Advancing Treatment for C3G; Targeting the Complement System for Personalized Kidney Care - Episode 5
Managing C3G: Comparing Conservative and Emerging Targeted Treatment Strategies
Panelists discuss how eculizumab initially provides short-term benefits for patients with C3 glomerulopathy (C3G) through C5a inhibition and anti-inflammatory effects but often loses efficacy over time as the disease progresses due to inadequate control at the C3 convertase level, suggesting newer complement-targeting therapies may offer better long-term management than C5 blockade.
Video content above is prompted by the following:
Current Treatment Landscape and Eculizumab Efficacy
Patients with C3G treated with eculizumab often show an initial response followed by breakthrough disease progression after 1 to 2 years of therapy. This pattern occurs because:
- Eculizumab targets C5, blocking both C5a (an anaphylatoxin) and C5b
- The early response primarily stems from reduced inflammation through C5a inhibition
- Long-term disease control fails because eculizumab does not address the underlying dysregulation at the C3 convertase level
Evidence Base
Italian study data demonstrates the transient benefit pattern:
- Initial proteinuria reduction and albumin improvement
- Over time, proteinuria increases to above baseline
- Albumin levels eventually drop below baseline
Alternative Complement Inhibitors
Avacopan (C5a receptor antagonist) has been evaluated:
- Similar mechanistic limitations to eculizumab (targeting downstream of C3)
- Clinical trials (ACCOLADE study) failed to demonstrate adequate disease control
Treatment Paradigm Comparison
The situation parallels breakthrough hemolysis in paroxysmal nocturnal hemoglobinuria (PNH):
- Both conditions highlight the importance of targeting the appropriate level of the complement cascade
- In PNH, C3-targeting drugs have proven superior to C5-targeting drugs
Future Directions
For progressive C3G with high risk of kidney failure:
- C5 blockade appears insufficient for long-term disease control
- C3-targeting therapies may offer more effective disease modification
Transition from current eculizumab treatment to newer, upstream complement inhibitors will likely be necessary
