Exciting, much-needed new treatment options are emerging for C3 glomerulopathy (C3G). Recent studies presented at the National Kidney Foundation (NKF) 2025 Spring Clinical Meetings (SCM25) shed additional light on 2 promising options for patients with this rare, progressive disease.

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

The long-term outcomes of C3G are generally very poor. In fact, 30% to 50% of patients with C3G will progress to kidney failure, requiring either dialysis or transplant within 10 years of diagnosis. Among patients who undergo a kidney transplant, up to 80% can have recurrence in the allograft, and allograft loss happens in approximately 50% of cases. These are dismal data points.

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C3G is a chronic, progressive disease that requires very close, regular follow-up. Compared with patients with C3 glomerulonephritis, individuals with dense deposit disease may have slightly faster progression to end-stage kidney disease, but there is variation among the studies that have reported on this difference. Patients who do not require dialysis or kidney transplant will often still have persistently low kidney function, high blood pressure, and protein and blood in the urine, and their quality of life is affected. We also know that patients with chronic kidney disease have an increased risk of associated cardiovascular disease. C3G puts a significant burden on patients and their families. It is a very mentally draining disease because we know that the best possible outcome is often still not very good.

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I would like to touch on 2 major studies that my colleague Benjamin Wooden, MD, discussed during his presentation at SCM25. The first is APPEAR-C3G, a randomized, placebo-controlled, double-blind, multicenter, phase 3 study that evaluated the efficacy and safety of iptacopan in adult patients with biopsy-confirmed C3G, reduced C3 of less than 77 mg/dL, proteinuria of greater than or equal to 1 g/g, and an estimated glomerular filtration rate (eGFR) of greater than or equal to 30 mL/min/1.73 m². Iptacopan is an oral factor B inhibitor that acts upstream in the alternative complement pathway. The study included a 6-month, randomized, double-blinded treatment period with iptacopan 200 mg twice daily vs placebo followed by a 6-month open-label treatment period with iptacopan 200 mg twice daily for all patients. The primary end point was the reduction in 24-hour urine protein to creatinine ratio (UPCR) from baseline at 6 months.

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The major takeaways from the APPEAR-C3G trial include, first, a 35.1% reduction in proteinuria in the iptacopan group compared with the placebo group as measured by 24-hour UPCR at 6 months, and this reduction was sustained at 12 months. Second, a greater proportion of patients treated with iptacopan achieved the composite renal end point at 12 months, which was defined as a 50% or greater reduction in UPCR and no more than a 15% reduction in eGFR. The authors of APPEAR-C3G also conducted exploratory analyses suggesting that iptacopan improved the trajectory of eGFR decline compared with the patient’s historical rate of kidney function loss. Finally, over the 12-month study, there were no new safety concerns and no infections with encapsulated organisms, which is the main concern with complement inhibitors. These data led to the US Food and Drug Administration (FDA) approval of iptacopan for adults with C3G in March 2025. This is a big landmark and a great new option for our patients with C3G.

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The second study that Dr Wooden discussed during his talk at the NKF meeting is the VALIANT trial of pegcetacoplan, a C3 and C3b inhibitor targeting the upstream alternative complement pathway. VALIANT is a double-blind, randomized, placebo-controlled, phase 3 study that assessed the efficacy and safety of pegcetacoplan in patients with C3G or primary immune complex–mediated membranoproliferative glomerulonephritis (IC-MPGN). The trial enrolled 124 patients aged 12 years or older with a diagnosis of C3G or primary IC-MPGN, including both native and post–kidney transplant recurrences. The primary outcome was a change in UPCR from baseline to 26 weeks.

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A major takeaway from the VALIANT trial is that the pegcetacoplan group achieved a 68.1% relative reduction in proteinuria compared with the placebo group after 26 weeks. There were also improvements reported in secondary end points, including the stabilization of eGFR at 26 weeks and a reduction of eGFR decline of 6.3 mL/min/1.73 m² compared with the placebo group. Both of these factors are extremely important in the progression of C3G. Another interesting finding from VALIANT was that kidney biopsies taken after 26 weeks of treatment showed clinically and statistically significant reductions in C3c, with 71% of adult patients treated with pegcetacoplan achieving 0-intensity C3c staining. That is a big deal, because it shows, on a pathologic level, that the C3 is being reduced on the kidney biopsy and that it is correlating with a reduction of protein in the urine and a stabilization of eGFR. Correlating clinical findings with pathology is always a positive outcome in glomerular disease. Finally, there was no increase in adverse events in the treatment group vs the placebo group, and no encapsulated bacterial infections were reported.

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As shown at SCM25, Andrew S. Bomback, MD, looked at post-transplant patients from the VALIANT study, and Marina Vivarelli, MD, and colleagues looked at adolescents from the VALIANT study, and both groups had similar results in proteinuria reduction as the general overall VALIANT population (posters G-450 and G-456, respectively). Based on these data, pegcetacoplan is set for expedited review by the FDA in 2025.

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Proximal complement pathway inhibitors have the potential to prevent kidney failure in patients with C3G. However, affordability and accessibility are concerns. Currently, the projected costs of both iptacopan and pegcetacoplan are estimated at approximately $500,000 per year per patient. These drugs are likely to be lifelong treatments, so making them affordable and accessible will be our next big challenges. Nonetheless, all of this is very encouraging news for patients with C3G.