New England Journal of Medicine October 22, 2026

Atacicept in IgA Nephropathy — Phase 3 Trial Final Efficacy Analysis

Jonathan Barratt, Robert M. Brenner, Sean J. Barbour, et al.

Bottom Line

In a phase 3 trial of adults with IgA nephropathy, the dual BAFF and APRIL inhibitor atacicept stabilized kidney function over two years, significantly reducing eGFR decline and the risk of kidney disease progression compared to placebo.

Key Findings

1. Atacicept nearly halted eGFR decline, with a mean change at week 52 of −0.11 mL/min/1.73 m² compared to −5.69 mL/min/1.73 m² with placebo.

2. The annualized eGFR slope through week 104 was −0.60 mL/min/1.73 m² per year in the atacicept group versus −5.60 mL/min/1.73 m² per year in the placebo group.

3. Atacicept significantly reduced the risk of composite kidney-disease progression by 76% compared to placebo (5.1% vs. 17.8%; Hazard Ratio, 0.24).

4. No patients in the atacicept group required dialysis, received a kidney transplant, or died, compared to 8 patients in the placebo group.

5. Serious adverse events occurred less frequently with atacicept (7.0%) than with placebo (15.4%), though trial regimen discontinuations were imbalanced (7.0% vs. 21.0%, respectively).

Study Design

Design

RCT

Double-Blind

Sample

431

Patients

Duration

104 wk

Median

Setting

Multinational

Population Adults with biopsy-confirmed IgA nephropathy and persistent proteinuria despite maximally tolerated supportive care (RAS inhibition)

Intervention Atacicept 150 mg administered subcutaneously once weekly

Comparator Matching placebo administered subcutaneously once weekly

Outcome Change in eGFR at week 52 and annualized eGFR slope through week 104 (key prespecified final efficacy endpoints following the interim proteinuria analysis)

Study Limitations

• High discontinuation rate in the placebo arm (21.0% vs. 7.0% for atacicept), largely attributed to progressive kidney function decline and the increasing commercial availability of other active therapies in the US, which complicates late-stage comparative analyses.

• Despite the 2-year duration (104 weeks) being robust for eGFR slopes, lifetime risk assessments for end-stage renal disease (ESRD) and mortality require longer follow-up.

• The trial was sponsor-funded and conducted by Vera Therapeutics, necessitating standard caveats regarding industry-sponsored research.

Clinical Significance

This final analysis establishes atacicept as a transformative, disease-modifying agent for IgA nephropathy. By neutralizing both BAFF and APRIL—key cytokines driving the production of pathogenic galactose-deficient IgA1—atacicept effectively halted eGFR decline to a rate mirroring normal physiologic aging (−0.60 mL/min/1.73 m² per year). The 76% reduction in hard clinical progression events validates the surrogate proteinuria reductions seen in the interim analysis, marking a paradigm shift from merely delaying ESRD to potentially arresting the disease entirely in high-risk patients.

Historical Context

IgA nephropathy is the most common primary glomerulonephritis worldwide, carrying a high lifetime risk of kidney failure. Historically, treatment was limited to optimized renin-angiotensin system (RAS) inhibition. The recent recognition that the disease is driven by a 'multi-hit' process involving the overproduction of aberrantly glycosylated IgA1 (promoted by BAFF and APRIL cytokines) spurred the development of targeted B-cell therapies. The ORIGIN 3 trial's interim analysis previously demonstrated a 46% reduction in proteinuria at week 36, earning atacicept accelerated FDA approval in mid-2026. This 2026 final efficacy report provides the confirmatory hard renal endpoint data required for full approval, published simultaneously with data for sibeprenlimab (an APRIL-only inhibitor), cementing 2026 as a landmark year for targeted immunotherapies in nephrology.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How does the dual inhibition of BAFF and APRIL by atacicept specifically interrupt the multi-hit pathogenesis model of IgA nephropathy?

Key Response

IgA nephropathy follows a 4-hit hypothesis: (1) production of galactose-deficient IgA1 (Gd-IgA1), (2) autoantibodies against Gd-IgA1, (3) immune complex formation, and (4) mesangial deposition causing inflammation. BAFF (B-cell activating factor) and APRIL (A proliferation-inducing ligand) are critical for B-cell survival and class switching to IgA. Atacicept directly suppresses the pathogenic production of Gd-IgA1 (Hit 1) and potentially the autoantibodies (Hit 2), offering a disease-modifying upstream therapy compared to downstream hemodynamic interventions.

Resident

Given the recent approvals of SGLT2 inhibitors and endothelin receptor antagonists for IgA nephropathy, in which patient phenotype would you prioritize a disease-modifying immunomodulator like atacicept over isolated hemodynamic optimization?

