#3391 Pegcetacoplan treatment appears to halt disease progression in C3G and primary (idiopathic) IC-MPGN patients: results from the phase 3 VALIANT study

Abstract Background and Aims C3 glomerulopathy (C3G) and primary (idiopathic) immune complex membranoproliferative glomerulonephritis (IC-MPGN) are rare diseases where uncontrolled C3 activation results in excessive glomerular deposition of C3 breakdown products. Current treatments, such as mycophenolate mofetil (MMF) and corticosteroids, are used off-label, primarily targeting inflammatory changes rather than the underlying disease mechanism. These treatments are associated with adverse effects and lack robust clinical evidence of efficacy. As a result, up to 50% of patients progress to kidney failure within 10 years. Pegcetacoplan (PEG) binds selectively to C3 and C3b to strongly block C3 activation by classical/lectin/alternative pathways, C3/C5 convertase activity and activation of downstream effectors. PEG targets the pathogenic process in C3G/primary IC-MPGN with the aim of stopping kidney damage. In the Phase 3 VALIANT study (NCT05067127) in pts aged ≥12 years with native or post-transplant recurrent C3G/primary IC-MPGN, PEG led to glomerular C3 clearance in 71% of pts and achieved significant and sustained reduction in proteinuria across all pt subgroups with stabilization of estimated glomerular filtration rate (eGFR). Change in proteinuria has been proposed as a predictor of progression to kidney failure [1]. Registry data show that a ≥50% reduction in proteinuria over time correlated with a significantly lower risk of kidney failure in C3G pts [1]. Pts with urine protein-to-creatinine ratio (UPCR) of <0.88 g/g 12 months after diagnosis have an 87% [2] reduction in kidney failure risk over 20 years. The aim of this analysis was to investigate the indicators suggesting a potential long-term protective effect of PEG in preventing kidney failure. Method Pts were randomized 1:1 to receive PEG (subcutaneous infusion twice weekly) or placebo (PBO) for 26 weeks as add-on to their stable treatment regimen. The primary endpoint was the log-transformed ratio of UPCR at Week 26 vs baseline. Secondary endpoints included the proportion of pts achieving a reduction in C3c staining on kidney biopsy and change in eGFR from baseline vs PBO. We present a pre-specified analysis on the effect of PEG on complement dysregulation and a post-hoc analysis on changes in proteinuria across the VALIANT population. Results Overall, 124 pts enrolled in VALIANT (63 PEG, 61 PBO). After PEG treatment, there was a rapid response in serum complement C3 and sC5b-9 from Week 4 that was maintained through 26 weeks. On treatment, C3 increased in all pts with a mean (standard deviation [SD]) change of 308.7 (94.7) mg/dL and soluble C5b-9 decreased with a mean (SD) reduction of 612.3 (614.7) ng/mL at Week 26 vs baseline, while no change was observed in PBO pts. Improvement in circulating complement biomarkers was associated with 25/35 (71%) PEG pts achieving 0 glomerular C3c staining at Week 26. Significant proteinuria reduction was observed as early as Week 4 in the PEG arm and remained stable up to Week 26 with no discernible change in UPCR over time in the PBO arm. Pts were categorized by proteinuria range at baseline and Week 26, and shift in proteinuria was evaluated. In the PEG arm, pt distribution across proteinuria ranges shifted towards lower values with 50.8% (32/63) achieving UPCR <1 g/g, including 31.7% (20/63) <0.5 g/g, and a decrease in proportion of pts in all higher UPCR ranges >1.5 g/g. In contrast, in the PBO arm at Week 26, there was no increase in the number of pts in the low proteinuria ranges while the proportion of pts in higher ranges either stabilized or increased, as expected (Figure). Conclusion PEG treatment led to an increase in serum C3 levels, a reduction in serum sC5b-9 and clearance of glomerular C3 deposition. Further, PEG treatment resulted in a significant and clinically meaningful decrease in UPCR to <0.5 g/g. These findings demonstrate a profound disease-modifying effect, regardless of baseline proteinuria levels. Based on registry data, the observed reduction in proteinuria across the cohort at 26 weeks suggests PEG treatment is likely to significantly lower the long-term risk of patients progressing to kidney failure.