Emerging drugs for the treatment of paroxysmal nocturnal hemoglobinuria

Eculizumab, the first anti-C5 monoclonal antibody approved for patients with paroxysmal nocturnal hemoglobinuria (PNH), has revolutionized the natural history of this disease, blocking intravascular hemolysis, reducing the risk of thromboembolic events, resulting in a significant improvement in survival and quality of life. However, the hematological response to eculizumab is extremely heterogeneous, with only one-third of PNH patients reaching normal hemoglobin levels.

This article reviews the current new drugs being investigated in phase II and III trials for adult PNH patients. Literature search was performed using Medline and Clinicaltrials.org databases.

The new molecules have been classified according to the target of the complement system on which they act; we have novel terminal complement inhibitors, which target C5, and proximal complement inhibitors, which interfere with C3 or even further upstream (factor B and D). Ravulizumab is the first next-generation C5 inhibitor, approved by FDA and EMA, which reproduced the excellent results achieved with eculizumab, trying to improve the convenience of patients. However, unresolved issues remain, such as C3-mediated extravascular hemolysis, on which novel proximal complement inhibitors are showing their efficacy. Pegcetacoplan is the first C3-inihibitor approved by FDA. Long-term safety data for novel complement inhibitors are needed.