Pegcetacoplan delivers in rare CMKDs causing nephrotic-range proteinuria

In patients with either of two rare complement-mediated kidney diseases (CMKDs) — complement component 3 glomerulopathy (C3G) or primary immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) — presenting with nephrotic-range proteinuria, treatment with pegcetacoplan reduces proteinuria and C3c renal biopsy staining and stabilizes kidney function, according to results from a post hoc analysis of the VALIANT trial presented at ERA 2025.

While improvements in these three efficacy endpoints with pegcetacoplan had been demonstrated in the overall VALIANT population, a population with nephrotic-range proteinuria (urine protein-creatinine ratio [UPCR] ≥3 g/g) at baseline in the phase III trial (n=40) also saw improvements with pegcetacoplan in the three established surrogate measures for clinical outcomes. [Kidney Week 2024, abstract SA-OR92; Clin J Am Soc Nephrol 2024;19:1201-1208]

Of these 40 patients, the mean baseline first-morning spot UPCR was 5.4 g/g for those randomized to receive pegcetacoplan and 5.3 g/g for those randomized to receive placebo. Treatment with subcutaneous pegcetacoplan resulted in a relative reduction in proteinuria of 72.1 percent at week 26 vs placebo (nominal p<0.0001). Substantially more pegcetacoplan-treated patients than placebo-treated patients had a ≥50 percent reduction in proteinuria at 26 weeks (66.7 percent vs 0 percent; nominal p<0.0001). [ERA 2025, abstract 3265]

More C3G patients who received the C3-targeted therapy vs placebo showed reduced glomerular C3c staining from baseline to week 26 (84.6 percent vs 0 percent; nominal p=0.0002).

Additionally, patients in the pegcetacoplan arm had a relative improvement in estimated glomerular filtration rate of +16.2 mL/min/1.73 m² at week 26 vs those in the placebo arm (least squares mean changes, +4.7 vs −11.5 mL/min/1.73 m²; nominal p=0.0046).

“In this particularly sensitive population with more severe disease, pegcetacoplan was efficacious,” said Dr Antonio Mastrangelo, a nephropathologist at the Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Lombardy, Italy. “While more severe disease can lead to chronic lesions in the kidneys that may manifest as nephrotic-range proteinuria, patients in the pegcetacoplan group showed controlled disease activity, even though chronic lesions may still be present.”

C3G and primary IC-MPGN are rare CMKDs affecting the glomeruli. The prognosis is variable but generally unfavourable, with approximately half of patients progressing to kidney failure within 10 years of diagnosis. However, a ≥50 percent reduction in proteinuria over time may lower this risk (hazard ratio, 0.61, 95 percent confidence interval, 0.46–0.75; p<0.001). [Kidney Int 2020;98:1135-1148; Kidney Int Rep 2025;10:1223-1236]

“Surprising” safety

By inhibiting C3 and C3b, pegcetacoplan targets the complement cascade at the central convergence point, resulting in ‘proximal’ complement inhibition. The more downstream C5 is not directly inhibited, meaning pegcetacoplan may regulate complement overactivation broadly while still allowing C5 activation to defend against meningococcal infections. [Front Immunol 2023:14:1180833]

“I’m really surprised how safe it is to block C3,” said moderator Professor Jürgen Floege from the RWTH Aachen University Hospital, Aachen, North Rhine-Westphalia, Germany.

Up to 26 weeks, no encapsulated bacterial infections were observed following pegcetacoplan treatment in VALIANT. This was consistent with clinical trials and post-marketing experience totalling >2,000 patient-years of pegcetacoplan exposure.

“I agree that the safety is surprising,” replied Mastrangelo. “There have been a lot of data on its use in paroxysmal nocturnal haemoglobinuria, so I think that we could be confident in this.”

Participants in VALIANT were adolescents aged ≥12 years and adults (n=124) with either naïve disease or post-transplant recurrent disease. In the population of the current analysis (mean age 26.2 years, 75 percent female), 67.5 percent had C3G as the underlying disease, while the remainder had primary IC-MPGN.