Opinion
Video
Emerging Therapies: Other Strategies and Important Considerations
Panelists discuss how targeted therapies for immunoglobulin A (IgA) nephropathy are advancing rapidly, with promising results from trials of B-cell modulating agents that inhibit APRIL/BAFF signaling and complement pathway inhibitors that address specific steps in the 4-hit cascade.
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.
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