#1467 Pegcetacoplan for post-transplant recurrent C3 glomerulopathy or immune complex membranoproliferative glomerulonephritis in NOBLE: 12-week evolution

Abstract Background and Aims C3 glomerulopathy (C3G) and primary immune complex membranoproliferative glomerulonephritis (IC-MPGN) are rare diseases caused by uncontrolled complement activation, resulting in excess deposition of C3 breakdown products in the kidneys, which leads to kidney damage and eventually kidney failure. Kidney transplantation is an option for end-stage kidney disease, but disease recurrence is common (up to 67% of patients), and up to 50% of transplant recipients lose renal allografts due to recurrence. Pegcetacoplan is a targeted C3 and C3b inhibitor that may prevent excess deposition of C3 and C5 breakdown products and subsequent glomerular inflammation and kidney damage in patients with C3G or IC-MPGN, potentially improving clinical outcomes. NOBLE (NCT04572854) was the first prospective randomized controlled trial of pegcetacoplan vs standard of care (SOC) in post-transplant patients with recurrent C3G or IC-MPGN. Method Adult patients were randomized 3:1 to subcutaneous pegcetacoplan 1080 mg twice weekly plus SOC (n = 10) or SOC only (n = 3) for 12 weeks followed by a 40-week non-controlled period in which all patients received pegcetacoplan. Primary and secondary endpoint results for Week-12 data have been reported. We conducted a patient-level post hoc analysis to describe key histology changes from renal biopsy (C3c staining, C3G histologic index activity score), clinical parameters (urine protein-to-creatinine ratio [uPCR; calculated from triplicate first-morning spot urine], estimated glomerular filtration rate [eGFR]), and biomarkers (serum C3, plasma sC5b-9) through Week 12. The C3G histologic index uses a semiquantitative scale of 0–3 for 7 markers of activity (mesangial hypercellularity, endocapillary proliferation, membranoproliferative morphology, leukocyte infiltration, cellular and/or microcellular crescent formation, fibrinoid necrosis, and interstitial inflammation), for a total activity score of 0–21. eGFR stability was defined as a decrease of no more than 25% versus baseline. Results Among the 10 pegcetacoplan-treated patients, 7 (70%) had 1 previous kidney transplant, 2 (20%) had 2, and 1 (10%) had 3. The mean (range) time to disease recurrence after most recent transplant was 10.8 (0.4–31.8) months and from most recent recurrence to randomization was 12.2 (2.1–37.7) months, with 60% randomized >6 months post-disease recurrence. Among the 3 SOC-only patients, 2 (66.7%) had 1 transplant and 1 (33.3%) had 2. Mean (range) time to recurrence was 32.8 (4.6–63.8) months and to randomization was 33.9 (7.0–65.4) months. At Week 12, 8 (80%) pegcetacoplan-treated patients had a reduction in C3c staining of at least 1 order of magnitude. Of these 8, 7 (70%) had a decrease in activity score, and 6 of these 7 (60%) had a decrease in proteinuria. Four (40%) patients had reduced C3c staining, decreased activity score, and cleared electron microscopy deposits at Week 12. eGFR remained stable in 9 (90%) patients. Six of 9 (67%) patients with available Week-12 data (4 of 5 patients with >1 g/g uPCR at baseline) had a reduction in uPCR with 5 of the 6 achieving ≥50% uPCR reduction (Table). All pegcetacoplan-treated patients had increased serum C3, as expected, and 9 (90%) had decreased sC5b-9. At Week 12, no TEAEs led to study discontinuation, treatment withdrawal, or death. No encapsulated bacterial infections or events of rejection/graft loss related to the study drug were reported. Conclusion As early as Week 12, more than half (6/10 [60%]) of post-transplant patients with recurrent C3G or IC-MPGN treated with pegcetacoplan achieved reductions in C3c staining, activity score of C3G histology index, and proteinuria, suggesting that pegcetacoplan targets the underlying pathophysiology of the C3G/IC-MPGN in kidney transplant recipients. The safety and efficacy of pegcetacoplan will be further evaluated at Week 52 of the NOBLE study and as part of the Phase 3 VALIANT (NCT05067127) trial, which enrolled patients with C3G or primary IC-MPGN who have native kidney or post-transplant disease.