Kidney Compass: Atacicept and ORIGIN 3 at Kidney Week 2025, with Richard Lafayette, MD

Welcome to Kidney Compass: Navigating Clinical Trials!

In this special edition episode of Kidney Compass: Navigating Clinical Trials, hosts Brendon Neuen, MBBS, PHD, and Shikha Wadhwani, MD, MS, are joined by Ricahrd Lafayette, MD, from the floor at the American Society of Nephrology (ASN) Kidney Week 2025 to discuss the late-breaking ORIGIN 3 results evaluating atacicept and how it adds to the totality of evidence supporting the use of the dual BAFF/APRIL inhibitor in IgA nephropathy (IgAN).

Lafayette describes the moment as “predictably exciting,” noting that the phase 3 findings strongly mirror the promising signals seen previously in the ORIGIN phase 2 program.

The phase 2 trial, which evaluated weekly atacicept dosing, demonstrated a robust biologic impact with approximate reductions of 75% in galactose-deficient IgA1 and 50% in proteinuria at 96 weeks, hematuria resolution in most affected patients, and an annual eGFR decline of only ~0.6 mL/min/1.73 m², which Lafayette noted was far below the expected trajectory in this population. These data guided the design of ORIGIN 3, which enrolled biopsy-proven IgA nephropathy with >1 g/day of proteinuria, eGFR >30 mL/min/1.73 m², and maximally tolerated background therapy. More than half of the participants were also taking an SGLT2 inhibitor.

Lafayette reports the 9-month primary outcome results aligned closely with phase 2. Atacicept achieved >45% reductions in proteinuria, compared with approximately 7% in the placebo group. Gd-IgA1 fell by approximately 75–80%, and hematuria resolved in most atacicept-treated patients with minimal change on placebo. Lafayette highlighted these effects were consistent across prespecified subgroups, including those on SGLT2 inhibitors.

Safety findings demonstrated there was no increase in infections or serious adverse events relative to placebo, aside from mild injection-site reactions. Lafayette pointed out, numerically, severe adverse events occurred more often in the placebo arm.

While regulatory restrictions prevent release of 9-month eGFR data, Lafayette notes the close resemblance to the phase 2 trajectory supports optimism for the upcoming 2-year readout. However, he emphasizes that atacicept-related biomarker improvements reverse when treatment stops, indicating that ongoing therapy may be necessary for sustained benefit.

The discussion concludes by situating atacicept within a rapidly expanding therapeutic landscape, including other B-cell–directed agents targeting APRIL alone. Head-to-head differences remain unknown, but atacicept’s dual BAFF/APRIL inhibition and consistent efficacy across optimized background therapy make it a compelling potential addition.

Relevant disclosures for Lafayette include Aurinia, Callidatas, Complexa, Mallinckrodt, Omeros, Pfizer, Vera Therapeutics, and others. Relevant disclosures for Neuen include AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, and others. Relevant disclosures for Wadhwani include Boehringer Ingelheim, Calliditas Therapeutics, GSK, Otsuka Pharmaceutical Co., Travere Therapeutics, and others.

Referneces:

Lafayette R, Barbour SJ, Brenner RM, et al. ORIGIN 3: A Phase 3 Trial of Atacicept in IgAN. Presented at the American Society of Nephrology (ASN) Kidney Week. Houston, Texas. November 05-09, 2025.

Vera Therapeutics Announces Atacicept Achieved 46% Proteinuria Reduction in ORIGIN Phase 3 Trial in Adults with IgA Nephropathy. Vera Therapeutics, Inc. June 2, 2025. Accessed June 2, 2025. https://ir.veratx.com/news-releases/news-release-details/vera-therapeutics-announces-atacicept-achieved-46-proteinuria