#3413 Targeted treatment with pegcetacoplan for adolescents with C3G or primary (idiopathic) IC-MPGN in the VALIANT Phase 3 trial

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, which may lead to kidney damage and ultimately kidney failure. Both C3G and primary IC-MPGN are frequently diagnosed in adolescence or early adulthood. At onset, children with C3G or primary IC-MPGN present with varying degrees of proteinuria (ranging from mild to nephrotic), hematuria (ranging from microscopic to macroscopic), and sometimes low serum C3 levels. Current treatments are associated with significant side effects and approximately 20% of children progress to kidney failure within 10–15 years of diagnosis, despite treatment. 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 patients (pts) aged ≥12 years with native or post-transplant recurrent C3G/primary IC-MPGN treated with a stable regimen, PEG led to glomerular C3 clearance in 71% of pts and achieved significant and sustained reduction in proteinuria across pt subgroups with stabilization of estimated glomerular filtration rate (eGFR). Here, we report results for the subgroup of adolescent pts (12–17 years). Method VALIANT study design and pt population have been previously described. Pts were randomized 1:1 to receive PEG (subcutaneous infusion twice weekly) or placebo (PBO) for 26 weeks as add-on to their standard of care regimen. Adolescent pts had a biopsy-proven diagnosis of C3G or primary IC-MPGN with evidence of active renal disease. Active disease was defined by either biopsy at baseline (optional for this subgroup) or, in those not providing a baseline biopsy, at least one of the following: elevated plasma sC5b-9 concentration, low serum C3 concentration, presence of active urine sediment, or presence of C3 nephritic factor. The primary endpoint was the log-transformed ratio of urine protein-to-creatinine ratio (UPCR) at Week 26 vs baseline. Key secondary endpoints were proportion of pts achieving a composite renal endpoint (≥50% reduction in UPCR and ≤15% reduction in eGFR at Week 26 vs baseline) and eGFR reduction. Results Overall, 124 pts were randomized in VALIANT including 55 adolescent pts (28 PEG, 27 PBO; Table 1). Among adolescent pts at Week 26, PEG treatment led to a significant and clinically meaningful relative reduction in proteinuria of 74.5% (relative change: −73.6% PEG vs 3.7% PBO, p < 0.0001; Table 1). In the PEG group, 16/28 pts (57.1%) achieved the composite renal endpoint, compared to 1/27 pts (3.7%) in the PBO group (p = 0.0016). Additionally, 20/28 pts (71.4%) in the PEG group achieved a ≥50% reduction in proteinuria at Week 26 from baseline vs 1/27 (3.7%) in the PBO group (p = 0.0002). Improvements in proteinuria were accompanied by stabilization of eGFR, with a +9.7 mL/min/1.73 m² relative difference compared to PBO. Mean change in proteinuria from baseline to Week 26 is shown in the Fig. 1. Among 6 adolescents with serious treatment-emergent adverse events (PEG, n = 3; PBO, n = 3), 1 event (pyrexia of undetermined origin) was considered PEG-related. Conclusion Results from VALIANT demonstrate that PEG, a C3/C3b inhibitor that blocks C3 overactivation, is the only treatment to induce clinically meaningful proteinuria reduction and eGFR stabilization compared with placebo in adolescent pts with C3G or primary IC-MPGN. The treatment was well-tolerated.

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