KEY POINTS: Participants who completed a 36-week double-blind study of atacicept were eligible for a 60-week, open-label extension study. Atacicept 96-week treatment resulted in sustained reductions in galactose-deficient IgA1, hematuria, and urine protein-creatinine ratio. The slope of the eGFR was similar to that observed in the general population without kidney disease. BACKGROUND: B-cell activating factor (BAFF) and A proliferation-inducing ligand (APRIL) play key roles in the pathogenesis of IgA nephropathy. Atacicept is a novel fully humanized fusion protein, self-administered at home by subcutaneous injection, that binds and inhibits BAFF and APRIL. By inhibiting BAFF and APRIL, atacicept targets the underlying B-cell–mediated pathogenesis driving disease progression. This study evaluated the long-term efficacy and safety of atacicept in patients with IgA nephropathy over 96 weeks. METHODS: Participants with IgA nephropathy who received atacicept (25, 75, or 150 mg) or placebo in a 36-week phase 2b, randomized, blinded trial were enrolled in an open-label extension study and received atacicept 150 mg for an additional 60 weeks. Key efficacy outcomes were changes in galactose-deficient IgA1 (Gd-IgA1), percentage of participants with hematuria, urine protein-creatinine ratio (UPCR), and eGFR over 96 weeks. Long-term safety data were also evaluated. RESULTS: There were 113 participants (67 [59%] male; 46 [41%] female) who ranged in age from 18 to 67 years who received ≥1 atacicept dose. Over 96 weeks, safety data demonstrated that atacicept was generally well tolerated. There were also sustained reductions (mean±SEM) in Gd-IgA1 (−66%±2%), percentage of participants with hematuria (−75%; 95% confidence intervals, −87 to −59; in participants with baseline hematuria), and UPCR (−52%±5%). The mean annualized slope of eGFR was −0.6±0.5 ml/min per 1.73 m2 through 96 weeks. CONCLUSIONS: Atacicept was well tolerated over the duration of the study. Atacicept treatment reduced Gd-IgA1, hematuria, and UPCR with stabilization of eGFR through 96 weeks. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER:: Atacicept in Subjects with IgA Nephropathy (ORIGIN 2), NCT04716231. PODCAST: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2024_10_26_KTS_October2024.mp3

AZ Delta Roeselare Belgium

College of Medicine Biological Sciences and Psychology University of Leicester Leicester United Kingdom

Department of Nephrology Faculty of Medicine Kocaeli University Kocaeli Turkey

Department of Renal Medicine Westmead Hospital Sydney New South Wales Australia

Division of Nephrology Department of Internal Medicine Hallym University Sacred Heart Hospital Anyang South Korea

Division of Nephrology The University of British Columbia Vancouver British Columbia Canada

Faculty of Medicine and Health The University of Sydney Sydney New South Wales Australia

General University Hospital Charles University Prague Czech Republic

Glomerular Disease Center Stanford University Stanford California

Prasanna School of Public Health Manipal Academy of Higher Education Manipal India

Rheinisch Westfälische Technische Hochschule Aachen University Hospital Aachen Germany

School of Public Health Imperial College London United Kingdom

The George Institute for Global Health India UNSW New Delhi India

Vera Therapeutics Inc Brisbane California

Western Nephrology P C Arvada Colorado

doi: 10.1681/ASN.0000000551 PubMed

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NCT04716231