Pegcetacoplan Maintains C3G Response at 76 Weeks, With Carla Nester, MD

Patients with C3 glomerulopathy (C3G) or primary immune complex membranoproliferative glomerulonephritis (IC-MPGN) maintained a 64.1% reduction in proteinuria through 76 weeks of pegcetacoplan (Empaveli) treatment, with relatively stable kidney function over the same period.¹

The interim findings from the phase 3 VALIANT trial and its VALE extension were presented at the American Society of Nephrology (ASN) Kidney Week 2026 in Denver, Colorado. The analysis suggests the proteinuria reduction observed during the randomized trial was sustained with continued treatment, while differences in estimated glomerular filtration rate (eGFR) by baseline kidney scarring raised questions about the potential importance of treatment timing.¹

Carla Nester, MD, MS, FASN, lead author of the analysis, professor of internal medicine and pediatrics, and director of pediatric nephrology at University of Iowa Stead Family Children’s Hospital, discussed the findings in an interview with HCPLive, including their implications for longer-term disease management and the questions remaining about complement-targeted treatment.

Why Longer-Term Proteinuria Reduction Matters in C3G

C3G and primary IC-MPGN are rare kidney diseases involving dysregulation of the complement system. Both can lead to progressive kidney damage and kidney failure. Historically, management relied on supportive care and nonspecific immunosuppression. In 2025, the US Food and Drug Administration (FDA) approved pegcetacoplan, a C3 and C3b inhibitor, for patients aged ≥12 years with C3G or primary IC-MPGN.³

During VALIANT’s 26-week randomized period, pegcetacoplan reduced proteinuria by 68.1% relative to placebo (P <.0001).² The extension analysis examined whether reductions in proteinuria persisted with continued treatment and how kidney function changed over a longer observation period.

“We want to know that the effect is lasting because obviously it doesn’t help if you treat, if you get a urine protein reduction, but then after seven months or eight months, it’s gone,” Nester said.

Nester explained that proteinuria reduction serves as an important surrogate marker for kidney outcomes in C3G and primary IC-MPGN. However, sustained reductions in proteinuria do not independently establish whether treatment prevents kidney failure, making longer-term kidney function data particularly relevant.

VALIANT+VALE 76-Week Analysis Design

VALIANT was a randomized, double-blind, placebo-controlled trial enrolling 124 patients aged ≥12 years with C3G or primary IC-MPGN, including patients with native kidneys or recurrent disease following kidney transplantation.² Patients completing VALIANT were eligible to enter VALE, an open-label extension in which they could receive pegcetacoplan.

The interim analysis included 120 patients with up to 76 weeks of pegcetacoplan exposure. Investigators aligned outcomes according to treatment duration and evaluated the overall population alongside subgroups defined by baseline interstitial fibrosis and tubular atrophy (IFTA), a histologic measure of kidney scarring.¹

The 2 reported subgroups were IFTA ≤25% and IFTA 26% to 50%.

Pegcetacoplan Proteinuria and eGFR Results Through 76 Weeks

In the overall population, the geometric mean change in proteinuria at week 76 was –64.1% (95% confidence interval [CI], –71.2 to –55.2). The least squares (LS) mean change in eGFR was –1.4 mL/min/1.73 m² (95% CI, –6.6 to 3.9), and the annualized eGFR slope was –1.4 mL/min/1.73 m² per year (95% CI, –4.8 to 1.9).¹

These findings indicate a sustained proteinuria response and relatively little mean change in eGFR over the observation period, although the confidence intervals allow for a range of kidney function outcomes.

Results varied by baseline IFTA. Among patients with IFTA ≤25% (n = 94), proteinuria decreased by 66.8% (95% CI, –73.8 to –57.9), and LS mean eGFR increased by 1.7 mL/min/1.73 m² (95% CI, –3.9 to 7.3). In patients with IFTA of 26% to 50% (n = 23), proteinuria decreased by 52.6% (95% CI, –68.7 to –28.1), while eGFR declined by 11.0 mL/min/1.73 m² (95% CI, –20.3 to –1.6).¹

Nester described the overall eGFR findings as encouraging in the context of observational data documenting kidney function decline in patients with C3G. However, the extension analysis was not a randomized comparison of long-term eGFR outcomes against an untreated control group.

