Real-world outcomes of pegcetacoplan treatment in C3 glomerulopathy and primary immune-complex membranoproliferative glomerulonephritis

Introduction: Pegcetacoplan is a novel C3/C3b inhibitor with potential as a treatment for C3 glomerulopathy (C3G) and primary immune-complex membranoproliferative glomerulonephritis (IC-MPGN), both caused by complement system dysfunction. Methods: We conducted a real-world observational cohort study to evaluate the efficacy and safety of pegcetacoplan in pediatric and adult patients, largely resistant to conventional immunosuppression. These patients were treated outside clinical trials and identified through the CompCure registry and an international survey. Changes in urine protein-to-creatinine ratio (uPCR), estimated glomerular filtration rate (eGFR), and serum C3 at one, three, six and twelve months were evaluated. Results: 25 patients (18 C3 glomerulonephritis, 3 Dense Deposit Disease, 4 primary IC-MPGN) initiated pegcetacoplan therapy at a median age of 14.9 years at a median 2.7 years after diagnosis. Median uPCR at baseline was 3.5 g/g, mean eGFR was 74 ml/min per 1.73 m2, and 19 of 25 patients had low serum C3. After pegcetacoplan initiation we observed a rapid and sustained reduction of proteinuria: uPCR decreased by 81% in six months, with 68% of patients achieving under 1 g/g and 12% achieving complete and 64% partial remission. Serum C3 increased to the normal or supranormal range in all but one case with suspected non-adherence. The eGFR significantly increased by month three (9.4 ml/min per 1.73 m2) and six (12 ml/min per 1.73m2) and remained stable at twelve months in patients with available follow-up data. Sequential biopsies available in four cases showed variable changes, ranging from complete disappearance to persistence of C3 deposits, of chronic lesions, and occasional tubulo-epithelial damage. No serious adverse events occurred during 222 months of cumulative exposure. Conclusions: Pegcetacoplan demonstrated rapid and sustained efficacy with good safety despite two potential drug-related concerns in C3G and primary IC-MPGN, highlighting its potential for broader application and the need for further research to optimize patient selection and treatment strategies.