Selective APRIL Inhibition and Its Impact on Patient Outcomes in IgA Nephropathy

A novel, mechanism-based approach that addresses the immune drivers of this progressive disease

Content sponsored by Otsuka Pharmaceutical Development & Commercialization, Inc., for which Dr. Jonathan Barratt and Dr. Dana Rizk are paid consultants.

IgA nephropathy (IgAN) is a progressive, immune-mediated kidney disease characterized by the accumulation of galactose-deficient IgA1 (Gd-IgA1) immune complexes in the glomeruli. In the early stages of the disease, symptoms may be mild or even asymptomatic, which can lead to a delayed diagnosis despite ongoing kidney damage¹. Clinical manifestations include proteinuria, hematuria, and worsening kidney function and damage that can eventually lead to kidney failure^1,2. Most patients with IgAN progress to kidney failure (KF) within 10 to 15 years of diagnosis, even those previously considered low risk³.

As the most common primary glomerulonephritis worldwide, typically diagnosed in adults aged 20 to 40 years, the prevalence and impact of IgAN underscore the importance of addressing both underlying disease drivers, in addition to the symptoms of kidney injury and the underlying cause of the disease^2,3,4. Recent commentary surrounding the 2025 Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines reflects a rapidly evolving treatment landscape and a growing focus on proactive treatment strategies that target the underlying cause of the disease. This includes the evaluation of novel therapeutic classes, such as therapies that selectively target A-PRoliferation-Inducing-Ligand (APRIL), into the treatment paradigm, alongside established approaches that manage clinical manifestations of IgAN⁵.

“As a clinician, one of the complexities I see with IgA nephropathy is that patients may initially appear relatively stable, even as kidney function is declining silently and leading to great long-term impact,” said Jonathan Barratt, MD, PhD, Professor of Renal Medicine, University of Leicester, UK. “This early, often unseen and undetected loss of kidney function underscores the need for interventional therapies earlier by targeting key drivers of disease progression, including pathways that selectively block APRIL.”

Recognizing Selective APRIL Inhibition as a Targeted Therapeutic Strategy

APRIL, a cytokine in the tumor necrosis factor (TNF) family, represents an important initiating and sustaining driver in IgAN’s pathogenesis⁶. It signals through receptors transmembrane activator and calcium-modulator and cyclophilin-ligand interactor (TACI) and B-cell maturation antigen (BCMA) to support plasma cell survival, mediate antibody class switching in mature B cells, and drive IgA production⁶. These processes contribute to pathogenic galactose-deficient IgA1 (Gd-IgA1) production and formation of associated immune complexes, which deposit in the glomeruli, triggering inflammatory responses, and may ultimately lead to progressive kidney injury⁶.

VOYXACT® (sibeprenlimab-szsi) is the first and only FDA-approved treatment indicated to reduce proteinuria in adults with primary IgAN at risk for disease progression that selectively binds to and blocks the biological activity of APRIL. Selectively inhibiting APRIL results in reduced Gd-IgA1 levels, directly targeting an upstream driver implicated in disease pathogenesis⁷. VOYXACT was granted accelerated approval by the FDA based on a VISIONARY Phase 3 clinical trial interim analysis, which demonstrated a significant placebo-adjusted treatment effect of 51% (P<0.0001) reduction in proteinuria at nine months (n=320) of treatment (-50% VOYXACT vs 2% placebo). The treatment effect (percentage reduction in urine protein-to-creatinine ratio [uPCR-24h] between VOYXACT and placebo) was consistent across the following subgroups and prespecified stratification factors: sex, age, race, ethnicity, and geographic region, baseline proteinuria (uPCR-24h), baseline eGFR, and SGLT2 inhibitor use.

“As a central regulator of Gd-IgA1 production and immune complex formation, APRIL is a biologically relevant therapeutic target that enables earlier and more targeted intervention in the disease process,” said Dana Rizk, MD, Professor of Medicine in the Division of Nephrology at the University of Alabama at Birmingham. “Continued clinical research will support the evaluation of selective APRIL inhibition as a targeted, mechanistically aligned strategy that addresses core disease drivers while avoiding broader B-cell depletion.”

The overall safety profile of VOYXACT was similar to placebo. In the study, the most common adverse reactions (reported in ≥10% of patients treated with VOYXACT and at a higher incidence than placebo) in patients treated with VOYXACT and placebo, respectively, were infections (49% versus 45%) and injection site reactions (24% versus 23%). Delivered as a 400 mg/2 mL subcutaneous injection once every four weeks, VOYXACT can be self-administered by a patient or administered by a caregiver, offering flexibility in treatment administration.

VISIONARY (NCT05248646) is a Phase 3, multicenter, randomized, double-blind, placebo-controlled trial in adults with biopsy-confirmed IgA nephropathy, uPCR ≥0.75 g/g or urine protein ≥1.0 g/d, and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 who were randomized to receive sibeprenlimab 400 mg/2 mL subcutaneous injection once every four weeks or placebo in addition to maximally tolerated standard of care therapy for 24 months.

Beyond Proteinuria: The Role of eGFR in IgAN

Estimated glomerular filtration rate is a clinical measure to assess kidney function and monitor disease progression⁸. Reductions in proteinuria are an established surrogate for future changes in eGFR in IgAN, with a growing body of evidence supporting its role as an early indicator of treatment effect⁹. In a condition characterized by gradual and often asymptomatic decline of kidney function, changes in eGFR provide important context for understanding how the disease evolves over time^3,8,10.

