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.