Highlights
- Zigakibart is a humanized IgG4 monoclonal antibody targeting APRIL with demonstrated safety and 60% proteinuria reduction over 100 weeks in IgA nephropathy (IgAN) patients.
- Sibeprenlimab, a humanized IgG2 APRIL-neutralizing antibody, significantly decreases proteinuria and stabilizes eGFR in a large Phase 2 trial of IgAN patients at high progression risk.
- Telitacicept, a dual BAFF/APRIL inhibitor, effectively reduces proteinuria and induces remission in refractory childhood IgA vasculitis nephritis (IgAVN) with a favorable safety profile.
- Targeting APRIL and related pathways offers a mechanistically rational, disease-modifying approach for immune complex–mediated glomerulonephritides characterized by aberrant IgA production.
Background
Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide and a leading cause of chronic kidney disease (CKD). It is characterized by mesangial deposition of galactose-deficient IgA1 (Gd-IgA1) and subsequent immune complex formation. Persistent proteinuria and progressive loss of glomerular filtration rate (GFR) drive prognosis. A Proliferation-Inducing Ligand (APRIL, TNFSF13), a member of the tumor necrosis factor superfamily, plays a pivotal role in the dysregulated IgA immune response in IgAN pathogenesis by promoting IgA class switching and plasma cell survival. Modulating APRIL signaling thus represents a promising therapeutic target to reduce pathogenic IgA production and inflammatory injury in IgAN and related IgA vasculitis nephritis (IgAVN). Currently, limited disease-modifying treatments exist beyond supportive care.
Key Content
Phase 1/2 Trial of Zigakibart in Healthy Volunteers and IgAN Patients
Zigakibart is a humanized IgG4 monoclonal antibody that binds to APRIL and inhibits its activity. In a Phase 1/2 trial (NCT03945318), 63 healthy volunteers received escalating intravenous doses (10-1350 mg single or 50-450 mg multiple dosing biweekly) with favorable tolerability and dose-proportional pharmacokinetics. Durable reductions in free APRIL, serum IgA and IgM levels, and modest IgG reduction were observed. Importantly, in 40 IgAN patients receiving 600 mg subcutaneously every 2 weeks, zigakibart demonstrated excellent safety without treatment-emergent serious adverse events leading to discontinuation or death.
At 100 weeks, patients experienced a 60% proteinuria reduction and stabilization of estimated GFR (eGFR), alongside marked decreases in hematuria and levels of total IgA, Gd-IgA1, and IgM, corroborating sustained pharmacodynamic effect. These findings suggest a potent disease-modifying effect by attenuating the pathogenic immunoglobulin milieu and consequent glomerular injury. The ongoing Phase 3 BEYOND study (NCT05852938) aims to confirm zigakibart’s long-term safety and efficacy.
Phase 2 Trial of Sibeprenlimab in High-Risk IgAN Patients
Sibeprenlimab is a humanized IgG2 monoclonal antibody that neutralizes APRIL. In a multicenter, randomized, double-blind, placebo-controlled Phase 2 trial (ENVISION, NCT04287985), 155 adults with high-risk biopsy-confirmed IgAN were assigned to receive intravenous sibeprenlimab (2, 4, or 8 mg/kg) or placebo monthly for 12 months. The primary endpoint was change in log-transformed 24-hour urinary protein-to-creatinine ratio (UPCR).
At 12 months, proteinuria reductions were dose-dependent and significantly greater for all sibeprenlimab groups (47.2%-62.0%) versus placebo (20.0%). eGFR was stabilized or mildly improved in the 4 mg/kg group versus decline in placebo. Safety profiles were consistent between sibeprenlimab and placebo, with no new safety signals detected. These results validate APRIL blockade as an effective strategy to reduce proteinuria and preserve renal function in IgAN, with potential to modify disease course amid standard care.
Telitacicept in Refractory Childhood IgA Vasculitis Nephritis
Telitacicept is a recombinant fusion protein acting as a dual inhibitor of B-cell activating factor (BAFF) and APRIL, key cytokines in B-cell maturation and antibody production. Given the overlapping pathophysiology of IgAVN and IgAN, particularly involving aberrant IgA1, telitacicept has been investigated in refractory childhood IgAVN characterized by persistent proteinuria despite prior immunosuppressive treatment.
