Alternative Complement Pathway Inhibition With Iptacopan for the Treatment of C3 Glomerulopathy-Study Design of the...

Complement 3 glomerulopathy (C3G) is a rare kidney disease characterized by dysregulation of the alternative pathway (AP) of the complement system. About 50% of patients with C3G progress to kidney failure within 10 years of diagnosis. Currently, there are no approved therapeutic agents for C3G. Iptacopan is an oral, first-in-class, potent, and selective inhibitor of factor B, a key component of the AP. In a Phase II study, treatment with iptacopan was associated with a reduction in proteinuria and C3 deposit scores in C3G patients with native and transplanted kidneys, respectively.

APPEAR-C3G (NCT04817618) is a randomized, double-blind, and placebo-controlled Phase III study to evaluate the efficacy and safety of iptacopan in C3G patients, enrolling 68 adults with biopsy-confirmed C3G, reduced C3 (<77 mg/dl), proteinuria ≥1.0 g/g, and estimated glomerular filtration rate (eGFR) ≥30 ml/min per 1.73 m². All patients will receive maximally tolerated angiotensin-converting enzyme inhibitor/angiotensin receptor blocker and vaccination against encapsulated bacteria. Patients with any organ transplantation, progressive crescentic glomerulonephritis (GN), monoclonal gammopathy of undetermined significance, or kidney biopsy with >50% interstitial fibrosis/tubular atrophy, will be excluded. Patients will be randomized 1:1 to receive either iptacopan 200 mg twice daily or placebo for 6 months, followed by open-label treatment with iptacopan 200 mg twice daily for all patients for 6 months. The primary objective is to evaluate the efficacy of iptacopan versus placebo on proteinuria reduction urine protein:creatinine ratio (UPCR) (24 h urine). Key secondary endpoints will assess kidney function measured by eGFR, histological disease total activity score, and fatigue.

This study aims to demonstrate the clinical benefits of AP inhibition with iptacopan in C3G.