EFFICACY OF PEGCETACOPLAN IN PATIENTS WITH LOWER BASELINE PROTEINURIA: A SUBGROUP ANALYSIS FROM THE VALIANT TRIAL

Proteinuria is a key prognostic marker in C3 glomerulopathy (C3G) and primary (idiopathic) immune-complex membranoproliferative glomerulonephritis (IC-MPGN). The VALIANT study – a randomised, multicentre, double-blind, placebo (PBO)-controlled trial – showed that the C3/C3b inhibitor, pegcetacoplan (PEG), was effective (68% reduction in proteinuria) and well tolerated in patients with proteinuria ≥1 g/g. Patients with lower baseline levels of proteinuria (i.e., <1 g/g) were excluded from VALIANT and, consequently, evidence of pegcetacoplan’s effectiveness in this subgroup is limited. Although patients with lower levels of proteinuria are often considered lower risk, recent studies suggest that even modest proteinuria may confer a significant risk of kidney function decline in C3G and IC-MPGN. Such evidence supports the need to evaluate therapeutic interventions in patients with lower baseline proteinuria.

In VALIANT, patients were randomised 1:1 to PEG (subcutaneous infusion twice weekly) or PBO for 26 weeks. This post hoc analysis focuses on patients with proteinuria
≤1.5 g/g at baseline (urine protein-to-creatinine ratio [UPCR] from first-morning urine [FMU]). Endpoints included log-transformed UPCR and estimated glomerular filtration rate (eGFR) (change from baseline to Week 26 for each endpoint), achieving ≥50% reduction in UPCR, reaching absolute UPCR thresholds for partial remission (≤0.5 g/g) and complete remission (≤0.2 g/g), and showing decreased C3 staining on kidney biopsy (proportion of patients for each endpoint at Week 26). Safety was assessed through treatment-emergent adverse event (TEAE) monitoring.

In total, 40 patients had proteinuria ≤1.5 g/g at baseline (PEG, n=15; PBO, n=25). Overall, the baseline characteristics of the PEG and PBO groups were well balanced. The median (range) baseline FMU UPCR values were 1.1 (0.7–1.4) g/g for PEG and 1.1 (0.8–1.5) g/g for PBO. The mean (standard deviation) eGFR at baseline was 89.0 (36.0) ml/min/1.73 m2 for PEG and 85.7 (39.4) ml/min/1.73 m2 for PBO. At Week 26, the PEG group showed a 71.2% reduction in UPCR versus PBO (based on a geometric mean ratio [95% confidence interval] of 0.288 [0.172, 0.483]). The proportion of patients achieving a ≥50% reduction in UPCR at Week 26 was statistically significantly greater for PEG than for PBO (66.7% [n=10/15] vs 8.0% [n=2/25]; p=0.0012), and more patients in the PEG group reached the UPCR thresholds for partial remission (≤0.5 g/g: 66.7% [n=10/15]) and complete remission (≤0.2 g/g: 46.7% [n=7/15]) versus PBO (8.0% [n=2/25], and 0.0% [n=0/25], respectively). The stabilisation of eGFR and reduction of C3 staining observed were consistent with the findings for the overall VALIANT population. TEAE frequency was similar between treatment groups; there were no encapsulated meningococcal infections.

In patients with lower baseline proteinuria, PEG demonstrated clinically meaningful improvements in relevant outcomes with an effect similar to the overall VALIANT population. These findings highlight the potential benefit of PEG treatment also in patients with a milder clinical phenotype.