Complement Inhibitors for the Treatment of C3G: The Dawn of a New Era

C3 glomerulopathy (C3G) is a rare form of glomerulonephritis, comprising two main subtypes: dense deposit disease and C3 glomerulonephritis. The pathogenesis of C3G centers on the dysregulation of the alternative complement pathway, often due to autoantibodies known as C3, C4, or C5 nephritic factors, or genetic mutations in key complement regulatory proteins. On kidney biopsy, C3G can sometimes resemble postinfectious glomerulonephritis or, rarely, be associated with monoclonal gammopathies; both conditions should be considered but were excluded in the clinical trials discussed in this article.

C3G primarily affects pediatric and young adult populations and, at present, lacks any US Food and Drug Administration (FDA)-approved therapies. As a result, patients frequently experience progressive kidney disease and intense proteinuria, often culminating in kidney failure requiring dialysis. Even for those who undergo kidney transplantation, the disease has a high recurrence rate, significantly impacting long-term outcomes. Within a decade of diagnosis, 30%–50% of individuals with C3G progress to kidney failure (1). Guidelines recommend initial treatment with steroids and mycophenolate mofetil, although there are no randomized controlled trial data to support this practice. Observational studies assessing the efficacy of this approach have been small and have demonstrated only modest improvements in clinical remission (2–4). Eculizumab, a C5 inhibitor, has been proposed as a more targeted treatment but has not been shown to be effective, leaving patients and practitioners with a dearth of therapeutic options (5).

New targeted factor B, C3, and C3b inhibitors are under investigation as therapeutic agents for C3G and have the potential to change the landscape of treatment for patients with this rare disease. The VALIANT trial (Phase III Study Assessing the Efficacy and Safety of Pegcetacoplan in Patients With C3 Glomerulopathy or Immune-Complex Membranoproliferative Glomerulonephritis), reported as a late-breaking clinical trial at ASN Kidney Week 2024, is a double-blind, randomized, placebo-controlled phase 3 trial investigating proteinuria reduction from pegcetacoplan, one such C3 and C3b inhibitor (6). This trial enrolled 124 patients aged 12 years or older with a diagnosis of C3G, including both native cases and post kidney transplant recurrences. Patients were randomized to receive twice-weekly subcutaneous pegcetacoplan infusions at home or placebo. The primary outcome measured was the change in the log-transformed urine protein-to-creatinine ratio (UPCR) from baseline to 26 weeks. Impressively, the pegcetacoplan group achieved a 68% relative reduction in proteinuria compared with the placebo group after just 6 months of treatment.

Investigators also observed significant improvements in key secondary endpoints, including stabilization of the estimated glomerular filtration rate (eGFR) at 26 weeks, with a reduced eGFR decline of 6.3 mL/min/1.73 m² compared with the placebo group. Kidney biopsies taken after 26 weeks of treatment revealed clinically and statistically significant reductions in C3c (protein fragment of C3) staining, with an impressive 71% of patients treated with pegcetacoplan achieving zero-intensity staining. Notably, there was no indication of increased adverse events in the treatment groups. These findings highlight a promising new therapeutic option for patients with C3G, with the potential to prevent kidney failure entirely in this population.

Another inhibitor of alternative complement activation, iptacopan, a factor B inhibitor, has also shown promising results in treating patients with C3G. In the APPEAR-C3G trial (Study of Efficacy and Safety of Iptacopan in Patients With C3 Glomerulopathy), patients receiving iptacopan, an oral therapy, achieved a 35% reduction in proteinuria at 6 months, with this effect sustained through 12 months of treatment. Additionally, iptacopan stabilized eGFR and significantly decreased C3 deposition scores on biopsy compared with placebo (7, 8).

These promising advances bring new hope that we may soon have effective, targeted treatments for individuals affected by this rare but serious disease. However, with pegcetacoplan projected to cost nearly $500,000 per year (it is FDA-approved for geographic atrophy and paroxysmal nocturnal hemoglobinuria), securing insurance or pharmaceutical coverage will be essential for accessibility. It is also likely that these treatments would be lifelong, and the effects of discontinuation on disease progression remain unknown—a critical factor to discuss with all patients, especially women of childbearing age, who may prefer to avoid these medications during pregnancy due to limited safety data. Additionally, these complement inhibitors necessitate vaccination against encapsulated organisms, such as those causing meningococcal infections. However, the long-term infectious risks associated with these treatments remain uncertain.

In the coming year, we may see FDA approval of two new therapies specifically demonstrated to improve meaningful clinical outcomes in patients with C3G—something we have never had before.

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