It’s the "New England Journal of IgA" these days, and we’re just living in it! In this special NephMadness edition of GN in Ten, hosts Dr. Kenar Jhaveri and Dr. Koyal Jain are joined by NephMadness co-creator Dr. Matt Sparks and Duke Fellow Dr. Ale Tomasi to break down the heavy hitters in the IgA Nephropathy bracket. Matt’s dog also joins us for a special, possibly biased cameo.

We’re moving past "ACE first, think later" and diving into the upstream battle: B-cell modulators (BAFF/APRIL inhibitors) versus Complement inhibitors. Whether you’re team "Hit Zero" or team "Alternative Pathway," this episode covers the latest trial data from ORIGIN, VISIONARY, and APPLAUSE to help you fill out your bracket. 

The "Hit Zero" Hypothesis

While we all know the classic four-hit hypothesis of IgAN, new therapies are targeting even further upstream—what some are calling "Hit Zero." 

• Pathophysiology Recap: IgAN starts with galactose-deficient IgA1 (Hit 1), leading to autoantibody production (Hit 2), immune complex formation (Hit 3), and mesangial deposition/damage (Hit 4). 
• B-Cell Modulators: These drugs target BAFF (B-cell activating factor) and/or APRIL (a proliferation-inducing ligand) to reduce the production of those pesky autoantibodies right at the source. 

The B-Cell Contenders: Sibeprenlimab & Atacicept

• Sibeprenlimab ("Sibi"): A monoclonal antibody directed at APRIL. 
  • The Data: Showed a 50% reduction in proteinuria at interim analysis and a nearly 98% reduction in APRIL levels. 
  • Status: Currently has conditional FDA approval. 
• Atacicept: A fusion protein that dual-blocks both BAFF and APRIL. 
  • The Data (ORIGIN trials): Demonstrated a 45.7% proteinuria reduction at 36 weeks and, notably, stabilization of eGFR slope in long-term follow-up. 
  • Pronunciation Debate: Is it "Attack-a-cept" or "A-tassi-cept"? The investigators say "Attack," because it’s out for blood. 

The Complement Contender: Iptacopan

• Mechanism: A factor B inhibitor that specifically targets the alternative complement pathway, which is increasingly recognized as a key driver of IgAN damage. 
• The APPLAUSE Study: This oral, twice-daily pill showed a 38% reduction in proteinuria at nine months. 
• Safety First: Because complement blockade increases the risk of infections from encapsulated bacteria, patients must be up to date with vaccinations for meningitis, streptococcal and pneumococcal infections. 

The Verdict: Who Wins the Bracket?

• Tune in to find out what our experts think… then fill out your own bracket!

References

Atacicept

Lafayette R, Barbour SJ, Brenner RM, Campbell KN, Doan T, Eren N, Floege J, Jha V, Kim BS, Liew A, Maes B, Pal A, Pecoits-Filho R, Phoon RKS, Rizk DV, Suzuki H, Tesař V, Trimarchi H, Wei X, Zhang H, Barratt J; ORIGIN Phase 3 Trial Investigators. A Phase 3 Trial of Atacicept in Patients with IgA Nephropathy. N Engl J Med. 2026 Feb 12;394(7):647-657. doi: 10.1056/NEJMoa2510198. Epub 2025 Nov 6. PMID: 41196369.

Lafayette R, Barbour S, Israni R, Wei X, Eren N, Floege J, Jha V, Kim SG, Maes B, Phoon RKS, Singh H, Tesař V, Lin CJF, Barratt J. A phase 2b, randomized, double-blind, placebo-controlled, clinical trial of atacicept for treatment of IgA nephropathy. Kidney Int. 2024 Jun;105(6):1306-1315. doi: 10.1016/j.kint.2024.03.012. Epub 2024 Mar 27. PMID: 38552841.

Sibeprenlimab

Perkovic V, Trimarchi H, Tesar V, Lafayette R, Wong MG, Barratt J, Suzuki Y, Liew A, Zhang H, Carroll K, Jha V, Quevedo A, Han SH, Praga M, Chacko B, Sahay M, Cheung CK, Kooienga L, Walsh M, Xia J, Fajardo C, Shah L, Hafkin J, Rizk DV; VISIONARY Trial Investigators Group. Sibeprenlimab in IgA Nephropathy - Interim Analysis of a Phase 3 Trial. N Engl J Med. 2026 Feb 12;394(7):635-646. doi: 10.1056/NEJMoa2512133. Epub 2025 Nov 8. PMID: 41211929.

Mathur M, Barratt J, Chacko B, Chan TM, Kooienga L, Oh KH, Sahay M, Suzuki Y, Wong MG, Yarbrough J, Xia J, Pereira BJG; ENVISION Trial Investigators Group. A Phase 2 Trial of Sibeprenlimab in Patients with IgA Nephropathy. N Engl J Med. 2024 Jan 4;390(1):20-31. doi: 10.1056/NEJMoa2305635. Epub 2023 Nov 2. PMID: 37916620; PMCID: PMC7615905.

Iptacopan

Perkovic V, Barratt J, Rovin B, Kashihara N, Maes B, Zhang H, Trimarchi H, Kollins D, Papachristofi O, Jacinto-Sanders S, Merkel T, Guerard N, Renfurm R, Hach T, Rizk DV; APPLAUSE-IgAN Investigators. Alternative Complement Pathway Inhibition with Iptacopan in IgA Nephropathy. N Engl J Med. 2025 Feb 6;392(6):531-543. doi: 10.1056/NEJMoa2410316. Epub 2024 Oct 25. PMID: 39453772.

Zhang H, Rizk DV, Perkovic V, Maes B, Kashihara N, Rovin B, Trimarchi H, Sprangers B, Meier M, Kollins D, Papachristofi O, Milojevic J, Junge G, Nidamarthy PK, Charney A, Barratt J. Results of a randomized double-blind placebo-controlled Phase 2 study propose iptacopan as an alternative complement pathway inhibitor for IgA nephropathy. Kidney Int. 2024 Jan;105(1):189-199. doi: 10.1016/j.kint.2023.09.027. Epub 2023 Oct 31. PMID: 37914086. 

The hosts and guests of this GN in 10 episode do not have any disclosures to make relevant to the content of this episode.