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Review
. 2022 Jan:59:101618.
doi: 10.1016/j.smim.2022.101618. Epub 2022 Jun 25.

Discovering C3 targeting therapies for paroxysmal nocturnal hemoglobinuria: Achievements and pitfalls

Antonio M Risitano  1 , Regis Peffault de Latour  2 , Luana Marano  3 , Camilla Frieri  4
Affiliations
Review

Discovering C3 targeting therapies for paroxysmal nocturnal hemoglobinuria: Achievements and pitfalls

Antonio M Risitano et al. Semin Immunol. 2022 Jan.

Abstract

The treatment of paroxysmal nocturnal hemoglobinuria (PNH) was revolutionized by the introduction of the anti-C5 agent eculizumab, which resulted in sustained control of intravascular hemolysis, leading to transfusion avoidance and hemoglobin stabilization in at least half of all patients. Nevertheless, extravascular hemolysis mediated by C3 has emerged as inescapable phenomenon in PNH patients on anti-C5 treatment, frequently limiting its hematological benefit. More than 10 years ago we postulated that therapeutic interception of the complement cascade at the level of C3 should improve the clinical response in PNH. Compstatin is a 13-residue disulfide-bridged peptide binding to both human C3 and C3b, eventually disabling the formation of C3 convertases and thereby preventing complement activation via all three of its activating pathways. Several generations of compstatin analogs have been tested in vitro, and their clinical evaluation has begun in PNH and other complement-mediated diseases. Pegcetacoplan, a pegylated form of the compstatin analog POT-4, has been investigated in two phase I/II and one phase III study in PNH patients. In the phase III study, PNH patients with residual anemia already on eculizumab were randomized to receive either pegcetacoplan or eculizumab in a head-to-head comparison. At week 16, pegcetacoplan was superior to eculizumab in terms of hemoglobin change from baseline (the primary endpoint), as well as in other secondary endpoints tracking intravascular and extravascular hemolysis. Pegcetacoplan showed a good safety profile, even though breakthrough hemolysis emerged as a possible risk requiring additional attention. Here we review all the available data regarding this innovative treatment that has recently been approved for the treatment of PNH.

Keywords: C3; Compstatin; Extravascular hemolysis; Intravascular hemolysis; Paroxysmal nocturnal hemoglobinuria; Pegcetacoplan.

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Conflict of interest statement

Conflict of interest AMR has received research support from Alexion, Novartis, Alnylam, and Rapharma; lecture fees from Alexion, Novartis, Pfizer, and Apellis; served as a member of the advisory/investigator board for Alexion, Roche, Achillion, Novartis, Apellis, Biocryst, and Samsung; and served as consultant for Amyndas. RPDL has received research funding from Alexion, Amgen, Jazz Pharmaceuticals, and Pfizer; and consulted for and received honoraria from Alexion, Amgen, Gilead, Jazz Pharmaceuticals, Keocyte, MSD, Novartis, Pfizer, Roche, Samsung, and Mallinckrodt.

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