Complement Inhibitors Reshape Treatment Landscape for C3 Glomerulopathy, With Sayna Norouzi

As complement-targeted therapies have entered the treatment landscape for C3 glomerulopathy (C3G), investigators suggest these agents hold the potential to modify the disease and may ultimately shift kidney failure from an expected outcome to a more “remote prospect” for patients.1

“For years and years, we didn’t have any FDA-approved medications for these patients,” said Sayna Norouzi, MD, clinical nephrologist and associate professor of medicine at Loma Linda University Medical Center. “Now we have two newly approved options, and it feels really good when a patient comes in, and we can actually discuss treatments and make a shared decision about what might work best for them.”

The first complement therapeutic used for C3G was eculizumab, a monoclonal antibody against C5, and is currently used off-label in native and transplanted kidneys. According to the report, evidence suggested ecuizumab is most effective when initiated before evidence of terminal pathway activation and before significant sclerotic changes develop.1

Other complement inhibitors have been evaluated but have not demonstrated meaningful clinical benefit in C3G.

Avacopan, an oral small-molecule C5a receptor antagonist, did not show a significant improvement in the primary endpoint—the percentage change in the histologic index of disease activity from baseline to week 26—in the phase 2 ACCOLADE trial.1

Similarly, danicopan, a factor D inhibitor evaluated in the phase 2 ACH471-204 trial, produced only partial inhibition of the alternative complement pathway. Investigators reported the therapy did not reach systemic concentrations sufficient for sustained pathway blockade, resulting in limited clinical response.1

More recently, complement-targeted therapies have achieved regulatory approval for C3G. The US Food and Drug Administration (FDA) approved iptacopan (Fabhalta) based on data from APPEAR-C3G. The primary efficacy endpoint evaluated the percent change in proteinuria, measured by urine protein-to-creatinine ratio (UPCR) from a 24-hour urine collection, after 6 months of treatment. At 6 months, treatment with iptacopan resulted in a 35% reduction from baseline in 24-hour UPCR compared with placebo.1,2

Another complement-targeted therapeutic that entered the treatment landscape for C3G in 2025 was pegcetacoplan, a peptide-based inhibitor of C3 and C3b, which the FDA approved in July. In an open-label extension of VALIANT, pegcetacoplan maintained a 70% reduction in proteinuria over 52 weeks in adolescents with C3G and primary immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN), with many patients achieving remission (≤0.5 g/g) or normalization (≤0.2 g/g).1

Norouzi also emphasized the importance of monitoring safety risks associated with complement inhibition.

“Any medication that works on the complement system can increase the chance of encapsulated infections, including meningococcal infections. They’re rare, but if they happen, they can be deadly, so vaccination and careful monitoring are really important for these patients.”

Editor’s Note: Norouzi reports relevant disclosures with Calliditas, Travere, Apellis and others.

References

1. Mashayekhi M, Zuckerman JE, Barratt J, et al. C3 Glomerulopathy Diagnosis, Current Treatments, and Emerging Therapies. Kidney Medicine. 2026;8(3):101258. doi:https://doi.org/10.1016/j.xkme.2026.101258

2. U.S. Food and Drug Administration. FDA approves first treatment for adults with complement 3 glomerulopathy, a rare kidney disease, to reduce proteinuria. U.S. Food and Drug Administration. Published 2025. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-first-treatment-adults-complement-3-glomerulopathy-rare-kidney-disease-reduce