Results of a randomized double-blind placebo-controlled Phase 2 study propose iptacopan as an alternative complement pathway inhibitor for IgA nephropathy.
A randomized, double-blind, placebo-controlled Phase 2 study found that the oral alternative-pathway complement inhibitor iptacopan produced a significant dose-dependent reduction in proteinuria in IgA nephropathy, supporting its advancement to Phase 3.
Background
Targeting the alternative complement pathway is an attractive therapeutic strategy in IgA nephropathy (IgAN) given its role in disease pathogenesis. Iptacopan (LNP023) is an oral, proximal alternative complement inhibitor that specifically binds Factor B, blocking alternative-pathway C3 and C5 convertase activity.
Study design
This randomized, double-blind, parallel-group adaptive Phase 2 study (NCT03373461) enrolled patients with biopsy-confirmed IgAN, an eGFR of 30 mL/min/1.73 m2 or higher, and urine protein of 0.75 g/24 hours or more on stable renin-angiotensin system inhibitors. Patients were randomized to iptacopan 10, 50, 100, or 200 mg twice daily or placebo for a three-month (Part 1; 46 patients) or six-month (Part 2; 66 patients) treatment period, with the primary analysis evaluating the dose-response on 24-hour urine protein-to-creatinine ratio (UPCR) at three months.
Key findings
A statistically significant dose-response effect was observed, with a 23% reduction in UPCR achieved at three months with iptacopan 200 mg twice daily (80% confidence interval 8-34%). UPCR decreased further through six months in the 100 and 200 mg arms, falling from a mean of 1.3 g/g at baseline to 0.8 g/g at six months in the 200 mg arm, accompanied by sustained reductions in complement biomarkers including plasma Bb, serum Wieslab, and urinary C5b-9. Iptacopan was well tolerated, with no deaths, treatment-related serious adverse events, or bacterial infections reported.
Clinical implications
By demonstrating strong inhibition of alternative-pathway activity and persistent proteinuria reduction, these findings support iptacopan as a targeted complement-directed option for IgAN. The results provided the rationale for the ongoing Phase 3 APPLAUSE-IgAN trial (NCT04578834) evaluating iptacopan in patients at high risk of progression to kidney failure.
Category
Research
Source
Kidney Int
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