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Jonathan Barratt, PhD, FRCP, joins Brendon Neuen, MBBS, PhD, and Shikha Wadhwani, MD, MS, to unpack final ORIGIN 3 eGFR data for atacicept in IgAN.
Recording from ASN Kidney Week 2026 in Denver, Colorado, cohosts Brendon Neuen, MBBS, PhD, and Shikha Wadhwani, MD, MS, sat down with Jonathan Barratt, PhD, FRCP, of the University of Leicester, shortly after he presented the final efficacy analysis of the phase 3 ORIGIN 3 trial at the opening plenary.
The results, published simultaneously in the New England Journal of Medicine, show atacicept, a dual B-cell activating factor (BAFF) and A proliferation-inducing ligand (APRIL) inhibitor, stabilized eGFR over 1 year.¹,² The conversation moved from the data to trial design, treatment sequencing, and global access.
ORIGIN 3 randomized 431 adults with biopsy-proven IgA nephropathy to weekly subcutaneous atacicept 150 mg or placebo.¹ Barratt explained the trial was originally designed around a 2-year eGFR end point. After phase 2b data showed near-flat eGFR trajectories, the investigators aligned with the FDA to move the final efficacy analysis to week 52.
00:00 - IgA nephropathy takes over the ASN plenary
01:33 - ORIGIN 3 final analysis: eGFR, proteinuria, and kidney outcomes
05:18 - Why the eGFR end point moved to week 52
06:44 - Consistency across prespecified subgroups
08:38 - Placebo-group discontinuations and future trial design
10:32 - Should B-cell therapy come first in IgA nephropathy?
13:57 - Choosing among APRIL and BAFF/APRIL inhibitors
15:37 - Global access to new IgA nephropathy therapies
The question, Barratt said, became “how do we spare the placebo arm from two years of just supportive care treatment?” He called ORIGIN 3 the first IgA nephropathy trial to shift its end point from a 2-year to a 1-year eGFR effect.
At week 52, mean eGFR change from baseline was −0.11 mL/min/1.73 m² with atacicept and −5.69 mL/min/1.73 m² with placebo (difference, 5.58; 95% CI, 3.68–7.48; P < .001).¹ Through week 104, the annualized eGFR slope was −0.60 vs −5.60 mL/min/1.73 m² per year (difference, 5.00; 95% CI, 3.55–6.45; P < .001). Composite kidney-disease progression occurred in 5.1% of atacicept-treated patients vs 17.8% of placebo recipients (hazard ratio, 0.24; 95% CI, 0.12–0.48; P < .001).¹
Neuen noted a treatment effect of this size on a hard kidney outcome is rarely seen in modern trials. Barratt added placebo patients reaching 2 years lost roughly 12 mL/min/1.73 m², or about 20% of baseline kidney function, at a mean age of about 40 years. Proteinuria fell 53% at week 52 with atacicept vs 5% with placebo, and hematuria resolved in 80.9% vs 21.4% of patients with baseline hematuria.¹
On subgroups, Barratt was direct: “It’s incredibly boring because it worked in everyone, which is not boring if you’re a patient,” he said. Results were consistent across age, sex, region, baseline eGFR, proteinuria, and SGLT2 inhibitor use, with 61% of patients on an SGLT2 inhibitor at baseline.¹
Wadhwani raised the imbalance in discontinuations. The trial regimen was stopped in 7.0% of the atacicept group vs 21.0% of the placebo group, and serious adverse events occurred in 7.0% vs 15.4%, respectively.¹ Barratt attributed much of the placebo dropout to declining kidney function and to the availability of approved therapies in the United States, a dynamic he said is forcing the field to rethink placebo-controlled trial design.
Neuen asked what effects of this magnitude mean for first-line therapy. Barratt argued for treating the underlying pathogenesis rather than relying on supportive care alone.
“There is a reason people are losing nephrons,” he said. In his view, SGLT2 inhibitors, RAS inhibitors, and other supportive agents protect kidneys without halting this process, and addressing the cause of nephron loss explains the responses seen with B-cell therapies.
He cautioned lost nephrons cannot be recovered, so a young patient presenting with an eGFR of 50 remains at risk even with disease control. Because the disease returns when therapy stops, he expects the field to borrow from vasculitis research to define maintenance regimens, stopping rules, and long-term safety.
Wadhwani asked how clinicians will choose between APRIL-selective and dual BAFF/APRIL agents when eGFR, proteinuria, and galactose-deficient IgA1 data look similar. Barratt compared the decision to hypertension management, where clinicians start one agent and switch based on response and tolerability.
“I think every IgA nephropathy patient needs to be on a B-cell directed therapy,” he said. “The most important thing is to deal with the inertia of treatment.”
The episode closed on access. Barratt noted Australia and the United Kingdom, along with many high-incidence regions, lack access to these agents despite global trial recruitment. “It’s not a global access to the drugs at the moment,” he said.
Editors’ Note: Disclosures for Neuen include AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, and others. Disclosures for Wadhwani include Boehringer Ingelheim, Calliditas Therapeutics, GSK, Otsuka Pharmaceutical Co., Travere Therapeutics, and others. Disclosures for Barratt include Argenx, Calliditas Therapeutics, Chinook Therapeutics, Galapagos NV, GSK, Novartis, Travere Therapeutics, and others.
