INTRODUCTION: IgA nephropathy is the most common primary glomerulonephritis and a leading cause of kidney failure worldwide. Treatments that target the underlying immune drivers of the disease to improve long-term patient outcomes are needed. Sibeprenlimab, a selective A Proliferation-Inducing Ligand (APRIL) inhibitor that significantly decreases pathogenic galactose-deficient IgA1 (Gd-IgA1) production and immune complex formation, is being investigated in the ongoing phase 3 VISIONARY trial. Here, we summarize the overall study design and report on the baseline characteristics of patients enrolled in the trial. METHODS: VISIONARY is a multicenter, double-blind, placebo-controlled trial (ClinicalTrials.gov identifier, NCT05248646; study date of registration: 2022-02-18). Adults with biopsy-confirmed IgA nephropathy were randomized 1:1 to receive subcutaneous (s.c.) sibeprenlimab 400 mg or placebo once every 4 weeks for 26 doses. The primary end point is the 24-hour urine protein-to-creatinine ratio (uPCR-24 h) at 9 months compared with the baseline. RESULTS: Of 510 enrolled patients across 31 countries, 58.8% were male, 59.0% were Asian, and 57.3% lived in East or South/Southeast Asia. The median age was 42.0 (range, 18.0-83.0) years; 97.8% of patients were using renin-angiotensin system inhibitors (RASis), and 45.1% were using sodium-glucose cotransporter 2 inhibitors. The mean (SD) baseline uPCR-24 h was 1.54 (0.92) g/g. The mean (SD) baseline urine protein was 2.1 (1.3) g/d, and the mean (SD) baseline estimated glomerular filtration rate (eGFR) was 64.2 (25.3) ml/min per 1.73 m2. CONCLUSION: VISIONARY, the largest IgA nephropathy trial to date, is evaluating the efficacy and safety of s.c. sibeprenlimab in a broadly representative population with IgA nephropathy at high risk of disease progression.

Charles University Prague Czechia

Concord Repatriation General Hospital Concord New South Wales Australia

Hospital Británico Buenos Aires Argentina

Juntendo University Faculty of Medicine Tokyo Japan

KJC Statistics Ltd Cheadle UK

Mount Elizabeth Novena Hospital Singapore

Otsuka Princeton New Jersey USA

Peking University 1st Hospital Beijing China

Stanford University Medical Center Stanford California USA

University Hospitals of Leicester Leicester UK

University of Alabama at Birmingham Birmingham Alabama USA

University of Leicester Leicester UK

University of New South Wales Sydney New South Wales Australia

Zobrazit více v PubMed

Caster D.J., Abner C.W., Walker P.D., et al. Clinicopathological characteristics of adult IgA nephropathy in the United States. Kidney Int Rep. 2023;8:1792–1800. doi: 10.1016/j.ekir.2023.06.016. PubMed DOI PMC

Hastings M.C., Bursac Z., Julian B.A., et al. Life expectancy for patients from the southeastern United States with IgA nephropathy. Kidney Int Rep. 2018;3:99–104. doi: 10.1016/j.ekir.2017.08.008. PubMed DOI PMC

Knoppova B., Reily C., Maillard N., et al. The origin and activities of IgA1-containing immune complexes in IgA nephropathy. Front Immunol. 2016;7:117. doi: 10.3389/fimmu.2016.00117. PubMed DOI PMC

Pitcher D., Braddon F., Hendry B., et al. Long-term outcomes in IgA nephropathy. Clin J Am Soc Nephrol. 2023;18:727–738. doi: 10.2215/CJN.0000000000000135. PubMed DOI PMC

Selewski D.T., Ambruzs J.M., Appel G.B., et al. Clinical characteristics and treatment patterns of children and adults with IgA nephropathy or IgA vasculitis: findings from the CureGN study. Kidney Int Rep. 2018;3:1373–1384. doi: 10.1016/j.ekir.2018.07.021. PubMed DOI PMC

Zhang X., Shi S., Ouyang Y., et al. A validation study of crescents in predicting ESRD in patients with IgA nephropathy. J Transl Med. 2018;16:115. doi: 10.1186/s12967-018-1488-5. PubMed DOI PMC

O'Shaughnessy M.M., Hogan S.L., Thompson B.D., et al. Glomerular disease frequencies by race, sex and region: results from the International Kidney Biopsy Survey. Nephrol Dial Transplant. 2018;33:661–669. doi: 10.1093/ndt/gfx189. PubMed DOI PMC

Lee M., Suzuki H., Nihei Y., Matsuzaki K., Suzuki Y. Ethnicity and IgA nephropathy: worldwide differences in epidemiology, timing of diagnosis, clinical manifestations, management and prognosis. Clin Kidney J. 2023;16(Suppl 2):ii1–ii8. doi: 10.1093/ckj/sfad199. PubMed DOI PMC

