What does the strongest evidence show?
The most robust data come from a phase 3 randomized controlled trial in IgA nephropathy, the most common primary glomerulonephritis. In that trial, iptacopan—a pill that blocks the alternative complement pathway—reduced 24-hour urine protein-to-creatinine ratio by 38.3% compared with placebo at 9 months (95% CI 26.0–48.6; P<0.001) [1]. That means patients on iptacopan lost nearly 40% more protein in their urine than those on placebo, a clinically meaningful drop because proteinuria is a strong predictor of kidney function decline. The trial enrolled over 440 patients, making it the largest and most definitive study among those reviewed here. Importantly, the drug was safe, with no increased infection risk, which is a key concern with complement blockade [1].
Is the benefit consistent across all proteinuric kidney diseases?
No—the evidence is strong for some diseases but thinner for others. In C3 glomerulopathy (C3G), a rare disease driven by uncontrolled alternative pathway activation, a phase 2 extension study of 26 patients showed a 57% reduction in proteinuria and a 6.83 ml/min/1.73 m² improvement in estimated glomerular filtration rate (eGFR) over 12 months [2]. That is a meaningful stabilization of kidney function in a disease where half of patients progress to kidney failure within 10 years [3]. However, this was a small, open-label study, not a randomized trial. In contrast, a small case series of 5 kidney transplant recipients with recurrent IgA nephropathy found that iptacopan dramatically reduced complement deposits in the kidney (C3 almost disappeared, C5b-9 markedly reduced) but did not consistently improve proteinuria [6]. This suggests that complement inhibition may be more effective in native kidney disease than in transplant recurrence, or that proteinuria in that setting is driven by other factors.
Does reducing proteinuria actually protect the kidney long-term?
That is the crucial unanswered question. Proteinuria is a surrogate marker, not the ultimate outcome. The phase 3 IgA nephropathy trial is designed to measure eGFR decline over 24 months, but the interim analysis only reported proteinuria at 9 months [1][5]. Similarly, the phase 3 C3G trial (APPEAR-C3G) is ongoing and will assess proteinuria, eGFR, and biopsy changes [3][4]. So far, the only long-term data come from the small phase 2 extension in C3G, which showed eGFR improvement at 12 months [2]. The case for complement inhibition is therefore strong on the surrogate endpoint of proteinuria, but the definitive proof—slowing or preventing kidney failure—is still pending. Until those trials report, clinicians should view complement inhibition as a promising but not yet proven therapy for long-term kidney preservation.
About These Sources
This answer is built on 6 peer-reviewed studies — published from 2022 to 2025, 3 from 2024 or later, 6 in Q1 journals, collectively cited 257 times — selected as the most relevant from 7 studies that passed quality screening, drawn from 37 papers retrieved from a database of over 500 million.
Sources used in this answer
Alternative Complement Pathway Inhibition with Iptacopan in IgA Nephropathy
In a phase 3 randomized placebo-controlled trial of 443 patients with IgA nephropathy, iptacopan reduced 24-hour urinary protein-to-creatinine ratio by 38.3% (95% CI 26.0–48.6; P<0.001) at 9 months, with no unexpected safety findings.
Iptacopan Reduces Proteinuria and Stabilizes Kidney Function in C3 Glomerulopathy
In a phase 2 extension study of 26 patients with C3 glomerulopathy, iptacopan reduced proteinuria by 57% (P<0.0001), improved eGFR by 6.83 ml/min/1.73 m² (P=0.0174), and increased serum C3 levels over 12 months.
Alternative Complement Pathway Inhibition With Iptacopan for the Treatment of C3 Glomerulopathy-Study Design of the APPEAR-C3G Trial
This paper describes the design of APPEAR-C3G, a phase 3 randomized placebo-controlled trial of iptacopan in C3G, which will evaluate proteinuria reduction as the primary endpoint and eGFR as a key secondary endpoint.
POS-038 ALTERNATIVE COMPLEMENT PATHWAY INHIBITION WITH IPTACOPAN TO ARREST DISEASE PROGRESSION IN C3 GLOMERULOPATHY (APPEAR-C3G): A PHASE 3 STUDY
This conference abstract reports that a phase 2 study of iptacopan in C3G showed a 45% reduction in proteinuria (p=0.0003) at 12 weeks and stabilization of eGFR in native kidneys, and describes the ongoing phase 3 trial.
Targeting the Alternative Complement Pathway With Iptacopan to Treat IgA Nephropathy: Design and Rationale of the APPLAUSE-IgAN Study
This paper outlines the rationale and design of the APPLAUSE-IgAN phase 3 trial, which will assess iptacopan's effect on proteinuria at 9 months and eGFR slope over 24 months in IgA nephropathy.
Targeting the alternative complement pathway by iptacopan abrogates C3 and strongly reduces C5b-9 deposition within glomeruli in IgA nephropathy recurrence after kidney transplantation
In a case series of 5 kidney transplant recipients with recurrent IgA nephropathy, iptacopan markedly reduced C3 and C5b-9 deposition in glomeruli but did not consistently improve proteinuria, suggesting a disconnect between complement modulation and clinical response in transplant recurrence.