Three Years On: The Role of Pegcetacoplan in Paroxysmal Nocturnal Hemoglobinuria (PNH) since Its Initial Approval

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease characterized by complement-mediated hemolysis and potentially life-threatening complications. Pegcetacoplan, an inhibitor of complement components C3 and C3b, was approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) in 2021. A recent expansion to its indication by the EMA has made pegcetacoplan available for the treatment of both complement inhibitor-naïve and -experienced patients with PNH who have hemolytic anemia, a similarly broad patient population as in the US. This approval was based on results from the Phase 3 PEGASUS study, where pegcetacoplan showed superiority over the C5 inhibitor eculizumab with regard to improving the hemoglobin level in patients with anemia despite eculizumab treatment, and the Phase 3 PRINCE study, where pegcetacoplan showed superiority over supportive care with regard to hemoglobin stabilization and improving the lactate dehydrogenase level in complement inhibitor-naïve patients. In light of this recent indication expansion by the EMA, this article describes how the strong efficacy of pegcetacoplan is linked to its mechanism of action, which provides broad hemolysis control over both intravascular and extravascular hemolysis to improve a range of disease markers and enhance patients' quality of life. Furthermore, additional data and learnings obtained from over 3 years of experience with pegcetacoplan are summarized, including long-term efficacy and safety results, real-world clinical experiences, pharmacokinetic characteristics, and extensive practical guidance for the first-to-market proximal complement inhibitor for PNH.

Keywords: C3; PNH; complement; paroxysmal nocturnal hemoglobinuria; pegcetacoplan; proximal inhibitor.

Figure 3

Practical guidance supporting the use of pegcetacoplan, derived from its prescribing information and peer-reviewed articles [22,23,28,48,63,64]. BIW, twice-weekly; BTH, breakthrough hemolysis; CAC, complement-amplifying condition; EMA, European Medicines Agency; IV, intravenous; LDH, lactate dehydrogenase; PI, Prescribing Information; Q2W; every 2 weeks; Q8W, every 8 weeks; RBC, red blood cell; SC, subcutaneous; SmPC, Summary of Product Characteristics; t1/2, half-life; ULN, upper limit of normal.

Figure 4

Population pharmacokinetic modeling of (A) pegcetacoplan concentration and (B) LDH level with a 96 h dose delay. The dose delay analysis was performed using a population pharmacokinetic model [60] (see Appendix A) and assuming a steady-state concentration of pegcetacoplan at a SC dose of 1080 mg twice weekly. EC, effective concentration; Hb, hemoglobin; IQR, interquartile range; LDH, lactate dehydrogenase; SC, subcutaneous.

Figure 1

The complement system and mechanism of action of pegcetacoplan. Dashed arrows represent processes with several steps. EVH, extravascular hemolysis; IVH, intravascular hemolysis.

Figure 2

Change from baseline in (A) C3 deposition and (B) RBC clone size upon pegcetacoplan treatment. Patients in PADDOCK, PALOMINO, and PRINCE were complement inhibitor-naïve, while PEGASUS enrolled patients with a suboptimal response to complement C5 inhibitor treatment. Only patient-level data for the PHAROAH study were reported, so these are not included here. The primary analysis for PADDOCK and PALOMINO occurred at Day 365, for PRINCE it occurred at week 26, and for PEGASUS it occurred at week 16 of pegcetacoplan treatment. PNH, paroxysmal nocturnal hemoglobinuria; RBC, red blood cell.