Magistroni R., D’Agati V.D., Appel G.B., Kiryluk K. New developments in the genetics, pathogenesis, and therapy of IgA nephropathy. Kidney Int. 2015;88:974–989. doi: 10.1038/ki.2015.252. PubMed DOI PMC

Yeo S.C., Goh S.M., Barratt J. Is immunoglobulin A nephropathy different in different ethnic populations? Nephrology (Carlton) 2019;24:885–895. doi: 10.1111/nep.13592. PubMed DOI

Feehally J., Cameron J.S. IgA nephropathy: progress before and since Berger. Am J Kidney Dis. 2011;58:310–319. doi: 10.1053/j.ajkd.2011.03.024. PubMed DOI

Floege J., Moura I.C., Daha M.R. New insights into the pathogenesis of IgA nephropathy. Semin Immunopathol. 2014;36:431–442. doi: 10.1007/s00281-013-0411-7. PubMed DOI

Gutiérrez E., Praga M., Rivera F., et al. Changes in the clinical presentation of immunoglobulin A nephropathy: data from the Spanish Registry of glomerulonephritis. Nephrol Dial Transplant. 2018;33:472–477. doi: 10.1093/ndt/gfx058. PubMed DOI

Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group KDIGO 2021 clinical practice guideline for the management of glomerular diseases. Kidney Int. 2021;100:S1–S276. doi: 10.1016/j.kint.2021.05.021. PubMed DOI

Lim R.S., Yeo S.C., Barratt J., Rizk D.V. An update on current therapeutic options in IgA nephropathy. J Clin Med. 2024;13:947. doi: 10.3390/jcm13040947. PubMed DOI PMC

Bagchi S., Mani K., Swamy A., et al. Supportive management of IgA nephropathy with renin-angiotensin blockade, the AIIMS Primary IgA Nephropathy Cohort (APPROACH) study. Kidney Int Rep. 2021;6:1661–1668. doi: 10.1016/j.ekir.2021.02.018. PubMed DOI PMC

Knoppova B., Reily C., King R.G., Julian B.A., Novak J., Green T.J. Pathogenesis of IgA nephropathy: current understanding and implications for development of disease-specific treatment. J Clin Med. 2021;10:4501. doi: 10.3390/jcm10194501. PubMed DOI PMC

Suzuki H., Kiryluk K., Novak J., et al. The pathophysiology of IgA nephropathy. J Am Soc Nephrol. 2011;22:1795–1803. doi: 10.1681/ASN.2011050464. PubMed DOI PMC

Cheung C.K., Barratt J., Liew A., Zhang H., Tesar V., Lafayette R. The role of BAFF and APRIL in IgA nephropathy: pathogenic mechanisms and targeted therapies. Front Nephrol. 2024;3 doi: 10.3389/fneph.2023.1346769. PubMed DOI PMC

Gutiérrez E., Carvaca-Fontán F., Luzardo L., Morales E., Alonso M., Praga M. A personalized update on IgA nephropathy: a new vision and new future challenges. Nephron. 2020;144:555–571. doi: 10.1159/000509997. PubMed DOI

Mathur M., Chan T.M., Oh K.H., et al. A PRoliferation-Inducing Ligand (APRIL) in the pathogenesis of immunoglobulin A nephropathy: a review of the evidence. J Clin Med. 2023;12:6927. doi: 10.3390/jcm12216927. PubMed DOI PMC

Muto M., Suzuki H., Suzuki Y. New insights and future perspectives of APRIL in IgA nephropathy. Int J Mol Sci. 2024;25 doi: 10.3390/ijms251910340. PubMed DOI PMC

Yeo S.C., Barratt J. The contribution of a proliferation-inducing ligand (APRIL) and other TNF superfamily members in pathogenesis and progression of IgA nephropathy. Clin Kidney J. 2023;16(Suppl 2):ii9–ii18. doi: 10.1093/ckj/sfad200. PubMed DOI PMC

Kiryluk K., Sanchez-Rodriguez E., Zhou X.J., et al. Genome-wide association analyses define pathogenic signaling pathways and prioritize drug targets for IgA nephropathy. Nat Genet. 2023;55:1091–1105. doi: 10.1038/s41588-023-01422-x. PubMed DOI PMC

Yu X.Q., Li M., Zhang H., et al. A genome-wide association study in Han Chinese identifies multiple susceptibility loci for IgA nephropathy. Nat Genet. 2011;44:178–182. doi: 10.1038/ng.1047. PubMed DOI

