Week 24 support atacicept 150 mg for further evaluation as a potential disease modifying treatment of patients with IgA nephropathy.”

Source: Lafayette R, Maes B, Lin C, et al. ORIGIN trial:24-wk primary analysis of a randomized, double-blind, placebo-controlled ph2b study of atacicept in patients with IgAN. Presentation #3848. Abstract of a presentation at the European Renal Association 60th Congress; June 15-18, 2023; Milan, Italy. ORIGIN is supported by Vera Therapeutics, Inc.