Patients with C3 glomerulopathy (C3G) face significant clinical challenges, including limited US Food and Drug Administration (FDA)–approved treatment options for this serious, progressive disease. Recent data presented at the National Kidney Foundation (NKF) 2025 Spring Clinical Meetings (SCM25) shed light on promising new targeted agents for patients with C3G.

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Following these presentations, featured expert Richard Lafayette, MD, FACP, was interviewed by Conference Reporter Associate Editor-in-Chief Rick Davis, MS, RPh. Dr Lafayette’s clinical perspectives on these findings are presented here.

There is a lot of excitement around the data discussed by Benjamin Wooden, MD, during his presentation at SCM25. C3G is a very rare disease. We have gained a better understanding of its pathogenesis, and we know that it is complement driven. After many genetic and immunologic studies, it has become increasingly clear that defects in the regulation of the alternative complement pathway drive the disease to cause the inflammation that leads to clinical signs and symptoms. Having therapies that are aligned with the disease pathogenesis and focus either directly on the alternative pathway or on the consequences of alternative pathway activation is important.

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For more than a decade, we have been using eculizumab and ravulizumab, which block complement protein C5, as rescue therapy for patients who have complement gene defects leading to an overactivation of their complement system. However, the results from studies of eculizumab and ravulizumab were modest, and many patients did not seem to respond to these treatments. We were left needing additional approaches.

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Until now, we did not have an FDA-approved treatment for C3G. Iptacopan was recently approved by the FDA for the treatment of adult patients with C3G because the randomized controlled APPEAR-C3G trial demonstrated a significant reduction in proteinuria, with good safety and tolerability. Overall kidney function was stable through the trial; numerically, patients on iptacopan had a better preservation of estimated glomerular filtration rate than patients on placebo. Iptacopan, like other complement inhibitor agents, carries a potential risk for infection, particularly encapsulated bacterial infections. Patients absolutely must be up to date on their vaccines before starting iptacopan therapy. Iptacopan seems to result in a very low—but not zero—rate of severe infections, but, so far, the rate is no different from that of placebo.

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The VALIANT trial of pegcetacoplan adds to the excitement in the field, and there is a great sense of anticipation that pegcetacoplan will also be an FDA-approved agent soon. VALIANT, the results of which were discussed by Marina Vivarelli, MD, and colleagues and Andrew S. Bomback, MD, at the NKF SCM25, had slightly different inclusion criteria than APPEAR-C3G, as VALIANT also enrolled children aged 12 years and older (poster G456) and included posttransplant patients (poster G-450). There was a remarkable reduction of proteinuria (ie, >68%) with the use of pegcetacoplan. Moreover, there was a nominal prevention of estimated glomerular filtration rate loss, and the biopsy arm of the study demonstrated that there was less C3 deposition. Patients tolerated the medication well, and there were no surprising safety signals. Overall, VALIANT is a thrilling study. The complement markers showed that the drug works as expected.

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The main difference between iptacopan and pegcetacoplan is that iptacopan aims directly at the aberrant alternative complement pathway, while pegcetacoplan aims at C3, which is the very beginning of the final common pathway for all 3 complement activation pathways (ie, the alternative, lectin, and classical pathways). This happens far enough upstream that it can block the final complement pathway and the inflammatory proteins C3a and C5a that result from complement activation of any of the pathways, including the alternative pathway. Hopefully, pegcetacoplan will provide us with another approach for patients with C3G who are at risk for progression because one agent will not fit all cases, and increasing the treatment options is very important in this disease state.

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It is important to acknowledge that there are additional C3G studies underway examining other ways to block the complement system. For example, there are agents using RNA interference technology to decrease the production of C3 in the liver. There is also monoclonal antibody therapy targeting C3bBb to reduce C3b formation. However, it is relatively early days, and we do not have the clinical data for these treatment options yet. It really is a celebratory time, as there is a lot of effort being focused on this rare disease. We already have 1 FDA-approved targeted drug; a second drug is likely on its way to being approved, and there will be others joining them. It really is exciting.

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Finally, it is also important to point out that there will be challenges in positioning these therapies and barriers in terms of appropriate vaccination, antimicrobial therapy, insurance company availability, and cost. Physicians need to understand that there may be some value in considering the risk of the patient and not overtreating someone who is at low risk. For example, patients with intact kidney function and very low-grade proteinuria may do well with only supportive care. For patients at greater risk with significant proteinuria, we may still have to consider traditional systemic immunosuppressives, perhaps as first-line therapy or cotherapy with these newer agents. We will have to learn exactly where these new options fit in the treatment paradigm as either primary or rescue therapies.