New England Journal of Medicine October 22, 2026

Sibeprenlimab in IgA Nephropathy — Final Phase 3 Trial Analysis

Dana V. Rizk et al.

Bottom Line

In adults with IgA nephropathy, 24 months of treatment with the APRIL-inhibiting monoclonal antibody sibeprenlimab stabilized kidney function and nearly eliminated the risk of clinical kidney function decline compared to placebo.

Key Findings

1. Treatment with sibeprenlimab stabilized the annualized eGFR slope over 24 months at 0.3 ml/min/1.73m2/year, compared to a decline of -4.2 ml/min/1.73m2/year with placebo (between-group difference, 4.5 ml/min/1.73m2/year; 95% CI, 3.6 to 5.4; P<0.001).

2. The least-squares mean treatment difference for the absolute change in eGFR from baseline to 24 months was 9.2 ml/min/1.73m2 (95% CI, 7.1 to 11.4; P<0.001) in favor of sibeprenlimab.

3. A composite kidney endpoint of kidney-function decline or kidney failure occurred in only 1 patient (0.4%) in the sibeprenlimab group versus 28 patients (11.2%) in the placebo group, yielding an adjusted difference of -10.8 percentage points and a massive risk reduction (Hazard Ratio, 0.029; 95% CI, 0.004 to 0.214; P<0.001).

4. Adverse events were highly comparable between groups (90.7% with sibeprenlimab vs 90.0% with placebo).

5. Serious adverse events were numerically lower with sibeprenlimab (8.1%) than placebo (12.7%), with serious infections occurring in 1.9% and 4.0% of patients, respectively. No deaths were reported in either arm.

Study Design

Design

RCT

Double-Blind

Sample

510

Patients

Duration

24 mo

Median

Setting

Multicenter

Population Adults with IgA nephropathy

Intervention Subcutaneous sibeprenlimab (400 mg) every 4 weeks

Comparator Placebo every 4 weeks

Outcome 24-hour urinary protein-to-creatinine ratio at 9 months (trial primary endpoint); annualized slope of the eGFR over 24 months (key secondary endpoint of this final analysis)

Study Limitations

• Although the 24-month duration provides highly robust eGFR data, even longer follow-up is necessary to evaluate the true lifetime prevention of end-stage kidney disease and the safety of prolonged APRIL suppression.

• The trial population reflects a rigorously selected cohort of adults with IgA nephropathy, which may limit generalizability to patients with very advanced baseline kidney disease or variant presentations.

• Long-term post-discontinuation data is required to determine whether the disease rebounds after stopping the biologic.

Clinical Significance

Sibeprenlimab offers a paradigm-shifting targeted biologic approach to IgA nephropathy. By neutralizing APRIL, it fundamentally alters the underlying pathophysiology rather than merely addressing downstream hemodynamics or employing untargeted immunosuppression. The near-total stabilization of eGFR over 2 years and the striking 97% relative risk reduction (HR 0.029) for the composite kidney failure endpoint establish sibeprenlimab as a highly potent, disease-modifying therapy capable of preventing progression to end-stage kidney disease in high-risk patients.

Historical Context

Historically, the treatment for IgA nephropathy has relied on non-specific therapies like RAAS blockade for blood pressure and proteinuria control, combined with broadly acting systemic immunosuppression (such as corticosteroids) which carry significant toxicity. According to the multi-hit hypothesis of IgAN, increased circulating galactose-deficient IgA1 (Gd-IgA1) is the primary driver of the disease. A proliferation-inducing ligand (APRIL) is a key cytokine regulating B-cell class switching and survival that leads to Gd-IgA1 production. Sibeprenlimab targets this cascade at its source. An earlier interim analysis of this phase 3 VISIONARY trial demonstrated massive proteinuria reductions at 9 months, paving the way for regulatory filings. This final analysis proves that early proteinuria reduction translates into definitive, long-term preservation of actual kidney function over 24 months.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Based on the mechanism of sibeprenlimab, how does inhibiting APRIL (A proliferation-inducing ligand) disrupt the pathogenesis of IgA nephropathy according to the multi-hit hypothesis?

Key Response

The multi-hit hypothesis involves production of galactose-deficient IgA1 (Hit 1), autoantibodies against them (Hit 2), immune complex formation (Hit 3), and mesangial deposition causing injury (Hit 4). APRIL stimulates B-cell class switching and survival, driving the production of galactose-deficient IgA1. Sibeprenlimab targets Hit 1 directly, fundamentally halting downstream pathogenesis.

