Iptacopan 200mg capsules

[This retracts the article DOI: 10.7759/cureus.67830.].

Abstract licence: CC BY

BACKGROUND: The alternative complement pathway plays a key role in the pathogenesis of IgA nephropathy. Iptacopan specifically binds to factor B and inhibits the alternative pathway. METHODS: In this phase 3, double-blind, randomized, placebo-controlled trial, we enrolled adults with biopsy-confirmed IgA nephropathy and proteinuria with a 24-hour urinary protein-to-creatinine ratio of 1 or higher (with protein and creatinine both measured in grams) despite optimized supportive therapy. Patients were randomly assigned, in a 1:1 ratio, to receive oral iptacopan (200 mg) or placebo twice daily for 24 months while continuing to receive supportive therapy. The primary objective of this prespecified interim analysis was to assess the efficacy of iptacopan as compared with that of placebo in reducing proteinuria at month 9; the primary end point was the change from baseline in the 24-hour urinary protein-to-creatinine ratio at month 9. The proportion of patients who had a 24-hour urinary protein-to-creatinine ratio of less than 1 at month 9 without receiving rescue or alternative medication or undergoing kidney-replacement therapy (dialysis or transplantation) was a secondary end point. Safety was also assessed. The effect of iptacopan on kidney function will be assessed at the end of the 2-year double-blind treatment period. RESULTS: The main trial population included 222 patients in the iptacopan group and 221 in the placebo group. The interim efficacy analysis included the first 250 patients who underwent randomization in the main trial population (125 patients in each group) and who remained in the trial until month 9 or discontinued the trial by month 9. Safety was assessed in all the patients in the main trial population. At month 9, the adjusted geometric mean 24-hour urinary protein-to-creatinine ratio was 38.3% (95% confidence interval, 26.0 to 48.6; two-sided P<0.001) lower with iptacopan than with placebo. The reduction in proteinuria was supported by consistent results in secondary end point analyses. There were no unexpected safety findings with iptacopan. The incidence of adverse events that occurred during the treatment period was similar in the two groups; most events were mild to moderate in severity and reversible. No increased risk of infection was observed. CONCLUSIONS: Among patients with IgA nephropathy, treatment with iptacopan resulted in a significant and clinically meaningful reduction in proteinuria as compared with placebo. (Funded by Novartis; APPLAUSE-IgAN ClinicalTrials.gov number, NCT04578834.).

Abstract licence: CC BY

IntroductionC3 glomerulopathy (C3G) is a rare complement-mediated kidney disease. Pegcetacoplan [targeted complement 3 (C3)/C3b inhibitor] and iptacopan (factor B inhibitor) target the complement system and are approved for treatment of C3G in adults and adolescents (pegcetacoplan) or adults only (iptacopan). Currently, no head-to-head randomized controlled trials (RCTs) have assessed their relative efficacy.MethodsIndirect treatment comparisons (ITCs) were conducted using the Bucher (primary analysis-preserves randomization) and matching-adjusted indirect comparison (MAIC; supportive analyses-adjusts for trial differences) methodologies and data from two similarly designed, placebo-controlled, Phase III RCTs in C3G/primary immune-complex membranoproliferative glomerulonephritis [VALIANT (NCT05067127)] and C3G only [APPEAR-C3G (NCT04817618)]. Relative efficacy was assessed at 6 months (anchored Bucher and MAIC) and 12 months (anchored Bucher/MAIC plus unanchored MAIC).ResultsAt 6 months, the Bucher analysis demonstrated pegcetacoplan was associated with a significantly greater reduction in urine protein-creatinine ratio (UPCR) relative to baseline versus iptacopan [mean difference -50.90% (95% confidence interval: - 67.34, - 26.18); p ConclusionThese ITCs indicate that, in patients with C3G, pegcetacoplan is associated with greater reductions in proteinuria levels, and more patients achieved the composite renal endpoint compared with iptacopan. The relative efficacy benefits for pegcetacoplan observed at 6 months were sustained at 12 months. These comparative effectiveness findings may help clinicians and payers better understand the utility of new therapies to treat patients with C3G.

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