New investigational clinical data evaluating eGFR from an analysis of the Phase 3 VISIONARY study of VOYXACT in adults with primary IgAN at risk for disease progression was recently presented at the GlomCon Hawaii 2026 conference. Results can be found in the official press release announcement.

“Lowering proteinuria remains a critical goal in IgAN patient care,” said Dr. Barratt. “As the RaDaR study has shown, for every 10% drop in proteinuria, the risk of kidney failure or death decreases by 11% after adjusting for age, sex, baseline eGFR, and time from diagnosis to baseline. What makes these finding so important is how we evaluate these changes alongside other clinical measures such as eGFR. Together, these measures provide a more complete view of kidney function in IgAN, and ongoing research will continue to inform how we assess and manage the disease over time.”

Evolving Treatment Approaches in IgA Nephropathy

Monitoring changes in eGFR over time provides insight into kidney function preservation^11,12. In a disease with significant patient burden and unmet need, continued clinical research is crucial to further evaluate the role of selective APRIL inhibition as a targeted approach that addresses underlying drivers of IgAN¹³.

“Therapies that target underlying immunologic drivers while demonstrating effects across multiple clinical measures may help inform future approaches to disease management,” said Dr. Rizk. “Notably, selectively targeting APRIL may allow us an opportunity to intervene earlier in the disease progression, which is an important step toward shifting the trajectory of IgAN rather than managing its consequences.”

To learn more about the impact of APRIL inhibition in IgAN, visit www.voyxacthcp.com

This information is intended for a healthcare provider audience.

INDICATION and IMPORTANT SAFETY INFORMATION for

VOYXACT® (sibeprenlimab-szsi)

INDICATION

VOYXACT is indicated to reduce proteinuria in adults with primary immunoglobulin A nephropathy (IgAN) at risk for disease progression.

This indication is approved under accelerated approval based on reduction of proteinuria. It has not been established whether VOYXACT slows kidney function decline over the long-term in patients with IgAN. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory clinical trial.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATION

VOYXACT is contraindicated in patients with serious hypersensitivity to sibeprenlimab-szsi or any of the excipients of VOYXACT.

WARNINGS AND PRECAUTIONS

Immunosuppression and Increased Risk of Infections: VOYXACT suppresses the immune system by reducing antibody production, which may increase the risk of infections. Patients with chronic or recurring infections may have an increased risk of serious infection. In clinical trials, infections occurred in 49% of patients treated with VOYXACT compared with 45% of patients treated with placebo.

Before initiating VOYXACT, assess patients for active infections. During treatment, monitor patients for signs and symptoms of infection. If a serious infection develops, consider interrupting VOYXACT until the infection is controlled.

Immunosuppression and Immunization Risks: Because of its mechanism of action, VOYXACT may interfere with immune responses to vaccines and increase the risk of infection from live vaccines. Live vaccines are not recommended within 30 days prior to initiation of VOYXACT or during treatment with VOYXACT as safety has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving VOYXACT or on the efficacy of immunizations administered while receiving VOYXACT.

Common Adverse Reactions: The most common adverse reactions (reported in ≥10% of patients treated with VOYXACT and at a higher incidence than placebo) in patients treated with VOYXACT and placebo, respectively, were infections (49% versus 45%) and injection site reactions (24% versus 23%). The most common infection was upper respiratory infection (15% versus 14%), and the most common injection site reaction was injection site erythema (13% versus 12%). Most adverse reactions were reported as mild or moderate in severity and resolved without treatment interruption or discontinuation.

Pregnancy: There are no available data on VOYXACT use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Monoclonal antibodies, such as sibeprenlimab-szsi, can be actively transported across the placenta as pregnancy progresses; therefore, potential effects on a fetus are likely to be greater during the second and third trimester of pregnancy.

Lactation: There are no data on the presence of sibeprenlimab-szsi in human milk, the effects of sibeprenlimab-szsi on the breastfed infant, or the effects of sibeprenlimab-szsi on milk production.

Pediatric Use: Safety and effectiveness of VOYXACT in pediatric patients have not been established.

Geriatric Use: Clinical studies of VOYXACT did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger adult patients.

Pregnant women exposed to VOYXACT, or their healthcare providers, should report VOYXACT exposure by calling 1-833-869-9228 or visiting www.VOYXACT.com

To report SUSPECTED ADVERSE REACTIONS, contact Otsuka America Pharmaceutical, Inc. at 1-800-438-9927 or FDA at 1-800-FDA-1088 (www.fda.gov/medwatch).

Please see FULL PRESCRIBING INFORMATION and PATIENT INFORMATION

References:

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8. Abenavoli C, Provenzano M, Ksiazek SH, Hu L, Cuna V, Manna G, Comai G, Baraldi O. Role of Estimated Glomerular Filtration Rate in Clinical Research: The Never-Ending Matter. Rev Cardiovasc Med. 2024 Jan 4;25(1):1. doi: 10.31083/j.rcm2501001. PMID: 39077647; PMCID: PMC11262368.
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10. IgA Nephropathy Foundation. (n.d.). Diagnosed with IgA nephropathy? What you need to know. https://igan.org/guides-and-worksheets/IgAN-booklet.pdf
11. What is estimated glomerular filtration rate?. Cleveland Clinic. (2026, March 9). https://my.clevelandclinic.org/health/diagnostics/21593-estimated-glomerular-filtration-rate-egfrhttps://my.clevelandclinic.org/health/diagnostics/21593-estimated-glomerular-filtration-rate-egfr
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June 2026 21US25EBP0157