Mathur M., Barratt J., Suzuki Y., et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of VIS649 (sibeprenlimab), an APRIL-neutralizing IgG2 monoclonal antibody, in healthy volunteers. Kidney Int Rep. 2022;7:993–1003. doi: 10.1016/j.ekir.2022.01.1073. PubMed DOI PMC

Myette J.R., Kano T., Suzuki H., et al. A Proliferation Inducing Ligand (APRIL) targeted antibody is a safe and effective treatment of murine IgA nephropathy. Kidney Int. 2019;96:104–116. doi: 10.1016/j.kint.2019.01.031. PubMed DOI

Mathur M., Barratt J., Chacko B., et al. A phase 2 trial of sibeprenlimab in patients with IgA nephropathy. N Engl J Med. 2024;390:20–31. doi: 10.1056/NEJMoa2305635. PubMed DOI PMC

Inker L.A., Mondal H., Greene T., et al. Early change in urine protein as a surrogate end point in studies of IgA nephropathy: an individual-patient meta-analysis. Am J Kidney Dis. 2016;68:392–401. doi: 10.1053/j.ajkd.2016.02.042. PubMed DOI

Thompson A., Carroll K., Inker L.A., et al. Proteinuria reduction as a surrogate end point in trials of IgA nephropathy. Clin J Am Soc Nephrol. 2019;14:469–481. doi: 10.2215/CJN.08600718. PubMed DOI PMC

VISIONARY study: phase 3 trial of sibeprenlimab in immunoglobulin A nephropathy (lgAN) Updated July 10, 2025. https://clinicaltrials.gov/study/NCT05248646 ClinicalTrials.gov identifier: NCT05248646.

Zhang X., Wang Y., Yarbrough J., et al. Safety, pharmacokinetics, and pharmacodynamics of subcutaneous sibeprenlimab in healthy participants. Clin Pharmacol Drug Dev. 2023;12:1211–1220.3. doi: 10.1002/cpdd.1316. PubMed DOI

Barratt J., Rovin B., Wong M.G., et al. IgA nephropathy patient baseline characteristics in the sparsentan PROTECT study. Kidney Int Rep. 2023;8:1043–1056. doi: 10.1016/j.ekir.2023.02.1086. PubMed DOI PMC

Heerspink H.J.L., Jardine M., Kohan D.E., et al. Study design and baseline characteristics of ALIGN, a randomized controlled study of atrasentan in patients with IgA nephropathy. Kidney Int Rep. 2025;10:217–226. doi: 10.1016/j.ekir.2024.10.004. PubMed DOI PMC

Phase 2/3 open-label trial of sibeprenlimab in the treatment of immunoglobulin A nephropathy; Last updated 2024. Updated December 9, 2024. https://clinicaltrials.gov/study/NCT05248659 ClinicalTrials.gov identifier: NCT05248659.

Barratt J., Lafayette R., Kristensen J., et al. Results from part A of the multi-center, double-blind, randomized, placebo-controlled NefIgArd trial, which evaluated targeted-release formulation of budesonide for the treatment of primary immunoglobulin A nephropathy. Kidney Int. 2023;103:391–402. doi: 10.1016/j.kint.2022.09.017. PubMed DOI

Perkovic V., Barratt J., Rovin B., et al. Alternative complement pathway inhibition with iptacopan in IgA nephropathy. N Engl J Med. 2025;392:531–543. doi: 10.1056/NEJMoa2410316. PubMed DOI

Rauen T., Eitner F., Fitzner C., et al. Intensive supportive care plus immunosuppression in IgA nephropathy. N Engl J Med. 2015;373:2225–2236. doi: 10.1056/NEJMoa1415463. PubMed DOI

Lv J., Wong M.G., Hladunewich M.A., et al. Effect of oral methylprednisolone decline in kidney function or kidney failure in patients with IgA nephropathy: the TESTING randomized clinical trial. JAMA. 2022;327:1888–1898. doi: 10.1001/jama.2022.5368. PubMed DOI PMC

EMPA-KIDNEY Collaborative Group Impact of primary kidney disease on the effects of empagliflozin in patients with chronic kidney disease: secondary analyses of the EMPA-KIDNEY trial. Lancet Diabetes Endocrinol. 2024;12:51–60. doi: 10.1016/S2213-8587(23)00322-4. PubMed DOI PMC

Wheeler D.C., Toto R.D., Stefansson B.V., et al. A pre-specified analysis of the DAPA-CKD trial demonstrates the effects of dapagliflozin on major adverse kidney events in patients with IgA nephropathy. Kidney Int. 2021;100:215–224. doi: 10.1016/j.kint.2021.03.033. PubMed DOI

Zobrazit více v PubMed

ClinicalTrials.gov
NCT05248646