The investigators identified baseline kidney scarring as a potential factor in treatment response, with more favorable eGFR findings among patients with less fibrosis. The subgroup with greater IFTA was relatively small, and the analysis did not directly evaluate whether initiating treatment earlier improves outcomes.

“For the average clinician, what that should mean, for me certainly it did, is that treating early is key,” Nester said. “So using targeted therapy early feels to me, you know, by this data to be the right thing to do.”

Longer-Term Safety of Complement Inhibition

The investigators reported no new safety signals through 76 weeks of pegcetacoplan exposure.¹ Nester described the findings as reassuring relative to earlier concerns about infection risk associated with complement inhibition, noting that observed adverse events included headaches and cough.

Nevertheless, pegcetacoplan carries an FDA boxed warning for serious infections caused by encapsulated bacteria, including potentially life-threatening infections. Patients require appropriate vaccination before treatment, and clinicians must follow prescribing information regarding infection-risk precautions, including additional measures when treatment cannot be delayed until the recommended vaccination interval has elapsed.³

The absence of new safety signals in this interim analysis does not eliminate the possibility of serious infections with longer exposure or in broader clinical populations.

In a separate HCPLive interview, Bradley Dixon, MD, discussed the potential role of earlier complement inhibition and considerations surrounding infection risk relative to conventional immunosuppressive approaches.

Earlier Treatment and Remaining Questions in C3G Care

Nester said additional long-term follow-up, real-world epidemiologic data, and formal treatment guidelines will be important for determining how complement inhibitors should be incorporated into routine care.

Based on her interpretation of the available evidence, she anticipates considering pegcetacoplan as a first-line targeted treatment and potentially as the sole immunosuppressive agent for appropriate patients, while continuing standard chronic kidney disease management, including blood pressure and lipid control.

She emphasized the need for further evidence to determine whether earlier initiation or reduced reliance on conventional immunosuppression improves long-term kidney outcomes.

Nester also highlighted the importance of including younger patients in discussions about complement-targeted treatment. Patients aged 12 to 17 years were eligible for VALIANT, and a separate 76-week analysis in adolescents reported sustained proteinuria reduction during continued pegcetacoplan exposure.

For Nester, the longer-term findings add to the evidence supporting sustained proteinuria reduction with pegcetacoplan, while the differences observed across baseline fibrosis subgroups underscore the need to better understand which patients may derive the greatest long-term kidney benefit.

Editor’s Note: Nester reports relevant disclosures involving Apellis Pharmaceuticals. The analysis was supported by Apellis Pharmaceuticals and Sobi.

References

1. Nester CM, Bomback AS, Ariceta Iraola MG, et al. Pegcetacoplan for 76 weeks maintains proteinuria reduction and stabilizes kidney function in C3 glomerulopathy or primary immune-complex membranoproliferative glomerulonephritis (IC-MPGN). Abstract SA-OR054. Presented at: American Society of Nephrology Kidney Week 2026; October 24, 2026; Denver, CO. Accessed November 5, 2026. https://www.asn-online.org/education/kidneyweek/2026/program-abstract.aspx?controlId=4555846

2. Fakhouri F, Bomback AS, Ariceta G, et al. Trial of pegcetacoplan in C3 glomerulopathy and immune-complex MPGN. N Engl J Med. 2025;393(22):2210-2220. doi:10.1056/NEJMoa2501510

3. Apellis Pharmaceuticals, Inc. Empaveli (pegcetacoplan) injection, for subcutaneous use: prescribing information. Revised August 2026. Accessed November 5, 2026. https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/215014s012lbl.pdf