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Pegcetacoplan Maintains Kidney Benefits at 52 Weeks
Pegcetacoplan, a targeted C3/C3b inhibitor, shows sustained, robust effects on key markers of kidney disease in patients with C3 glomerulopathy and primary immune complex membranoproliferative glomerulonephritis (IC-MPGN), according to 52-week results from the VALIANT trial.
The 26-week results, which were presented last October at Kidney Week 2024, showed a highly significant difference in change in proteinuria from baseline, as measured by the urine protein-to-creatinine ratio (uPCR); the reduction was 67.2% with pegcetacoplan vs 2.9% with placebo ( P < .0001).
The current findings showed that not only were these benefits sustained in patients who remained on pegcetacoplan, patients who switched from placebo to pegcetacoplan also experienced reductions of similar magnitude, said Fadi Fakhouri, MD, of Lausanne University Hospital and the University of Lausanne, Switzerland.
Fakhouri presented the 1-year results at the 62nd European Renal Association (ERA) Congress 2025.
VALIANT Open-Label Period
The phase 3 VALIANT trial involved 124 patients with native or post-transplant
recurrent C3 glomerulopathy or primary IC-MPGN who were randomly assigned to treatment two times a week with either subcutaneous pegcetacoplan 1080 mg, or weight-based doses for adolescents weighing ≤50 kg (n = 63); or to placebo (n = 61). In the subsequent 26-week open-label period, the placebo group crossed over and all patients received pegcetacoplan.
Overall, 59 (93.7%) people in the pegcetacoplan group and 55 (90.2%) in the placebo group completed the study treatment and 52-week assessment.
At week 52, patients in the original pegcetacoplan group maintained the significant proteinuria reduction that was observed at week 26, with a mean urine protein-to-creatinine ratio (UPCR) change at week 26 of –67.2% and at week 52 of –68.3%.
Patients in the placebo group, who experienced a +3.2% change in uPCR at week 26, experienced a reduction of –51.3% at week 52 after being switched to pegcetacoplan.
In addition, eGFR levels in the pegcetacoplan group dropped slightly from -1.2 mL/min/1.73 m2 at week 26 to -3.7 mL/min/1.73 m2 at week 52; in the placebo-to-pegcetacoplan group, the corresponding changes were -7.9 mL/min/1.73 m2 at week 26 and -4.7 mL/min/1.73 m2 at week 52.
In terms of safety, pegcetacoplan remained well-tolerated in the second 26 weeks, and treatment-emergent adverse events (TEAEs) were similar between the two arms during the open-label period (pegcetacoplan-to-pegcetacoplan, 77%; placebo-to-pegcetacoplan, 73.7%).
Overall, infusion-related TEAEs decreased from the randomized to open-label period in the pegcetacoplan-to-pegcetacoplan group (33.3% vs 9.8%, respectively), suggesting an improvement in tolerability over time.
Adherence was high, at 97.6% of patients having an adherence of ≥90% to ≤100%, overall.
Infections included two cases of pneumococcal pneumonia (including one that was serious) occurring during the open-label period, and there was one case each of streptococcal pharyngitis and urinary tract infection caused by Escherichia .
No patient deaths or allograft losses were reported.
'The open-label period results confirm pegcetacoplan's significant effect on kidney function,' Fakhouri said.
'Patients in the placebo arm experienced a decline in eGFR during the randomized controlled period, but a stabilization after switching to pegcetacoplan, comparable to randomized controlled period results in the pegcetacoplan group,' he added.
Patients With Baseline Nephrotic Range Proteinuria
The results of subanalyses looking at several other trial outcomes were also presented at the meeting.
These included an analysis of patients with nephrotic range proteinuria at baseline, who are at a notably high risk of rapid disease progression to kidney failure.
At baseline, 24 patients in the pegcetacoplan arm (38.1%) and 16 in the placebo arm (26.2%) had nephrotic range proteinuria, defined as a uPCR ratio ≥3 g/g.
At the end of the initial 26-week period, among patients with nephrotic range proteinuria, those treated with pegcetacoplan had a relative reduction of proteinuria of 72.1% compared with placebo ( P < .0001).
Patients Treated With Immunosuppressive Therapies
A second subanalysis evaluated outcomes among 48 (76%) participants in the pegcetacoplan group and 42 (69%) in the placebo group who were receiving concomitant immunosuppressive therapy at baseline.
Patients were permitted to continue the immunosuppressants provided that the doses had remained stable during the preceding 12-week period and throughout the trial.
The outcomes between the two groups were similar: Immunosuppressant-treated patients who received pegcetacoplan had a relative reduction of 70% in proteinuria vs placebo ( P < .0001), and among patients who did not receive immunosuppressants, the relative reduction was 64.5% compared to placebo ( P = .0005).
At week 26, 62.5% (30/48) of immunosuppressant‐treated patients receiving pegcetacoplan achieved a ≥50% reduction in proteinuria from baseline vs 4.8% (2/42) on placebo ( P < .0001). Among those not on immunosuppressants, 53.3% (8/15) of the pegcetacoplan group met the same endpoint compared with 5.3% (1/19) in the placebo arm ( P = .0087).
'Reassuringly, proteinuria was reduced in both groups, and the immunosuppressed group had a highly statistically significant reduction,' said David Kavanagh, MD, of the National Renal Complement Therapeutics Centre, Newcastle University, Newcastle upon Tyne, United Kingdom, who presented this subanalysis.
Other outcomes, including stabilization of eGFR, were also similar to the overall reductions, including those patients not on immunosuppressants.
Importantly, rates of TEAEs were also comparable between the immunosuppressed and non-immunosuppressed patients.
'If you can reduce your proteinuria by at least 50%, you're going to have an outcome that can reduce the risk of kidney failure,' Kavanagh concluded.
The studies were sponsored by Apellis. Fakhouri reported relationships with Apellis, Sobi, Novartis, Roche, Alexion Pharmaceuticals, and AstraZeneca. Kavanagh reported relationships with Idorsia, Novartis, Chemocentryx, Alexion Pharmaceuticals, Samsung, Sobi, Gyroscope Therapeutics, Purespring, and Apellis.