Resident

A 35-year-old patient with IgA nephropathy continues to have 1.5g of proteinuria despite maximal tolerated lisinopril and dapagliflozin. How would the introduction of an APRIL inhibitor like sibeprenlimab change your management approach compared to traditional immunosuppression like systemic corticosteroids?

Key Response

Standard guidelines recommend maximizing RAS inhibition and SGLT2i first. For persistent proteinuria, systemic steroids carry high toxicity (as seen in the TESTING trial). Sibeprenlimab offers a targeted, disease-modifying alternative with potentially fewer systemic side effects than broad immunosuppressants, fundamentally shifting second-line management away from steroids.

Fellow

With the emergence of multiple novel agents for IgA nephropathy, how should we conceptualize the choice between a hemodynamic approach (e.g., sparsentan) versus an immunomodulatory approach targeting the APRIL pathway like sibeprenlimab?

Key Response

Fellows must integrate competing new therapies. Non-immunologic therapies reduce intraglomerular pressure and proteinuria rapidly but do not stop immune complex formation. Immunomodulators like sibeprenlimab target upstream pathogenesis, which might offer more durable eGFR stabilization as seen in this 24-month trial, suggesting a potential role for combination or sequential use based on patient phenotype.

Attending

This Phase 3 trial notes that 24 months of sibeprenlimab nearly eliminated the risk of clinical kidney function decline. How should this unprecedented degree of eGFR stabilization reshape our prognostic discussions with young adults newly diagnosed with high-risk IgA nephropathy?

Key Response

Historically, high-risk IgAN inevitably progressed to ESKD over 10-20 years, and counseling focused on delaying dialysis. If sibeprenlimab truly stabilizes eGFR, attendings must shift the paradigm from delaying disease to disease remission, which drastically alters life planning, transplant discussions, and long-term adherence counseling.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The trial relies on a 24-month analysis of kidney function decline. In the context of slowly progressive glomerular diseases, what statistical models are most robust for validating stabilization, and how might non-linear eGFR trajectories confound these results?

Key Response

Researchers must critically evaluate endpoint validity. Acute hemodynamic effects upon drug initiation can create non-linear eGFR dips or rises. Chronic slope analysis (excluding the first 3-6 months) is essential to differentiate true structural preservation from reversible hemodynamic changes, especially when comparing an immunomodulator to placebo.

Journal Editor

As a reviewer evaluating this Phase 3 trial, what long-term safety data regarding prolonged APRIL inhibition, specifically concerning hypogammaglobulinemia and opportunistic infections, would you demand to see detailed before endorsing publication?

Key Response

APRIL is crucial for plasma cell survival and antibody production. A major threat to the therapeutic viability of sibeprenlimab is the risk of profound immunosuppression over time. Reviewers must scrutinize infection rates, IgG/IgA/IgM nadirs, and vaccine response data to ensure the dramatic efficacy is not outweighed by hidden safety signals.

Guideline Committee

The KDIGO 2021 guidelines suggest considering immunosuppression only after 3-6 months of optimized supportive care if proteinuria remains elevated. Given the robust 24-month eGFR stabilization seen with sibeprenlimab, is there sufficient evidence to upgrade APRIL inhibitors to first-line, concurrent therapy with RASi/SGLT2i for high-risk patients?

Key Response

Guideline committees must weigh delaying highly effective targeted therapy (which risks irreversible nephron loss) against the cost and overtreatment risk of starting it immediately. If sibeprenlimab halts decline, the rationale for a 6-month delay weakens, potentially prompting KDIGO to recommend upfront combination therapy for patients with aggressive clinical features.

Clinical Landscape

Noteworthy Related Trials

2022

TESTING Trial

n = 503 · JAMA

Tested

Methylprednisolone

Population

Patients with IgA nephropathy and high risk of progression

Comparator

Placebo

Endpoint

Composite of kidney failure, 40% decline in eGFR, or death

Key result: Methylprednisolone significantly reduced the risk of the composite kidney outcome compared to placebo but increased the risk of serious adverse events.

2023

NefIgArd Trial

n = 364 · Lancet

Tested

Nefecon (targeted-release budesonide)

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 preservation of kidney function, significantly reducing eGFR decline compared with placebo.

2023

PROTECT Trial

n = 404 · Lancet

Tested

Sparsentan

Population

Patients with IgA nephropathy and proteinuria despite ACE/ARB therapy

Comparator

Irbesartan

Endpoint

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

Key result: Sparsentan significantly reduced proteinuria compared to irbesartan, providing a meaningful non-immunosuppressive mechanism to preserve kidney function.

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