#2548 Long-term stabilization of kidney function (estimated glomerular filtration rate) with iptacopan in patients with native C3 glomerulopathy

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. The estimated glomerular filtration rate (eGFR) slope (i.e. the rate of decline over time) is accepted as a surrogate endpoint in glomerular diseases. We have previously reported stabilization of eGFR parameters with iptacopan treatment across Phase 2 and 3 studies. This pooled analysis aims to demonstrate the long-term stabilization of eGFR observed with iptacopan treatment in patients with native C3G. Method In this pooled exploratory analysis, data spanning up to 57 months were combined for all patients with native C3G from Study X2202 (Phase 2), APPEAR-C3G (Phase 3), and Study B12001B (Phase 3b, roll-over extension; Table 1). Improvement in kidney function through long-term stabilization of eGFR was evaluated by comparing the change in eGFR slope from prior to treatment with iptacopan to post-iptacopan treatment initiation (200 mg b.i.d.) in the overall study population and subgroups of participants with baseline eGFR <90 mL/min/1.73 m2 versus ≥90 mL/min/1.73 m2 (normal range). Historical serum creatinine data (collected up to 2 years before randomization) were used to calculate eGFR using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula. Pooling the data allowed for more precise eGFR slope reporting. Before iptacopan treatment, a common eGFR slope was assumed for all treatment arms. Results A total of 90 patients with native C3G were included in the pooled analysis (baseline eGFR ≥90 mL/min/1.73 m2, n = 47; <90 mL/min/1.73 m2, n = 43). In the overall study population, an improvement in post-iptacopan treatment initiation eGFR slope was observed (change in slope: 7.62 mL/min/1.73 m2/year, P < 0.0001; Table 2). Subgroup analyses demonstrated an improvement in post-iptacopan treatment initiation eGFR slope in participants with baseline eGFR <90 mL/min/1.73 m2 (eGFR slope change: 12.98 mL/min/1.73 m2/year, P < 0.0001) but not in participants with baseline eGFR ≥90 mL/min/1.73 m2 (eGFR slope change: 0.57 mL/min/1.73 m2/year, P = NS; Table 2). In the subgroup with eGFR ≥90 mL/min/1.73 m2, the eGFR slope was only minimally negative in the prior to treatment with iptacopan period and remained unchanged post-iptacopan treatment initiation. These pooled data are consistent with eGFR slopes from the individual studies. Conclusion The findings from this pooled analysis indicate that in patients with native C3G, treatment with iptacopan 200 mg b.i.d. resulted in the stabilization of eGFR trajectory, with significant change observed in patients with at least mild renal impairment from C3G disease at baseline (<90 mL/min/1.73 m2) and maintenance of stable eGFR in those with normal baseline eGFR (≥90 mL/min/1.73 m2). eGFR slope analysis has demonstrated valuable utility in monitoring kidney function over time, and these data suggest iptacopan treatment results in a long-term, clinically relevant positive impact on kidney function.

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