Trial of Pegcetacoplan in C3 Glomerulopathy and Immune-Complex MPGN
In the phase 3 VALIANT trial, the C3/C3b inhibitor pegcetacoplan produced a 68% relative reduction in proteinuria versus placebo in C3 glomerulopathy and primary immune-complex MPGN, with glomerular C3 clearance and stabilization of kidney function.
Background
C3 glomerulopathy and primary immune-complex membranoproliferative glomerulonephritis are rare diseases driven by uncontrolled complement C3 activation, with glomerular deposition of C3 breakdown products and progression to kidney failure in up to half of patients within 10 years. Current off-label treatments such as mycophenolate mofetil and corticosteroids target inflammation rather than the underlying complement dysregulation, leaving a high unmet need.
Study design
VALIANT was a phase 3, double-blind, placebo-controlled trial that randomized 124 adolescents and adults (aged 12 and older) with native or post-transplant recurrent C3 glomerulopathy or primary immune-complex MPGN 1:1 to subcutaneous pegcetacoplan twice weekly or placebo for 26 weeks, added to a stable background regimen. The primary endpoint was the log-transformed ratio of the urinary protein-to-creatinine ratio at week 26 compared with baseline.
Key findings
Pegcetacoplan reduced proteinuria with a geometric mean change of -67.2% versus 2.9% with placebo, a relative reduction of 68.1%. More pegcetacoplan-treated patients met the composite renal endpoint of eGFR stabilization plus at least a 50% proteinuria reduction (49% vs 3%) and achieved at least a 50% proteinuria reduction (60% vs 5%); glomerular C3c clearance was seen in about 71% of treated patients. Benefits were consistent across subgroups including nephrotic-range proteinuria, post-transplant recurrence, and adolescents, and pegcetacoplan was not associated with more adverse events than placebo. The change in the C3 glomerulopathy histologic activity score did not differ significantly between groups.
Clinical implications
VALIANT provides the first phase 3 randomized evidence that targeting proximal complement at C3 yields significant, clinically meaningful proteinuria reduction, complement biomarker improvement, and kidney function stabilization in these rare glomerular diseases. Because proteinuria reduction is linked to lower long-term risk of kidney failure, the findings suggest a disease-modifying effect, though longer follow-up is needed to confirm durable kidney protection.
Category
Research
Source
New England Journal of Medicine
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