Efficacy and Safety of Pegcetacoplan in Kidney Transplant Recipients With Recurrent Complement 3 Glomerulopathy or Primary Immune Complex Membranoproliferative Glomerulonephritis

Abstract

Introduction: Complement 3 glomerulopathy (C3G) and primary immune complex membranoproliferative glomerulonephritis (IC-MPGN) have high risks for disease recurrence and allograft loss in transplant kidneys. Pegcetacoplan (targeted complement 3 [C3]/C3b inhibitor) may prevent excessive deposition of C3 and complement 5 [C5] breakdown products and associated renal damage.

Methods: NOBLE (NCT04572854) is a prospective, phase 2, multicenter, open-label, randomized controlled trial evaluating the efficacy and safety of pegcetacoplan in posttransplant patients with recurrent C3G or IC-MPGN. The primary end point was reduction in C3c staining on renal biopsy at week 12 for patients who received either pegcetacoplan 1080 mg twice weekly by subcutaneous infusion plus standard-of-care (SOC) or SOC only.

Results: Ten patients received pegcetacoplan and 3 received SOC only through week 12. At week 12, 5 of 10 pegcetacoplan-treated patients (50%) achieved ≥2 orders of magnitude (OOM) reduction in C3 staining (4 of these 5 had 0 staining and absent electron microscopy deposits) and 8 of 10 (80%) achieved ≥1 OOM reduction; 1 of 3 (33%) SOC-only patients showed staining reduction. Mean C3G histology activity score decreased by >54% in 8 of 10 pegcetacoplan-treated patients (80.0%). Pegcetacoplan-treated patients with baseline urine protein-to-creatinine ratio (uPCR) ≥1000 mg/g showed a median (interquartile range [IQR]) 54.4% (-56.33 to -53.95) reduction in proteinuria at week 12. In addition, pegcetacoplan-treated patients showed stable estimated glomerular filtration rate (eGFR), reduced plasma sC5b-9, and increased serum C3. Pegcetacoplan was well-tolerated and most adverse events were mild/moderate. No discontinuations, treatment withdrawals, or deaths were reported.

Conclusion: NOBLE demonstrated efficacy, safety, and tolerability of pegcetacoplan for patients with posttransplant recurrent C3G and primary IC-MPGN.

Keywords: C3 glomerulopathy; complement; immune complex membranoproliferative glomerulonephritis; pegcetacoplan; proteinuria.

Graphical abstract

Figure 1

Study design. OOM, orders of magnitude; SC, subcutaneous; SOC, standard-of-care. Note: Kidney biopsy was performed during the screening period, within 8 weeks of randomization. ^aProportion of patients with reduction in renal biopsy C3c staining (defined as a decrease of ≥2 OOM) at week 12 from baseline.

Figure 2

CONSORT flow diagram. SOC, standard-of-care.

Figure 3

Changes in histologic parameters from baseline to week 12. (a) Changes in C3c staining intensity. (b) Changes in C3G histology activity score. C3G, C3 glomerulopathy; IF, immunofluorescence; SOC, standard-of-care. Note: Solid lines represent patients who received pegcetacoplan plus SOC week 0–12. Dashed lines represent patients who received only SOC weeks 0–12.

Figure 4

Changes in uPCR from baseline to week 12. (a) Median (IQR) uPCR^a (mg/g) ratio to baseline change. (b) Changes in uPCR from baseline to week 12. (c) Median (IQR) uPCR^a (mg/g) ratio to baseline change for patients with uPCR ≥1000 mg/g at baseline. ^aMeasured by triplicate first-morning spot urine. IQR, interquartile range; ITT, intent-to-treat; Peg, pegcetacoplan; SOC, standard-of-care; uPCR, urine protein-to-creatinine ratio.

Figure 5

Change in complement biomarkers from baseline to Week 12 for (a) serum C3 and (b) plasma sC5b9. Note: Blue boxes represent normal ranges (serum C3: 94–166 mg/dl; sC5b-9: 59–207 ng/ml). C3, complement 3; IQR, interquartile range; ITT, intent-to-treat; Peg, pegcetacoplan; sC5b9, soluble complement 5b9; SOC, standard-of-care.