#3391 Pegcetacoplan treatment appears to halt disease progression in C3G and primary (idiopathic) IC-MPGN patients: results from the phase 3 VALIANT study
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.002 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".