Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired,
hematologic disease characterized by
complement-mediated
hemolysis,
thrombosis, and various degrees of bone marrow dysfunction. Until recently, C5 inhibition with
eculizumab or
ravulizumab represented the only
therapies approved for patients with PNH by the United States Food and Drug Administration (US FDA). Although C5-inhibitors reduce PNH-related signs and symptoms, many patients continue to exhibit persistent
anemia and require frequent
blood transfusions. In May 2021,
pegcetacoplan became the third US FDA-approved treatment for adults with PNH, and the first to target C3, a
complement component upstream of C5. The novel strategy of inhibiting proximal
complement activity with
pegcetacoplan controls C5-mediated
intravascular hemolysis and prevents C3-mediated
extravascular hemolysis. Here, we review the results from multiple
pegcetacoplan clinical studies on the efficacy and safety of
pegcetacoplan treatment in adults with PNH. This review summarizes findings from three studies in
complement-inhibitor-naïve patients with PNH (PADDOCK [phase Ib], PALOMINO [phase IIa], PRINCE [phase III;
pegcetacoplan versus standard treatment excluding
complement-inhibitors]), and one phase III study (PEGASUS) that compared
eculizumab to
pegcetacoplan in patients who remained anemic (
hemoglobin levels < 10.5 g/dL) despite stable
eculizumab treatment (⩾3 months). These studies found that
pegcetacoplan contributed to superior improvements in primary and secondary endpoints related to
hemoglobin levels and other hematologic parameters and provided effective management of
anemia and
anemia-related complications (i.e. transfusion burden, reticulocyte production, and
fatigue). Furthermore, we summarize results from the 32-week open-label period from the PEGASUS trial, which confirmed the long-term safety and durable efficacy of
pegcetacoplan as demonstrated by sustained improvements in clinical and hematologic outcomes in
pegcetacoplan-treated patients.
Pegcetacoplan is approved for the treatment of adults with PNH in the United States (Empaveli™) and for adult patients who remain anemic after at least 3 months of stable C5-inhibitor
therapy in the European Union (Aspaveli®) and Australia (
Empaveli; also approved for patients intolerant to C5-inhibitors).