Oral iptacopan therapy in patients with C3 glomerulopathy: a randomised, double-blind, parallel group, multicentre, placebo-controlled, phase 3 study
In the phase 3 APPEAR-C3G trial, oral iptacopan, an alternative-complement-pathway factor B inhibitor, produced a statistically significant and clinically meaningful reduction in proteinuria versus placebo in adults with C3 glomerulopathy, with an acceptable safety profile.
Background
C3 glomerulopathy is an ultra-rare, severe glomerulonephritis driven by overactivation of the alternative complement pathway, and roughly half of patients progress to kidney failure within a decade. Iptacopan (LNP023) is an oral, proximal complement inhibitor that targets factor B to selectively block the alternative pathway, addressing the underlying disease mechanism.
Study design
APPEAR-C3G was a multicenter, randomized, double-blind, placebo-controlled phase 3 study enrolling 74 adults with biopsy-confirmed C3 glomerulopathy, reduced serum C3, urine protein-creatinine ratio of at least 1.0 g/g, and eGFR of at least 30 mL/min/1.73 m2. Participants were randomized 1:1 to iptacopan 200 mg twice daily (n=38) or placebo (n=36) on top of supportive care for a 6-month double-blind period, followed by open-label iptacopan; the primary endpoint was relative reduction in proteinuria at 6 months.
Key findings
The trial met its primary endpoint, with a relative reduction in 24-hour urine protein-creatinine ratio for iptacopan versus placebo of 35.1% at 6 months (95% CI 13.8 to 51.1; p=0.0014). Treatment-emergent adverse events were mostly mild or moderate; there were no deaths, no discontinuations due to adverse events, and no meningococcal infections, with serious adverse events in three iptacopan and one placebo participant.
Clinical implications
Iptacopan offers the first targeted, mechanism-based oral therapy for C3 glomerulopathy, a disease that previously had no approved treatments. By reducing proteinuria on top of RAAS inhibition and immunosuppression with good tolerability, it represents a potentially important addition to management of this progressive disease.
Category
Research
Source
The Lancet
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