Could Earlier Complement Inhibition Preserve Kidney Function in C3G?

Whether initiating complement-targeted treatment earlier can improve long-term kidney outcomes in patients with C3 glomerulopathy (C3G) or primary immune complex membranoproliferative glomerulonephritis (IC-MPGN) remains an open question. Bradley P. Dixon, MD, FASN, argues that waiting for conventional immunosuppression to fail could allow kidney damage to accumulate before targeted therapy begins.

Dixon, associate professor of pediatrics and medicine and head of the Section of Nephrology at the University of Colorado School of Medicine, discussed the rationale for earlier intervention in an interview with HCPLive following his presentation of 76-week adolescent data from the phase 3 VALIANT trial and its VALE extension at the American Society of Nephrology (ASN) Kidney Week 2026 in Denver, Colorado.¹

The available VALIANT+VALE data do not directly establish whether initiating complement inhibition earlier produces better long-term outcomes than delayed treatment.

Heavy Proteinuria Despite Preserved Kidney Function

In the post hoc VALIANT+VALE adolescent analysis, investigators reported outcomes from 53 patients aged 12 to 17 years who received pegcetacoplan (Empaveli), a C3 and C3b inhibitor, over 76 weeks. The geometric mean change in urine protein-to-creatinine ratio (UPCR) from baseline was –67.5% (95% CI, –77.0 to –54.1), while estimated glomerular filtration rate (eGFR) remained stable (least squares mean change, +8.4 mL/min/1.73 m²; SE, 4.43).¹

Related:Pegcetacoplan Sustains Proteinuria Reduction at 76 Weeks in Adolescents

Dixon emphasized that the adolescents entered treatment with substantial proteinuria but relatively preserved kidney function. He views that combination as an opportunity to intervene before further loss of kidney function occurs.

“I think this highlights that these adolescent patients in particular had significant disease burden with heavy proteinuria, but also had relatively preserved kidney function,” Dixon said. “And I think a take-home message from this data, especially with the preservation in kidney function over a longer-term exposure, is that intervening early in patients with C3 glomerulopathy and immune complex MPGN does allow for greater preservation of kidney function. So time is kidney.”

The longer-term analysis demonstrated sustained proteinuria reduction and stable eGFR during treatment. Because it was a post hoc analysis of treatment exposure across VALIANT and its open-label extension, however, it cannot determine whether earlier treatment initiation prevents kidney function decline compared with later initiation.

Does Baseline Kidney Damage Influence Treatment Outcomes?

A separate 76-week analysis of the overall VALIANT+VALE population examined outcomes according to the extent of interstitial fibrosis and tubular atrophy (IFTA) at baseline, a measure of chronic kidney damage.²

Proteinuria decreased in both baseline IFTA subgroups. At week 76, the geometric mean reduction was 66.8% among patients with IFTA of 25% or less (n = 94), compared with 52.6% among those with IFTA of 26% to 50% (n = 23).²

Differences also emerged in kidney function. The least squares mean change in eGFR was +1.7 mL/min/1.73 m² (95% CI, –3.9 to 7.3) in the lower-IFTA subgroup, compared with –11.0 mL/min/1.73 m² (95% CI, –20.3 to –1.6) in the higher-IFTA subgroup.²

These exploratory findings suggest that baseline chronic kidney damage may influence kidney function trajectories during treatment. However, the subgroup sizes were unequal, and the analysis did not randomize patients according to treatment timing. The findings therefore cannot establish that earlier complement inhibition would have prevented the greater decline observed among patients with more extensive baseline fibrosis.

Weighing Infection Risk Against Conventional Immunosuppression

Safety remains an important consideration in decisions about complement inhibition. Pegcetacoplan carries an FDA boxed warning for serious and potentially life-threatening infections caused by encapsulated bacteria, including Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type B.³

The prescribing information requires appropriate vaccination against encapsulated bacteria, generally at least 2 weeks before treatment initiation. When urgent treatment cannot be delayed and vaccination is not up to date, antibacterial prophylaxis is recommended. Vaccination does not eliminate the risk of serious infection, and pegcetacoplan is available only through a restricted Risk Evaluation and Mitigation Strategy (REMS) program.³

Dixon acknowledged these risks but questioned the assumption that conventional immunosuppressive therapies necessarily carry a more favorable safety profile.

“It’s true that infection risk is associated with these medicines, and that risk has to be mitigated with vaccination and careful surveillance, but I think the misconception is that untargeted immunosuppression is safer,” he said. “I would argue that these medications also greatly increase the risk of infection, particularly opportunistic infections, and so at the end of the day, complement-targeted therapeutics with an appropriate risk mitigation strategy are actually safer than untargeted immunosuppression.”

The relative safety of these approaches remains an important distinction. VALIANT compared pegcetacoplan with placebo during its randomized period, not with a conventional immunosuppressive regimen. The trial therefore does not establish whether complement inhibition carries a lower overall infection risk than corticosteroids or mycophenolate-based treatment.

What the Findings Mean for Treatment Timing

The longer-term VALIANT+VALE results provide evidence of sustained proteinuria reduction and eGFR stabilization during pegcetacoplan treatment. The exploratory IFTA findings also raise questions about how existing kidney damage may influence outcomes.

Together, these findings provide context for Dixon's perspective on treatment timing, although additional comparative evidence is needed to determine which patients benefit most from earlier complement inhibition.

Dixon called for clinicians to reassess the safety and tolerability of complement-targeted therapies and to “really begin to use these earlier to achieve maximum benefit.”

Whether earlier initiation improves long-term kidney survival, and how its risks compare with conventional immunosuppression, remain questions requiring additional comparative evidence.

Editor's Note: Dixon reports relevant disclosures with Apellis Pharmaceuticals, Novartis, and others.

References

1. Dixon BP, Greenbaum LA, et al. Pegcetacoplan for 76 weeks maintains proteinuria reduction and eGFR stabilization for pediatric patients: VALIANT+VALE subgroup analysis. Abstract TH-OR070. Presented at: American Society of Nephrology Kidney Week 2026; October 22-25, 2026; Denver, CO. ASN abstract.

2. Nester CM, Bomback AS, 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 22-25, 2026; Denver, CO. ASN abstract.

3. Empaveli (pegcetacoplan) injection, for subcutaneous use. Prescribing information. Apellis Pharmaceuticals, Inc. Revised August 2026. Accessed November 4, 2026. FDA prescribing information.