Iptacopan Reduces Proteinuria and Stabilizes Kidney Function in C3 Glomerulopathy

Abstract

Introduction: C3 glomerulopathy (C3G) is a complex, chronic, ultra rare, progressive primary glomerulonephritis, resulting from alternative complement pathway overactivation, leading to kidney failure in most patients, and frequent recurrence in transplants. Iptacopan (LNP023) is an oral, proximal complement inhibitor specifically targeting factor B, that selectively inhibits the alternative complement pathway.

Methods: This was a phase 2 extension study of 26 adult patients with native kidney (cohort A), or recurrent C3G (post kidney transplantation; cohort B) receiving open label iptacopan.

Results: At 12 months, patients in cohort A had a significant reduction in 24-hour urine protein-to-creatinine ratio (UPCR; 57%; P < 0.0001; confidence interval [CI]: 0.31-0.59), an improvement in estimated glomerular filtration rate (eGFR; 6.83 ml/min per 1.73 m²; P = 0.0174; CI: 1.25-12.40), and an increase in serum C3 levels (geometric mean ratio to baseline: 3.53; P < 0.0001; CI: 3.01-4.15). In cohort B, most patients had normal urinary protein excretion at baseline (mean [range] 24-hour UPCR: 121 [9-445]), which was slightly lower by 12 months (21% reduction; CI: 0.48-1.31; P = 0.3151). In cohort B at 12 months, mean eGFR was at baseline values (mean change from baseline: -0.96 ml/min per 1.73 m²; P = 0.7335; CI: -6.60 to 4.69). Cohort B patients had significantly higher serum C3 values at 12 months compared with baseline (ratio:1.96; CI: 1.70-2.27; P < 0.0001). In cohorts A + B combined, the median difference in C3 deposit score on renal biopsy from baseline was -7.00 (CI: -12.00 to 4.00;) at 9 to 12 months treatment with iptacopan.

Conclusion: These data provide a clinical rationale for further evaluation of long-term treatment of C3G with iptacopan.

Keywords: C3 glomerulopathy; C3G; complement pathway; iptacopan; kidney; transplantation.

Graphical abstract

Figure 1

Study design of extension study. 1d refers to the day 1 visit for this extension study. At the final treatment visit of the 3-month phase 2 PoC study, patients who wished to continue to the extension study were asked to review and sign an informed consent form specific to the extension study in advance of the 3-month assessments for the phase 2 PoC study; these data were also used for the day 1 visit of the extension study. At screening for the extension study, inclusion and exclusion criteria were assessed and patients meeting these requirements were enrolled into the extension study and given their first dose of 200 mg bid iptacopan of the extension study. Patients returned to the study center for planned visits approximately every 3 months for the first year, and every 6 months thereafter for the duration of the study. For patients of the phase 2 PoC study, data collection during the open-label treatment period in the extension study was separated into 2 distinct periods, a “primary data collection period” ending at 9 months (i.e., 12 months of continuous treatment including that which occurred in the phase 2 PoC study), and a “longer-term data collection period” beginning at 9 months and continuing until the end of the study. The extension study is anticipated to last up to approximately 66 months. bid, twice daily; d, day; IA, interim analysis; mo, month; PoC, proof of concept.

Figure 2

Reduction in 24-hour urine protein-to-creatinine ratio (UPCR) in cohort A. Model-estimated geometric mean ratio to baseline (95% CI) of 24h UPCR (g/mol) from baseline to 12 months.CI, confidence interval; mo, month.

Figure 3

Individual time profiles (spaghetti plots) of eGFR with historical data (cohort A). Only patients with historical data are included. The blue shaded area is 95% confidence band, and the thick blue line is predicted fit. d, day; eGFR, estimated glomerular filtration rate; mo, month.

Figure 4

Arithmetic mean (± SE) of serum C3 (g/l) by cohort (safety analysis set). d, day; LLN, lower limit of normal; mo, month; SE, standard error.

Figure 5

Percentage of patients meeting the criteria of 3-point composite kidney end point over time in cohort A (safety analysis set). A patient was considered to have met the criteria for the 3-point composite kidney end point if they fulfilled all of the individual components: individual component 1: a stable or improved eGFR, defined as ≤10% reduction in eGFR compared to baseline; 2: either a ≥50% reduction in UPCR compared with baseline or a reduction to <300 mg/g in UPCR; 3: either a ≥50% increase in serum C3 compared with baseline or an increase to ≥90 mg/dl in serum C3 (i.e., ≥LLN). bid, twice daily; eGFR, estimated glomerular filtration rate; m, number of patients at each time point; mo, month; n, number of patients meeting the criteria at each time point; UPCR, urine protein-to-creatinine ratio; w, week.

Figure 6

Overlaying individual time profiles of % change from baseline in eGFR (ml/min/1.73 m²) in cohort B. d, day; eGFR: estimated glomerular filtration rate; mo, month.

Figure 7

Individual time profiles (spaghetti plots) of C3 deposit total score (cohorts A and B; safety analysis set). C3 deposit intensity was graded on a 0 to 3 scale for the mesangial and capillary location (both scored separately). The score for each location was multiplied by a factor of 1 for segmental (<50%) and a factor of 2 for global (≥50%) extent, resulting in a total score range of 0 to 12. d, day; mo, month.

Figure 8

Overlaying individual time profiles (spaghetti plots) of disease activity total score in kidney biopsies (cohorts A and B; safety analysis set). Two patients from cohort A and the remaining profiles are from patients in cohort B. mo, month.

Figure 9

Overlaying individual time profiles (spaghetti plots) of disease chronicity biopsy total score (cohorts A and B; safety analysis set). Two patients are from cohort A; the remaining profiles are from patients in cohort B. mo, month.

Figure 10

Biomarkers measured over time for cohort A and cohort B (safety analysis set)) Wieslab Assay (arithmetic mean [± SE] raw), (b) Bb (arithmetic mean [± SE] raw), (c) SC5b-9 (arithmetic mean [± SE] raw), (d) Lipocalin-2 (NGAL)/Cr (arithmetic mean [± SE] raw) for cohorts A and B. Cr, creatinine; d, day; m, month; NGAL, neutrophil gelatinase-associated lipocalin: SE, standard error; w, week.