Key Response

Patients with active immune-mediated disease characterized by rapidly rising proteinuria, active urinary sediment (hematuria), and elevated inflammatory markers despite maximal tolerated RAS and SGLT2 inhibition are prime candidates for upstream immunomodulation with atacicept. Conversely, those with 'burnt-out' disease and chronic fibrotic changes (bland sediment, slowly progressive eGFR decline) may only benefit from hemodynamic agents.

Fellow

What are the theoretical advantages and potential immunological risks of dual BAFF and APRIL inhibition with atacicept compared to selective APRIL inhibition (e.g., sibeprenlimab) in the long-term management of IgA nephropathy?

Key Response

Dual inhibition suppresses both B-cell survival (via BAFF) and plasma cell survival/IgA class switching (via APRIL), potentially offering a more profound reduction in Gd-IgA1 and better efficacy. However, this broader immunomodulation could theoretically increase the risk of hypogammaglobulinemia and serious opportunistic infections over years of therapy, necessitating careful monitoring of IgG levels and infectious complications compared to selective APRIL blockade.

Attending

As atacicept demonstrates eGFR stabilization over two years, how does this redefine our concept of 'clinical remission' in IgA nephropathy, and should we shift our primary monitoring biomarker from proteinuria to serum Gd-IgA1 levels?

Key Response

Historically, remission in IgAN was defined by proteinuria reduction via hemodynamic optimization. Atacicept's disease-modifying mechanism suggests we might achieve true 'immunologic remission.' Consequently, measuring upstream biomarkers like Gd-IgA1 could become standard practice to titrate therapy and confirm disease quiescence, moving away from relying solely on proteinuria, which can often reflect irreversible podocyte damage or secondary focal segmental glomerulosclerosis rather than active inflammation.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

In evaluating the 2-year eGFR slope for atacicept, how must the statistical analysis plan account for acute hemodynamic effects to isolate the true structural, disease-modifying benefit of the drug?

Key Response

Nephrology trials often use the chronic eGFR slope (e.g., calculated from month 3 to month 24) to exclude acute hemodynamic dips that occur upon starting medications, or they utilize an off-treatment washout period to assess the true eGFR (total slope). A rigorous mixed-effects model analysis must demonstrate that the difference in eGFR preservation represents halted glomerulosclerosis rather than altered intraglomerular pressure.

Journal Editor

With the rapidly evolving standard of care during the enrollment period of this phase 3 trial, how does the variable background use of SGLT2 inhibitors and targeted-release corticosteroids threaten the internal validity and estimation of atacicept's independent effect size?

Key Response

If background therapy was not strictly stratified, or if SGLT2 inhibitor initiation occurred disproportionately across arms during the trial, it could heavily confound the eGFR stabilization attributed to atacicept. A critical reviewer must scrutinize the baseline characteristics, protocol rules for add-on therapies, and whether predefined subgroup analyses confirm atacicept's efficacy regardless of concurrent novel therapies.

Guideline Committee

Based on the sustained 2-year eGFR stabilization, should future KDIGO guidelines elevate dual BAFF/APRIL inhibitors to first-line therapy alongside RAS inhibition for high-risk patients, or should they remain a second-line option for patients failing optimized supportive care?

Key Response

Current KDIGO guidelines emphasize maximizing supportive care (ACEi/ARB, SGLT2i) before considering systemic immunosuppression or clinical trials for patients with persistent proteinuria greater than 1 g/day. The committee must weigh atacicept's strong efficacy and upstream mechanism against its long-term safety profile and cost to determine if it warrants a Grade 1A recommendation as initial therapy for progressive disease, potentially replacing the fraught use of systemic glucocorticoids entirely.

Clinical Landscape

Noteworthy Related Trials

2022

TESTING Trial

n = 503 · JAMA

Tested

Oral methylprednisolone

Population

Patients with IgA nephropathy and high risk of progression

Comparator

Placebo

Endpoint

Composite of kidney failure, death due to kidney disease, or 40 percent eGFR decline

Key result: Treatment with oral methylprednisolone reduced the risk of the composite kidney outcome but significantly increased the risk of serious adverse events.

2023

NefIgArd Trial

n = 364 · Lancet

Tested

Nefecon (targeted-release budesonide) 16 mg daily

Population

Adults with primary IgA nephropathy at risk of disease progression

Comparator

Placebo

Endpoint

Time-weighted average change in eGFR over 2 years

Key result: Nefecon provided a clinically relevant and statistically significant benefit on kidney function compared to placebo, alongside a substantial reduction in proteinuria.

2023

PROTECT Trial

n = 404 · Lancet

Tested

Sparsentan 400 mg daily

Population

Patients with IgA nephropathy and persistent proteinuria despite RAS inhibition

Comparator

Irbesartan 300 mg daily

Endpoint

Change in urine protein-to-creatinine ratio at 36 weeks

Key result: Sparsentan significantly reduced proteinuria compared with irbesartan and demonstrated a sustained preservation of kidney function over 110 weeks.

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