C3 Inhibition with Pegcetacoplan Targets the Underlying Disease Process of C3 Glomerulopathy (C3G) and Improves Proteinuria

Abstract

Background: C3G is a rare renal disease in which C3 overactivation leads to the accumulation of C3 breakdown products in the glomeruli. Progression to end-stage renal disease occurs in up to 50% of patients (pts) within 10 years of diagnosis; no therapies target the underlying pathophysiology of C3 activation. The study aims to assess whether pegcetacoplan (APL-2; Apellis Pharmaceuticals, Waltham, MA), a C3 inhibitor, targets C3G complement dysregulation and reduces proteinuria. Methods: This phase 2 open-label study was designed to evaluate preliminary efficacy and safety of pegcetacoplan in pts with complement-mediated glomerulopathies. Pts with C3G who were ≥16 years old, with proteinuria >750 mg protein/g creatinine, and eGFR ≥30 mL/min/1.73 m2 were eligible for inclusion. Pegcetacoplan was administered as 360 mg daily subcutaneous infusions with transition to 1080 mg twice weekly from Week 24. The primary endpoint was change in proteinuria from baseline to Week 48, measured by 24-hour urine protein-to-creatinine ratios (uPCR). Serum C3, albumin, and creatinine as well as safety were also evaluated. Results: Eight C3G pts were enrolled in the study. Three pts were excluded from efficacy analyses for self-reported non-compliance or interrupted study drug administration. Data showed a greater than 65% reduction in 24-hour uPCR from baseline to Week 48. Serum albumin and C3 increased, and serum creatinine was stable (Table). No serious or severe adverse events were reported and no TEAEs led to discontinuation. Conclusions: These data suggest that pegcetacoplan targets the underlying pathophysiology of C3G, resulting in proteinuria reduction with stable renal function. Pegcetacoplan also appeared to be well-tolerated. Further studies are warranted to investigate the therapeutic potential of pegcetacoplan in the treatment of C3G. Funding: Commercial Support - Apellis Pharmaceuticals, Inc.