Efficacy and Safety of Iptacopan in Patients With C3 Glomerulopathy

Abstract

Introduction: Complement 3 glomerulopathy (C3G) is a rare inflammatory kidney disease mediated by dysregulation of the alternative complement pathway. No targeted therapy exists for this aggressive glomerulonephritis. Efficacy, safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) (measured by complement biomarkers) of iptacopan were assessed in patients with C3G.

Methods: In this phase 2, multicenter, open-label, single-arm, nonrandomized study, adults with biopsy-proven, native kidney C3G (native cohort) and kidney transplant recipients with C3G recurrence (recurrent kidney transplant [KT] cohort) received iptacopan twice daily (bid) for 84 days (days 1-21: 10-100 mg; days 22-84: 200 mg). The primary end point was the urine protein-to-creatinine ratio (UPCR; native cohort) and the change in the C3 deposit score of kidney biopsy (recurrent KT cohort). The complement pathway measures included Wieslab assay, soluble C5b9, and serum C3 levels.

Results: A total of 27 patients (16 native cohort and 11 recurrent KT cohort) were enrolled and all completed the study. In the native cohort, UPCR levels decreased by 45% from baseline to week 12 (P = 0.0003). In the recurrent KT cohort, the median C3 deposit score decreased by 2.50 (scale: 0-12) on day 84 versus baseline (P = 0.03). Serum C3 levels were normalized in most patients; complement hyperactivity observed pretreatment was reduced. Severe adverse events (AEs) included post-biopsy hematuria and hyperkalemia. No deaths occurred during the study.

Conclusion: Iptacopan resulted in statistically significant and clinically important reductions in UPCR and normalization of serum C3 levels in the native cohort and reduced C3 deposit scores in the recurrent KT cohort with favorable safety and tolerability. (ClinicalTrials.gov identifier: NCT03832114).

Keywords: complement 3 glomerulopathy; inflammatory kidney disease; iptacopan; kidney transplant; urine protein-to-creatinine ratio.

Graphical abstract

Figure 1

Kidney function and C3 deposit score after iptacopan treatment in patients with native and recurrent KT C3G^¶. (a) UPCR (adjusted GM [80% CI] of log ratio to baseline) in patients with native C3G; (b) C3 total deposit score (individual plots; n = 9) for patients with recurrent KT C3G. ^†Baseline is defined to be the 24-hour urine collection on day −1 to day 1. ^‡Patients with only baseline values; day 84 biopsy was either not taken or was damaged. ^§For patient represented by the blue line, the C3G recurrence was confirmed by investigator based on a previous biopsy as per inclusion criteria. ^¶A patient with recreational drug overdose was excluded from analysis. C3G, complement 3 glomerulopathy; CI, confidence interval; GM, geometric mean; KT, kidney transplant; UPCR, urine protein-to-creatinine ratio.

Figure 2

Pharmacokinetic profile of iptacopan. Arithmetic mean + SD PK plasma concentration over time (hour) for iptacopan doses in native cohort (a) and in recurrent KT cohort (b). bid, twice daily; KT, Kidney transplant; PK, pharmacokinetic.

Figure 3

Effect of iptacopan on biomarkers. Arithmetic mean ± SE, serum C3 (a), serum Wieslab activity (b), plasma sC5b9 (c), creatinine normalized urine sC5b9 (d), plasma Bb (e). Values below LLOQ are imputed as LLOQ/2 and values above ULOQ are imputed as ULOQ for the analysis. Baseline visit is defined to be the baseline 1 visit assessment (day −30). ∗Baseline is defined as day 1 predose assessment. LLOQ, lower limit of quantification; SE, standard error; ULOQ, upper limit of quantification.