Pegcetacoplan Shows Promise for Treating C3 Glomerulopathy

Research study background

Complement pathway dysregulation causes glomerular inflammation and progressive kidney damage. It is the primary driver of C3 glomerulopathy (C3G), a rare kidney disease typically appearing during adolescence, and contributes to other closely related diseases including immunoglobulin A nephropathy (IgAN), lupus nephritis (LN) and primary membranous nephropathy (PMN). Without effective treatment, patients with C3G often face poor outcomes: 30% to 50% will progress to end stage renal disease within 10 years of diagnosis, and up to 50% who undergo a kidney transplant will experience disease reoccurrence.

Pegcetacoplan, a targeted C3 and C3b inhibitor, is in development to treat C3G and has the potential to address the primary pathogenic driver of disease. Bradley Dixon, MD, director of the Kidney Center at Children’s Hospital Colorado and an internationally recognized expert on complement-mediated kidney disease, led a multi-center, phase 2 clinical trial of pegcetacoplan to evaluate its safety and effectiveness.

Efficacy results from the 48-week treatment were reported solely for the C3G cohort due to low participation by patients with IgAN, LN and PMN, while 24-week observational safety results were reported for all groups.

Over the course of the 48-week study, pegcetacoplan treatment reduced proteinuria by at least 50%, which correlates with enhanced kidney survival in patients with chronic kidney disease and substantially reduced risk of kidney failure. It also increased mean serum C3 and decreased sC5b-9, suggesting that underlying complement dysregulation is mitigated. Notably, proteinuria was reduced to <0.5 mg/mg in two patients, which is a common key criterion for complete remission of C3G in medical literature. Overall, pegcetacoplan was well-tolerated in all cohorts, with no observed serious treatment-related adverse events and no reports of meningitis or sepsis.

Clinical implications

Results of this study offer evidence for a clinically meaningful complement blockade in patients with C3G, and they support further development of pegcetacoplan for C3G and other conditions with overlapping pathogenesis. An expanded phase 3 trial for adolescents and adults with C3G and the closely related immune complex-mediated membranoproliferative glomerulonephritis is underway at Children’s Colorado and other international sites.

If a similar degree of effectiveness is noted in the phase 3 study, that could open the door to pegcetacoplan being widely used to treat patients with these conditions, which currently have no highly effective treatment options approved for use.