In a retrospective single-center study of 7 children (median age 15 years) with refractory IgAVN, weekly subcutaneous telitacicept (80 or 160 mg based on weight) resulted in proteinuria reduction in 86% of patients, ranging between 23.6% and 97.5%, and complete remission in 29% over the follow-up period. All patients demonstrated decreased hematuria and were able to discontinue steroids and other immunosuppressants. No severe adverse events were recorded, indicating favorable tolerability. These findings highlight telitacicept’s potential to effectively target B cell pathways and clinical manifestations in IgAVN and similar immune complex diseases.
Comparative Analysis and Mechanistic Insight
| Therapeutic | Antibody Class/Mechanism | Patient Population | Dosing | Duration | Primary Outcome | Proteinuria Reduction | eGFR Outcome | Safety Profile |
|---|---|---|---|---|---|---|---|---|
| Zigakibart | Humanized IgG4 mAb against APRIL | 40 IgAN patients | 600 mg SC every 2 weeks | 100 weeks | Proteinuria, eGFR stabilization | ~60% reduction | Stable eGFR | Well tolerated; no discontinuations or deaths |
| Sibeprenlimab | Humanized IgG2 mAb neutralizing APRIL | 155 high-risk IgAN adults | 2-8 mg/kg IV monthly | 12 months | Change in 24h UPCR | 47-62% reduction dose-dependent | eGFR stable or mild decline vs placebo | Comparable adverse events to placebo |
| Telitacicept | Dual BAFF/APRIL inhibitor fusion protein | 7 children with refractory IgAVN | 80 or 160 mg SC weekly | Retrospective approx. several months | Proteinuria reduction and remission | 23.6 to 97.5% reduction | Not reported | No serious adverse reactions |
Expert Commentary
The therapeutic targeting of APRIL in IgAN and IgAVN represents a significant advance beyond traditional non-specific immunosuppression or supportive care. The consistency across trials of APRIL blockade yielding clinically meaningful proteinuria reduction, immunoglobulin normalization, and preservation or stabilization of renal function supports APRIL’s central role in disease pathogenesis, particularly via IgA overproduction and deposition pathways.
Zigakibart’s long-term follow-up data extends confidence in durable efficacy and tolerability, crucial for a chronic progressive disease with limited approved disease-modifying options. Sibeprenlimab’s phase 2 results reinforce APRIL as a validated target, with dose-dependent benefits on proteinuria and kidney function preservation.
Telitacicept’s dual inhibition of BAFF and APRIL may offer enhanced efficacy in refractory or pediatric populations, although larger prospective controlled studies are warranted to define its role more precisely. Mechanistic understanding underscores APRIL’s intersection with B-cell biology and mucosal immunity, suggesting that these biologics modulate pathogenic IgA production and immune complex-mediated glomerular injury at an upstream level.
Unresolved questions include the optimal dosing regimen, long-term safety in larger cohorts, combination with other immunomodulators or renin-angiotensin-aldosterone system blockers, and biomarker-guided patient selection. Current guideline incorporation awaits confirmatory phase 3 trial evidence, as ongoing studies such as zigakibart’s BEYOND trial will provide pivotal data.
Conclusion
The emergence of APRIL-targeted therapies—zigakibart, sibeprenlimab, and telitacicept—marks an important therapeutic innovation addressing key pathogenic mechanisms in IgA nephropathy and IgA vasculitis nephritis. Clinical data demonstrate acceptable safety profiles and clinically meaningful efficacy in proteinuria reduction and renal function preservation or stabilization. These advances offer hope for disease modification in disorders historically managed by nonspecific or supportive approaches.
Future research should focus on phase 3 validation, mechanistic biomarkers, patient stratification, long-term safety, and combination strategies. The progressive refinement of immunological targeting promises to reshape the clinical landscape of IgAN and related disorders, ultimately improving patient outcomes.
References
- Kooienga L, et al. Zigakibart demonstrates clinical safety and efficacy in a Phase 1/2 trial of healthy volunteers and patients with IgA nephropathy. Kidney Int. 2025 Sep;108(3):445-454. doi:10.1016/j.kint.2025.05.006. PMID: 40482854.
- Mathur M, et al.; ENVISION Trial Investigators Group. A Phase 2 Trial of Sibeprenlimab in Patients with IgA Nephropathy. N Engl J Med. 2024 Jan 4;390(1):20-31. doi:10.1056/NEJMoa2305635. PMID: 37916620; PMCID: PMC7615905.
- Jin Y, et al. Telitacicept as a BAFF/APRIL dual inhibitor: efficacy and safety in reducing proteinuria for refractory childhood IgA vasculitis nephritis. Pediatr Nephrol. 2025 Aug;40(8):2561-2569. doi:10.1007/s00467-025-06769-3. PMID: 40214779.
