Complement inhibitors have dramatically improved the lives of patients with paroxysmal nocturnal hemoglobinuria (PNH), reducing hemolysis and thrombosis and increasing survival. Currently, there are 5 US Food and Drug Administration (FDA)–approved agents for PNH. Although there is a lack of comparative studies, the results of phase 3 trials can be used to help determine the best treatment for each patient.

It has been fascinating to watch the evolution of treatments for PNH, going from nothing but supportive care to now having 5 FDA-approved drugs. This has really changed the therapeutic landscape. While there is a lack of comparative studies, the results of phase 3 trials can be used to help choose the best therapy for individual patients.

I roughly divide treatments for PNH into 2 categories: (1) the distal inhibitors that inhibit C5 (ie, eculizumab and ravulizumab), thus inhibiting the formation of the membrane attack complex; and (2) the proximal inhibitors that inhibit signaling before C5 and include the C3 inhibitors (ie, pegcetacoplan) and inhibitors of factor D (ie, danicopan) and factor B (ie, iptacopan). Eculizumab was the first anti-C5 agent to receive FDA approval, and it was a fairly miraculous drug at the time, stopping intravascular hemolysis very quickly, reducing the incidence of blood clots, and improving survival to near-normal levels. Ravulizumab is similar to eculizumab but has been modified to have a longer half-life. With this modification, C5 inhibition with ravulizumab stays at higher levels for a longer period. Ravulizumab is administered intravenously every 8 weeks.

An issue with C5 inhibitors is that the PNH red blood cells are still coated with C3 fragments because they do not have CD55 or CD59 on their surfaces, which would clear these fragments. The C3 fragments can lead to extravascular hemolysis. This is probably why hemoglobin levels never normalize in most patients who are on C5 inhibitors. This led us to think about inhibiting the proximal pathway to prevent extravascular hemolysis.

Pegcetacoplan is a C3 inhibitor that is given subcutaneously by a pump, which patients can do at home. The phase 3 PEGASUS trial compared pegcetacoplan with eculizumab in patients who had a suboptimal response to eculizumab, and pegcetacoplan showed superiority, with a rise in hemoglobin levels to 11.5 g/dL. However, there can be injection site reactions and breakthrough hemolysis with the use of this drug.

We also have the oral factor B inhibitor iptacopan, which received FDA approval in December 2023. It was evaluated in the randomized phase 3 trials APPLY-PNH and APPOINT-PNH. APPLY-PNH and APPOINT-PNH were conducted in C5-treated and complement inhibitor–naive patients with PNH, respectively. In the APPLY-PNH trial, the majority of patients had an increase in hemoglobin of at least 2 g/dL, with hemoglobin levels averaging around 12 g/dL at 48 weeks and an improvement in transfusion avoidance compared with those who were randomized to stay on the C5 inhibitor. Iptacopan is a wonderful step forward. The big concern is compliance because iptacopan has a short half-life and has to be taken twice per day.

The most recent agent to receive FDA approval is danicopan, an oral factor D inhibitor. It was evaluated in the randomized phase 3 ALPHA trial and was approved in March 2024 for use in combination with a C5 inhibitor. As factor D is a cofactor for the activation of C3, the hope is that, by blocking both C3 and C5, we could see less extravascular hemolysis and breakthrough hemolysis with this agent. However, the need for both oral and intravenous or injectable drugs with this treatment option could be seen as a disadvantage.

The rate of thrombosis appears to be similar between the 5 FDA-approved drugs based on the phase 3 studies, and this is important because thrombotic events used to be the major cause of death in patients with PNH. So, how do we choose which agent to give? I think that it is an easy decision if someone has a suboptimal response to a C5 inhibitor to change them to a proximal inhibitor. In treatment-naive patients, it is hard to answer whether there is an advantage to taking a proximal inhibitor over a C5 inhibitor. I think that we have to look at both patient factors, such as compliance, and patient preferences. Some patients may like receiving an intravenous or injectable drug less often than they would have to take a pill. Others are going to prefer the pills. Those patients who prefer an oral drug have to be educated on and committed to taking their medications as prescribed.