Atacicept Approval Brings BAFF/APRIL Targeting to IgAN With Richard Lafayette, MD

The US Food and Drug Administration (FDA) has granted accelerated approval to atacicept (Trutakna) for adults with primary IgA nephropathy (IgAN) at risk for disease progression, introducing the first BAFF and APRIL inhibitor designed to target upstream immune pathways driving disease.

The FDA based the approval on data from the phase 3 ORIGIN 3 trial, an ongoing randomized study evaluating atacicept in adults with IgAN. Richard Lafayette, MD, FACP, professor of medicine in nephrology and director of the Glomerular Disease Center at Stanford University Medical Center and a principal investigator in the ORIGIN clinical program, said the findings reinforce the role of B-cell dysregulation in IgAN and highlight the potential of targeting disease biology earlier in the disease process.

Atacicept inhibits B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL), 2 cytokines involved in B-cell survival, activation, and antibody production. By targeting these pathways, the therapy reduces production of galactose-deficient IgA1 (Gd-IgA1), a key component of IgAN pathogenesis.

“I think this is really an amazing event,” Lafayette told HCPLive. “Patients really now have access to medication that can completely retarget their disease course and can actually give them the promise of not slowing but completely preserving their kidney function.”

Although long-term kidney outcomes remain under evaluation, Lafayette said the improvements observed with atacicept in proteinuria, hematuria, and Gd-IgA1 provide optimism that the therapy may meaningfully alter disease progression.

ORIGIN 3 Demonstrates Significant Proteinuria Reduction With Atacicept

The phase 3 ORIGIN 3 trial is a global, multicenter, randomized, double-blind, placebo-controlled study evaluating atacicept in adults with primary IgAN.

The trial enrolled 431 adults with IgAN who were randomized in a 1:1 ratio to receive atacicept 150 mg once weekly through subcutaneous injection or placebo.

Among the first 203 participants included in the prespecified interim analysis, atacicept reduced 24-hour urine protein-to-creatinine ratio (UPCR) by 46% from baseline, with a statistically significant 42% reduction compared with placebo at 36 weeks (P <.0001).

The proteinuria reduction was consistent across prespecified subgroups, including age, sex, race, geographic region, baseline proteinuria, baseline estimated glomerular filtration rate (eGFR), and baseline sodium-glucose cotransporter-2 inhibitor use.

Participants treated with atacicept also experienced a 68% reduction in Gd-IgA1, although this secondary endpoint was considered observational because it was not adjusted for multiplicity.

The safety profile of atacicept was comparable with placebo, with adverse events occurring in 59.3% of patients receiving atacicept compared with 50.0% of patients receiving placebo.

BAFF/APRIL Inhibition Highlights Role of B-Cell Dysregulation in IgAN

The approval of atacicept provides clinical evidence supporting a growing understanding of IgAN as a disease driven by abnormal immune regulation.

IgAN develops through a multistep process in which immune dysregulation leads to production of Gd-IgA1, formation of pathogenic immune complexes, and subsequent kidney injury.

For years, treatment strategies have focused primarily on reducing downstream consequences of disease, including proteinuria and kidney function decline. However, recent advances have shifted attention toward therapies that target the immune pathways responsible for generating pathogenic IgA.

“The fact that a BAFF plus APRIL inhibitor is being so effective at managing these biomarkers of IgA nephropathy really lends credence to this being a disease of B-cell misregulation or dysregulation, and that both BAFF and APRIL have key elements in controlling the disease,” Lafayette said.

He added that atacicept provides an opportunity to directly address the source of abnormal IgA production.

“This really gives us the first opportunity to really control the source of the galactose-deficient IgA production and do it effectively,” Lafayette said.

Where Atacicept Fits in the Expanding IgAN Treatment Landscape

Atacicept enters an increasingly expanding IgAN treatment landscape, with therapies now targeting multiple components of disease progression, including immune activation, complement pathways, and downstream kidney injury.

For clinicians incorporating new therapies into practice, Lafayette emphasized the importance of achieving rapid and effective disease control among patients who remain at risk for progression.

“We have very clear goals from KDIGO and other treatment guidelines to get the patient’s disease activity under control rapidly and effectively,” Lafayette said.

Patients who fail to achieve adequate disease control with supportive therapy may represent those most likely to benefit from targeted immune intervention.

“If patients are not already near goal where they can be simply modified with supportive therapy, atacicept really represents a true way forward that’s targeted, effective, well tolerated, and really should be a tool that we reach for in the vast majority of patients who have the need for intervention,” Lafayette said.

ORIGIN 3 Will Determine Long-Term Kidney Impact

Although proteinuria reduction and biomarker improvements demonstrate atacicept’s biological activity, investigators must still determine whether these changes translate into long-term preservation of kidney function.

The ongoing ORIGIN 3 trial will continue evaluating kidney outcomes, including changes in eGFR over 2 years, as part of the confirmatory requirements following accelerated approval.

Lafayette said those data will ultimately determine whether atacicept can alter the trajectory of kidney decline in IgAN.

“We certainly have to wait for the GFR data for ORIGIN 3,” Lafayette said. “Again, I’m confident that it will look similar to the phase 2b study, but seeing it is believing, and actually getting to that data will be really important.”

Beyond efficacy, continued follow-up will provide additional information regarding the long-term safety and tolerability of once-weekly BAFF/APRIL inhibition, including whether the therapy maintains its safety profile without increased infection risk.

Editor’s Note: Relevant disclosures for Lafayette include Aurinia, Callidatas, Complexa, Mallinckrodt, Omeros, Pfizer, Vera Therapeutics, and others.

References

1. Vera Therapeutics. Vera Therapeutics Receives FDA Accelerated Approval for TRUTAKNA™ for Adult Patients with Primary IgA Nephropathy. July 7, 2026.

2. Lafayette R, Barbour SJ, Brenner RM, et al. A Phase 3 Trial of Atacicept in Patients with IgA Nephropathy. N Engl J Med. Published online November 6, 2025. doi:10.1056/nejmoa2510198