#376 Evaluation of C3 deposition in patients with C3G: insights from the APPEAR-C3G Phase 3 study in patients treated with iptacopan

Abstract Background and Aims C3 glomerulopathy (C3G), is an ultra-rare primary glomerulonephritis caused by overactivation of the alternative complement pathway (AP). Iptacopan (LNP023) is an oral, proximal complement inhibitor that targets Factor B to selectively inhibit the AP of the complement cascade. We previously reported data from the Phase 3 APPEAR-C3G study (NCT04817618), showing a significantly reduced glomerular C3 deposit score in patients with C3G following 6 months of iptacopan treatment (200 mg twice-daily [bid]), compared with placebo. Here we provide an overview of a histopathologic approach currently used for C3 deposit staining, offer clarity on the methodology and scoring system employed in the APPEAR-C3G study, and rationale to better contextualize the results. The pattern of C3 deposition, either capillary or mesangial, in C3G can have clinical implications and be associated with prognosis. Method For the APPEAR-C3G study (NCT04817618), patients with biopsy-confirmed C3G were randomized to receive either iptacopan 200 mg bid or placebo for 6 months, followed by 6-month open-label iptacopan treatment for all patients. To examine the status of C3G disease progression, renal histopathology was evaluated in biopsies obtained at Day 45, Day 180 (mandatory) and Day 360 (optional), as an exploratory objective. All tissue samples were sent by sites to a central pathology vendor for processing. C3 staining uses a polyvalent antibody that binds to various complement breakdown products tagging human C3, C3b, iC3b and C3c. A positive immunofluorescence (IF) on tissue biopsies with the C3 polyvalent antibody visualizes C3 deposition associated with solid phase C3b and iC3b. C3 staining does not visualize fluid phase breakdown products (C3/C3b/iC3b/C3c). C3 staining represents a comprehensive estimate of C3 deposition and is currently the standard for clinical diagnosis and was used in APPEAR-C3G. APPEAR-C3G used a 12-point C3 deposit scoring system that incorporates IF intensity score graded from 0 to 3 for C3 deposition in the mesangium and capillary separately and a deposition extent multiplication factor (1 for segmental or 2 for global extent) for each region. Mesangial and capillary values were summed for a total scoring range of 0 to 12. A histopathology assessment committee comprising three independent pathologists and an independent reviewer for evaluation of concordance was incorporated for the C3 deposition score. Results All of the 74 patients that were randomized 1:1 to receive either iptacopan (n = 38) or placebo (n = 36), completed the 6-month double-blind period. Glomerular C3 deposit score assessments from 67 patients (iptacopan n = 32; placebo n = 35) were available at Day 180. Iptacopan reduced glomerular C3 deposition by an adjusted mean difference for iptacopan vs placebo of −1.88 in the C3 deposit score at Day 180 (1-sided, P = 0.0053). Individual components (mesangial and capillary) showed consistent reduction in glomerular C3 deposit score up to 6 months following treatment with iptacopan. However, C3 deposit scores in the placebo arm increased for both the individual components. Conclusion C3 deposit staining using the polyvalent antibody is the gold standard for diagnosis of C3G and shows comprehensive changes in C3 deposits. Iptacopan treatment significantly reduced C3 deposition in the glomeruli after 6 months of treatment in the APPEAR-C3G trial compared to placebo. Iptacopan showed reduction of both mesangial and capillary staining. Additional follow up is necessary to investigate the clinical association of these findings.