#1352 A multicenter, randomized, double-blind, placebo-controlled Phase 3 study in patients with idiopathic IC-MPGN: APPARENT protocol amendment

Abstract Background and Aims Immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) is a rare, fast-progressing kidney disease that may be idiopathic (primary) or secondary to chronic infection, autoimmune disorders, or monoclonal gammopathies. Idiopathic IC-MPGN has a comparable clinical course to complement 3 glomerulopathy (C3G). Iptacopan (LNP023) is an oral, proximal complement inhibitor that targets Factor B to selectively inhibit the alternative pathway (AP) of the complement cascade. Based on the learnings from the Phase 3 APPEAR-C3G study evaluating iptacopan 200 mg twice daily (b.i.d.) in patients with C3G, and to strengthen the evaluation of the treatment effect on preservation of kidney function, the APPARENT Phase 3 study design has been amended by extending the double-blind treatment period from 6 months to 12 months, introducing ‘inadequate response criteria (to enable participants to receive open-label iptacopan after 6 months of double-blind treatment)’, while the recruitment of adult patients is ongoing. Methods APPARENT (NCT05755386), a randomized, double-blind, multicenter, placebo-controlled Phase 3 study, is the first study to evaluate the efficacy and safety of iptacopan on top of supportive care in patients with idiopathic IC-MPGN. Approximately 106 adult and adolescent participants with biopsy-confirmed IC-MPGN, proteinuria (urine protein–creatinine ratio [UPCR]) ≥1 g/g, and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 will be enrolled in the study. All participants will have received maximally recommended or tolerated dose of renin angiotensin system inhibitors and vaccination against encapsulated bacteria. Participants with any cell or organ transplant, rapidly progressive crescentic glomerulonephritis, or kidney biopsy with >50% interstitial fibrosis/tubular atrophy, as well as secondary IC-MPGN, will be excluded. Eligible participants will be randomized 1:1 to receive either iptacopan 200 mg b.i.d. or placebo during the double-blind period, followed by open-label treatment with iptacopan 200 mg b.i.d. for all participants. The study consists of two Cohorts. Cohort 1 (Fig. 1A) includes adult participants enrolled in previous protocol versions who completed the Day 180 (6 months) visit and/or those who have not yet reached Day 180 and choose to continue with the 360 days (12 months) treatment period when the amended protocol is implemented. Cohort 2 (Fig. 1B) includes the newly enrolled adult participants after the implementation of the amended protocol along with those who enrolled in the previous protocol versions but have not yet reached Day 180 visit and have consented to the amended 540 days study period, as well as the adolescent participants (adolescent recruitment will start based on the amended protocol). All participants from both Cohorts after completion of the treatment period may transition to the roll-over extension program (NCT03955445). The primary objective of the study is to demonstrate the superiority of iptacopan versus placebo on proteinuria reduction measured as 24-h UPCR at 6 months. Key secondary endpoints include demonstrating the superiority of iptacopan versus placebo on proteinuria reduction measured as 24-h UPCR at 12 months, demonstrating the superiority of iptacopan versus placebo on stabilizing eGFR at 12 months (change from baseline in eGFR and annualized total eGFR slope), and participants who achieve composite renal endpoint (≤15% reduction in eGFR + ≥50% reduction in UPCR compared to baseline) at 6 and 12 months. Similar endpoints will be assessed for the open label treatment periods. The safety objectives are to evaluate the safety and tolerability of iptacopan in all participants and perform cardiovascular surveillance in adolescent participants (blood pressure, heart rate, cardiac function and biomarkers) during the double-blind and open-label periods. Results Recruitment is ongoing, and study is expected to complete in Q4 2028. Conclusion This study will provide evidence towards the efficacy and safety of iptacopan in idiopathic IC-MPGN in adult and adolescent patients.