<p>Complement inhibitors have dramatically decreased the risk of hemolysis and thrombosis and have increased survival for patients with paroxysmal nocturnal hemoglobinuria (PNH). However, even with therapy, patients with PNH may continue to experience burdensome symptoms of the disease. Inhibitors of proximal signaling in the alternative pathway and more effective C5 inhibitors have the potential to address such unmet needs.</p>

For many years, people were very afraid of manipulating the complement system, knowing that patients with inherited complement deficiencies are at risk of infection, especially with Neisseria meningitidis. Now we can effectively use complement inhibitors in combination with vaccines, prophylactic antibiotics, and patient education to improve outcomes in patients with PNH. Those with PNH who previously had a median life expectancy of approximately 12 years can now have a life expectancy that is almost identical to that of age-matched controls.

 

The more proximal inhibitors iptacopan, which inhibits factor B, and danicopan, which inhibits factor D, are critical for the amplification of C3b through the formation of C3 convertase. This means that these agents are working at the critical first step in activating C3 and can block just one pathway of the complement cascade. Theoretically, inhibiting C3 or C5 could be more immunosuppressive than blocking factor D or factor B, which only activate the alternative pathway.

 

So, there is a focus on novel complement inhibitors targeting the alternative pathway. These include vemircopan, a small-molecule factor D inhibitor; OMS906, a monoclonal antibody that targets MASP-3 (an activator of pro-factor D); and ruxoprubart (NM8074), a monoclonal antibody that inhibits Bb.

 

I also think that there is some interest in more effective C5 inhibition with the combination of cemdisiran and pozelimab. Pozelimab is a monoclonal antibody that targets C5, but it has a fairly short half-life. The strategy here is that if you combine it with cemdisiran, a small-interfering RNA agent that decreases C5 production, the levels of C5 will be lower, and the effect of pozelimab will be longer.

 

While C5 inhibitors have been effective at blocking intravascular hemolysis and preventing thrombosis, not every patient who is on a C5 inhibitor will achieve a significant improvement in hemoglobin. In fact, quite a few patients will continue to require intermittent transfusions, so the proximal inhibitors have the advantage in that they are more likely to improve hemoglobin and extravascular hemolysis, which occurs in approximately 25% of patients with PNH who are receiving a C5 inhibitor.

 

When complement inhibitors first became available, the primary goal was to block intravascular hemolysis and prevent thrombosis, but, as new therapies become available, we have additional goals. In addition to preventing intravascular hemolysis and thrombosis, we are also trying to improve hemoglobin and reduce fatigue even more. We want to give patients with PNH a better quality of life so that they can be socially active with family and friends and lead productive lives. These are some of the challenges that the newer therapies are trying to address.