Clinical Safety and Efficacy of Pegcetacoplan in a Phase 2 Study of Patients with C3 Glomerulopathy and Other Complement-Mediated Glomerular Diseases

Abstract

Introduction: Dysregulated complement activation is likely the primary driver of disease in C3 glomerulopathy (C3G) and contributes to other complement-mediated diseases, including immunoglobulin A nephropathy (IgAN), lupus nephritis (LN), and primary membranous nephropathy (PMN). No complement inhibitors are proven to halt disease progression in these diseases. Pegcetacoplan, a targeted C3 and C3b inhibitor, may mitigate complement-mediated kidney damage in C3G and other glomerular diseases in which complement may have a pathogenic role.

Methods: This open-label, phase 2, 48-week study evaluated the preliminary efficacy and safety of subcutaneous pegcetacoplan for patients with complement-mediated glomerular diseases. The primary end point was proteinuria reduction, measured as 24-hour urine protein-to-creatinine ratio. Secondary end points included remission status, changes in estimated glomerular filtration rate (eGFR), and pharmacodynamic biomarkers. Treatment-emergent adverse events (TEAEs) were monitored.

Results: Efficacy results for the C3G cohort are reported herein, along with safety results for the study population. In the C3G cohort, mean proteinuria reduction from baseline to week 48 was 50.9% in the intent-to-treat (ITT) population (n = 7) and 65.4% in the per-protocol (PP) population (n = 4). Mean serum albumin normalized and mean eGFR was stable over 48 weeks. Mean serum C3 levels increased 6-fold and mean soluble C5b-9 levels decreased by 57.3% at week 48. The most common adverse events (AEs) were upper respiratory tract infection, injection site erythema, nausea, and headache. No meningitis or sepsis cases were reported, and no serious treatment-related AEs were observed.

Conclusion: Pegcetacoplan may provide therapeutic benefit for C3G and has a favorable safety profile across the 4 glomerular diseases studied.

Keywords: C3 glomerulopathy; complement; end-stage kidney disease; glomerulonephritis; pegcetacoplan; proteinuria.

Graphical abstract

Figure 1

Role of the complement pathway in glomerulonephritis. Complement activation with or without immunoglobulin deposition is achieved through the classical, alternative, and/or lectin complement pathways, which converge to form a C3 convertase that converts C3 to its active split product C3b. Upon C3 cleavage, the amplification loop promotes rapid generation of more C3 convertase (C3bBb). Released C3b mediates opsonization for phagocytosis, leading to deposition of C3 breakdown products in glomeruli. Activation of C3b through factor B and factor D also results in formation of a C5 convertase complex that activates the terminal effector pathway and cleaves C5 into C5a and C5b. Whereas C3a and C5a trigger inflammatory response in tissue, C5b binds with C6, C7, C8, and C9 to form the MAC, which causes cell lysis. MAC, membrane attack complex.

Figure 2

Study schema. This phase 2 open-label study included a screening period, a 48-week treatment period, 24-week observational safety follow-up, and an optional long-term extension phase. Starting on day 1, 4 patient cohorts received self-administered daily SC doses of 360 mg of pegcetacoplan until at least week 24 and then could be switched over to twice weekly dosing with 1080 mg as early as week 24. Efficacy and safety end points were assessed at baseline and at the end of the treatment period at week 48. AH50, alternative complement pathway hemolytic activity; C3G, C3 glomerulopathy; CH50, classical pathway hemolytic activity; eGFR, estimated glomerular filtration rate; IgAN, immunoglobulin A nephropathy; LN, lupus nephritis; PMN, primary membranous nephropathy; SC, subcutaneous; sC5b-9, soluble C5b-9; TEAE, treatment-emergent adverse event; UPCR, urine protein-to-creatinine ratio.

Figure 3

(a) Mean and individual 24-hour UPCR at baseline and week 48 in the C3G cohort (b) Mean and individual percent change from baseline to week 48 in 24-hour UPCR in the C3G cohort. Patients in the C3G cohort of the ITT population with a post-baseline measurement were included in the plot. The PP population includes n = 4; those included in ITT only are shown in blue, and those included in both the ITT and PP population are shown in yellow. (a) C3G cohort mean and individual 24-hour UPCR at baseline and week 48. (b) C3G cohort %CFB at week 48 of individual patients’ 24-hour UPCR for both the ITT and PP sets and for the corresponding individual patient values. Baseline ITT (n = 8) mean 24-hour UPCR includes 1 patient who did not have follow-up at week 48. C3G, C3 glomerulopathy; CFB, change from baseline; ITT, intent-to-treat; PP, per-protocol; UPCR, urine protein-to-creatinine ratio.

Figure 4

Mean (a) serum albumin, (b) eGFR, (c) serum C3, and (d) plasma sC5b-9 through week 48 in the C3G cohort. Mean (SD) values of (a) serum albumin, (b) eGFR, (c) serum C3, and (d) plasma sC5b-9 levels over time in the C3G cohort (ITT set, n = 8). Blue boxes indicate normal reference ranges for variables. C3G, C3 glomerulopathy; eGFR, estimated glomerular filtration rate; ITT, intent-to-treat; LLN, lower limit of normal; sC5b-9, soluble C5b-9; ULN, upper limit of normal.