The Promise of Emerging Therapies for IgA Nephropathy and Future KDIGO Guidelines

EP: 1.Advancing IgA Nephropathy Care: Emerging Therapies, Unmet Needs, and Economic Considerations

EP: 2.Introduction to IgA Nephropathy

EP: 3.Pathogenesis of IgA Nephropathy: The 4-Hit Cascade, A Proliferation-Inducing Ligand (APRIL), and cytokines

EP: 4.Diagnosing IgA Nephropathy

EP: 5.Signs and Symptoms of IgA Nephropathy

EP: 6.Challenges in Timely Identification of IgA Nephropathy

EP: 7.Clinical Impact of IgA Nephropathy and Quality of Life

EP: 8.Overview of Treatment Landscape for IgA Nephropathy: Standard of Care and KDIGO Guidelines

EP: 9.Current Treatments for IgA Nephropathy and the 4-Hit Cascade

EP: 10.Gaps in Patient Care for IgA Nephropathy

EP: 11.Emerging Anti-BATH- and Anti-APRIL Therapies

EP: 12.Emerging Therapies: Other Strategies and Important Considerations

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EP: 13.The Promise of Emerging Therapies for IgA Nephropathy and Future KDIGO Guidelines

EP: 14.Sequencing and Individualizing Treatments for IgA Nephropathy

Emerging Therapies in IgA Nephropathy: Targeting the 4-Hit Cascade

Sibeprenlimab (VISIONARY)

Mechanism: Sibeprenlimab is a monoclonal antibody that targets APRIL (A PRoliferation-Inducing Ligand), a key cytokine in the first hit of the pathogenic cascade.

Relation to 4-Hit Cascade: By inhibiting APRIL signaling, sibeprenlimab reduces the production of galactose-deficient IgA1 (Gd-IgA1) by plasma cells. APRIL plays a critical role in B-cell activation and IgA class switching, particularly in mucosal tissues. Blocking this pathway addresses the root cause of IgAN by diminishing the production of the aberrantly glycosylated IgA1 that initiates the disease process.

Clinical significance: The VISIONARY trial has shown promising results with significant reductions in proteinuria and stabilization of estimated glomerular filtration rate. Its targeted approach may provide efficacy without the broad immunosuppressive effects of conventional therapies.

Povetacicept (RAINIER)

Mechanism: Povetacicept is a dual-target fusion protein that simultaneously blocks both APRIL and BAFF by acting as a decoy receptor.

Relation to 4-Hit Cascade: This therapy addresses multiple aspects of the pathogenic cascade:

• First hit: Inhibits production of Gd-IgA1 by blocking APRIL signaling
• Second hit: Reduces autoantibody formation against Gd-IgA1 by limiting B-cell activation and survival via BAFF inhibition
• Third hit: Consequently decreases immune complex formation by reducing both the aberrant IgA1 and the autoantibodies that target it

Clinical significance: The RAINIER trial demonstrated substantial reductions in Gd-IgA1 levels and significant proteinuria reduction. The dual-targeting approach may provide more comprehensive disease modification by addressing multiple pathogenic mechanisms simultaneously, potentially offering advantages over single-target therapies.

Both therapies represent a paradigm shift in IgAN treatment from broad immunosuppression to precise targeting of disease-specific pathways, potentially offering improved efficacy with reduced systemic adverse effects.