MO148A MULTI-CENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO CONTROLLED, PARALLEL GROUP, PHASE III STUDY TO EVALUATE THE EFFICACY AND SAFETY OF LNP023 IN PRIMARY IGA NEPHROPATHY PATIENTS

Background and Aims IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. It is an autoimmune disease characterized by deposits of IgA1-containing immune complexes in the glomerular mesangium leading to local inflammation and subsequent decline in kidney function. Currently, there are no targeted therapies for IgAN. The KDIGO guidelines (2012) recommend optimized long-term supportive care including inhibition of the RAS (ACEi or ARB) as well as lifestyle modification for blood pressure control and proteinuria reduction. Patients who remain at high risk of progressive CKD despite maximal supportive care might be considered for high-dose corticosteroids or immunosuppressants. In recent years, mounting evidence has supported an important role for complement activation in disease onset and progression of IgAN. The alternative complement pathway (AP) and lectin complement pathway (LP) are found to be activated in 75-90% and 17-25% of IgAN patients, respectively (Floege et al 2014, Maillard et al 2015). Factor B (FB) is an essential component of C3- and C5-convertases. Iptacopan (LNP023) is an oral, first-in-class, highly potent selective inhibitor of FB and thereby blocks the activity of AP C3 and C5 convertases, inhibiting the AP as well as the amplification of the classic and lectin complement pathways. Currently, iptacopan is being evaluated in an ongoing adaptive seamless double-blind and placebo-controlled dose-ranging Phase 2 study (CLNP023X2203, Part 1 and Part 2) in patients with biopsy-confirmed IgAN and elevated proteinuria [urine protein to creatinine ratio (UPCR) ≥ 0.75 g/g]. An interim analysis (IA) at 90 days of treatment in the Part 1 study showed that iptacopan administered up to 200 mg b.i.d for 90 days was safe, well tolerated and may be effective in reducing proteinuria. A further IA combining participants in Part 1 and Part 2 will be completed in early 2021 and the pivotal phase 3 trial is to start in early 2021. Aim APPLAUSE-IgAN (NCT04578834; CLNP023A2301) is a multicenter, randomized, double-blind, placebo-controlled parallel-group Phase 3 study which aims to evaluate the efficacy and safety of iptacopan (LNP023) compared with placebo in addition to supportive therapy on proteinuria reduction and slowing kidney disease progression in primary IgAN patients. Method Adult patients diagnosed with primary IgAN (based on kidney biopsy and elevated proteinuria [UPCR ≥ 1 g/day]) will be recruited. A run-in period will ensure that patients have received ACEi/ARB at a maximally tolerated dose for at least 90 days and receive required vaccinations at least 2 weeks prior to first dosing. Patients will be randomized in a 1:1 ratio to either iptacopan 200 mg b.i.d or matching placebo for a 24-month treatment period. The trial will enroll approximately 450 participants, aiming for 430 with eGFR ≥30 mL /min/1.73m2 (main study population). About 20 participants with eGFR 20 to <30 mL/min/1.73m2 (severe renal impairment population) will also be enrolled to explore PK and safety of iptacopan in this group, but will not be included in the efficacy analyses. Primary objectives 1) At IA (when approximately 250 patients have completed the 9 months visit): To demonstrate superiority of iptacopan vs. placebo in the reduction of proteinuria. The IA results may be submitted to support accelerated/conditional approval. 2) At final analysis (when approximately 430 patients have completed 24 months of active treatment): to demonstrate superiority of iptacopan vs. placebo in slowing kidney disease progression measured by the annualized total slope of eGFR decline over 24 months. Results Recruitment will start in Q1 2021. Conclusion This trial will evaluate the efficacy of iptacopan, a promising new therapy for IgAN, in reducing proteinuria and slowing loss of kidney function over 2 years.