Emerging Anti-BATH- and Anti-APRIL Therapies

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

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

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

Novel Targeted Therapies in IgA Nephropathy: Paradigm Shift Toward Pathophysiologic Mechanisms

Therapeutic Evolution

Novel targeted therapies for IgA nephropathy (IgAN) represent a fundamental shift from broad immunosuppression to precision medicine approaches that address specific pathophysiologic mechanisms within the 4-hit cascade:

• Mechanistic targeting: Moving from symptom management and general anti-inflammatory approaches to therapies that directly address disease-specific pathways
• Reduced systemic effects: More selective interventions with potentially improved safety profiles compared with traditional immunosuppressants
• Biomarker-guided therapy: Emerging ability to match specific therapies to individual disease endotypes

First-Hit Targeted Therapies

• APRIL inhibitors: Monoclonal antibodies targeting APRIL (a B-cell stimulating factor) reduce production of galactose-deficient IgA1 (Gd-IgA1)
• Targeted enteric release corticosteroids: Act locally on mucosal-associated lymphoid tissue to modulate IgA1 production
• B-cell modulators: Selective approaches to reduce pathogenic B-cell subsets while preserving protective immunity

Second-Hit Targeted Therapies

• Specific cytokine inhibitors: Target key cytokines involved in autoantibody formation against Gd-IgA1
• Costimulation blockers: Disrupt T-B cell interactions required for autoantibody production
• Mucosal immune modulators: Address gut-kidney axis dysregulation contributing to aberrant immune responses

Third-Hit Targeted Therapies

• Fc receptor antagonists: Block binding of IgA immune complexes
• Glycan-targeted therapies: Interfere with immune complex formation and mesangial deposition
• Complement inhibitors: Target specific complement pathways involved in immune complex processing

Fourth-Hit Targeted Therapies

• Selective complement inhibitors: Target alternative pathway components specifically activated in IgAN
• Antifibrotic agents: Address progressive kidney scarring through novel mechanisms
• Endothelial protective agents: Preserve glomerular filtration barrier integrity

Clinical Implications

This targeted approach enables the following:

• More precise patient selection based on disease mechanisms
• Potential for combination therapies addressing multiple hits simultaneously
• Reduced reliance on systemic immunosuppression
• Improved therapeutic index with better efficacy and safety balance

The paradigm shift toward mechanism-based therapies promises to revolutionize IgAN management, potentially modifying disease course rather than merely managing symptoms and complications. This evolution represents a significant advancement in the field of glomerular diseases more broadly.