Kidney Week

Abstract: FR-OR59

The Anti-APRIL Antibody Sibeprenlimab Reduces Circulating Immune Complexes in Patients with IgAN: The Phase 2 ENVISION Randomized Controlled Trial

Session Information

• IgA Nephropathy: New Therapies and Insights
  October 25, 2024 | Location: Room 6D, Convention Center
  Abstract Time: 05:50 PM - 06:00 PM

Category: Glomerular Diseases

• 1402 Glomerular Diseases: Clinical, Outcomes, and Therapeutics

Authors

• Barratt, Jonathan, University of Leicester, Leicester, Leicestershire, United Kingdom

Jonathan Barratt, MBChB, PhD

• Mathur, Mohit, Visterra Inc., Waltham, Massachusetts, United States

Mohit Mathur, MD, FASN

• Liew, Adrian, Mount Elizabeth Novena Hospital, Singapore, Singapore

Adrian Liew, MD, MBBS, FASN

• Wong, Muh Geot, Concord Repatriation General Hospital, New South Wales, New South Wales, Australia

Muh Geot Wong, MBBS, PhD

• Kooienga, Laura, Colorado Kidney Care, Denver, Colorado, United States

Laura Kooienga, MD

• Lafayette, Richard A., Department of Medicine, Stanford University, Stanford, California, United States

Richard A. Lafayette, MD

• Sahay, Manisha, Department of Nephrology, Osmania General Hospital and Osmania Medical College, Hyderabad, India

Manisha Sahay, MD, MBBS

• Chacko, Bobby, John Hunter Hospital and University of Newcastle, New South Wales, New South Wales, Australia

Bobby Chacko, MD, FASN

• Andrews, Lee G., Visterra Inc., Waltham, Massachusetts, United States

Lee G. Andrews

• Olinski, Lauren E., Visterra Inc., Waltham, Massachusetts, United States

Lauren E. Olinski, PhD

• Kong, Elizabeth, Visterra Inc., Waltham, Massachusetts, United States

Elizabeth Kong, PhD

• Zhang, Zhen, Otsuka, Princeton, New Jersey, United States

Zhen Zhang, PhD

• Suzuki, Yusuke, Juntendo University, Nephrology, Tokyo, Japan

Yusuke Suzuki, MD, PhD

Background

Deposition of IgA-containing circulating immune complexes (CICs) in the kidney is a hallmark of IgA nephropathy (IgAN); A PRoliferation-Inducing Ligand (APRIL) is a driver in this pathogenesis. Sibeprenlimab, an APRIL-neutralizing, humanized IgG2 monoclonal antibody, demonstrated acceptable safety with robust reductions in circulating IgA and uPCR, with eGFR stability at 12 months in the Phase 2 ENVISION trial of patients with IgAN.¹ We now report the effect of sibeprenlimab on change in IgA-containing CICs in IgAN patients.

Methods

ENVISION (NCT04287985) was a 12-month, global, randomized, controlled trial evaluating monthly sibeprenlimab (2, 4, or 8 mg/kg IV) in adults with IgAN. Change in IgG/IgA- and IgM/IgA-CICs over time was examined as an exploratory endpoint. Serum CICs were measured using a semi-quantitative plate-based sequential electrochemiluminescence immunoassay (ECLIA). IgG/IgA- and IgM/IgA-CICs were captured with an anti-IgA antibody and detected with ruthenylated anti-IgG or anti-IgM antibody, respectively.

Results

Sibeprenlimab recipients exhibited sustained, dose-dependent, reversible reductions in IgG/IgA- and IgM/IgA-CICs vs placebo (Figure). Median percent of baseline at Month 12 for sibeprenlimab 2, 4, and 8 mg/kg was 81.65, 72.34, and 66.67 for IgG/IgA-CIC, respectively (placebo, 102.26), and 37.05, 30.37, and 30.11 for IgM/IgA-CIC, respectively (placebo, 95.54).

Conclusion

Sibeprenlimab demonstrated robust reduction of IgG/IgA- and IgM/IgA-CICs at all study doses. In the ENVISION trial, reduction of CICs along with galactose-deficient IgA1 and uPCR over time provide further mechanistic evidence for the effects of APRIL inhibition, resulting in stabilization of kidney function as demonstrated by reduction in proteinuria and improvement in eGFR profiles. Together, these results support the disease-modifying activity of sibeprenlimab in the treatment of IgAN.
¹Mathur M et al., N Engl Med. 2024;390(1):20–31.

Funding

• Commercial Support – Funded by Otsuka