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IC-MPGN is an ultra-rare, fast-progressing complement-mediated kidney disease characterized by immunoglobulin deposits in the kidneys, which may be idiopathic (primary) or secondary to chronic infections, autoimmune disorders, or monoclonal gammopathies. The clinical presentation and disease course are comparable to complement 3 glomerulopathy, also characterized by membranoproliferative histology. Dysregulation of the alternative pathway (AP) is strongly implicated in the pathogenesis of both glomerulonephritis entities including children and adults.
Primary IC-MPGN is frequently diagnosed by adolescence with no approved treatments that target the underlying complement-mediated pathophysiology. Given the fast-progressing nature of the disease, there is a high unmet need for treatment in patients with IC-MPGN. Iptacopan (LNP023) is an oral, highly potent proximal complement inhibitor that specifically binds to factor B and inhibits the AP.
This randomized, double-blind, placebo-controlled, pivotal Phase 3 study is the first to evaluate the efficacy and safety of iptacopan in patients with idiopathic IC-MPGN (see Figure). Approximately 68 patients will be randomized to a 1:1 ratio (iptacopan:placebo), including at least 10 adolescents aged 12–17 years, (recruited in cohorts of 5). All patients will have biopsy-confirmed idiopathic (primary) IC-MPGN (within 12 months [adults] and 3 years [adolescents]) prior to enrollment, proteinuria ≥1 g/g, and eGFR ≥30 mL/min/1.73 m2 and will receive maximally tolerated renin-angiotensin inhibitors (e.g., ACEi/ARBs) and vaccination against encapsulated bacteria. Patients with an organ transplant, secondary IC-MPGN, kidney biopsy with >50% interstitial fibrosis/tubular atrophy, as well as those receiving systemic prednisone >7.5 mg/day or other immunosuppressants (except mycophenolic acids), within 90 days of iptacopan administration will be excluded.
Study treatment phase comprises a 6-month double-blind period (either iptacopan 200 mg [2 x 100 mg capsules for adolescents] twice daily [bid] or placebo) followed by a 6-month open-label period (iptacopan 200 mg bid) for all study participants.
The primary objective is to demonstrate the superiority of iptacopan versus placebo on proteinuria reduction as measured by UPCR (24h urine collection) at 6 months. Key secondary endpoints will assess improvement in eGFR, proportion of patients who achieve a proteinuria–eGFR composite endpoint, and improvement in patient-reported fatigue. The safety objectives will evaluate the safety and tolerability of iptacopan in all patients. Adolescents will be evaluated for blood pressure and heart rate effects at the first open-label dosing. Supplementary cardiovascular safety surveillance will be carried out in these patients to assess the potential effect of iptacopan on blood pressure, heart rate, cardiac function and biomarkers of cardiac injury at study visits.
The study has already started (NCT05755386) and is expected to start recruiting adolescent patients in 2024.
This study will provide evidence towards the efficacy and safety of iptacopan in adult as well as adolescent patients with idiopathic (primary) forms of IC-MPGN.