Topline Results for the APPEAR C3G Trial: Repeat Biopsy Results

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APPEAR-C3G Trial Summary: Iptacopan in C3 Glomerulopathy

Study Design

• Multicenter, randomized, double-blind, placebo-controlled trial
• Enrolled approximately 70 patients with biopsy-proven C3G, proteinuria >1g/day, GFR >30 mL/min, and low serum C3 levels

Primary Outcome

• 35% reduction in proteinuria at 6 months, statistically significant and sustained through 12 months
• No new safety signals in open-label extension
• Historical comparisons suggest iptacopan attenuates GFR decline

Biopsy and Histologic Findings

• Study used a unique glomerular C3 deposit score, not standard in clinical practice, including C3 breakdown products
• Significant reduction in C3 deposits in the treatment group (P = .0005), whereas placebo group showed worsening
• Data on complete C3 clearance (e.g., 3+ to 0) were not made publicly available

Notable Observations

• Dense deposit disease (DDD), considered a more aggressive subtype, was overrepresented in the treatment arm (9 of 10 patients), suggesting efficacy despite a bias toward more severe disease.
• Use of low serum C3 as an inclusion criterion aimed to demonstrate mechanism of action (complement inhibition), though this may have excluded patients with normal C3 but active disease.

Conclusion
Iptacopan demonstrated clear efficacy in reducing proteinuria, improving complement activity markers, and possibly slowing renal function decline in C3G. The trial supports its safety and potential role in managing patients with complement-driven glomerulopathies.