Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, acquired, life-threatening disease where mutations in the PIG-A gene of red blood cells cause them to become targets of the complement system. This leads to destruction of these cells via a process called haemolysis. Treatment of PNH has been revolutionised by the development of C5 inhibitor therapies, which began with the approval of eculizumab in 2007 and was followed by ravulizumab in 2018.
Prior to this, there was no real treatment strategy available for PNH patients, with only supportive therapies such as transfusion and iron-replacement methods accessible. C5 inhibitors work by interfering with the formation of the membrane attack complex (MAC), thus alleviating the primary source of intravascular haemolysis within PNH patients.
Despite the advancements made, there are aspects of the current treatment regime that can be improved. The major unmet need is that whilst C5 inhibitors target intravascular haemolysis, they do not reduce extravascular haemolysis caused by the opsonization of erythrocytes. Upstream inhibitors have clinically shown benefit in these instances, and in May 2021, pegcetacoplan opened the door for new drug classes when it was approved as the first C3 inhibitor for PNH treatment.
Another limitation is that the current route of administration for all approved therapies are through subcutaneous/intravenous (IV) methods, and thus newer therapies may provide more convenient methods for PNH patients.
Clinical therapies currently in development are looking at either optimising the route of administration via oral tablets, utilising recycling-technology (similar to ravulizumab) to enable longer action and/or targeting more proximal signalling molecules of the complement pathway for greater haemolytic control.
These new therapies, if successful, will prove to be beneficial in advancing the treatment landscape for PNH. Notably, danicopan (as an add-on to C5 inhibitor) and iptacopan are both proximal inhibitor therapies that recently reached statistical significance in the primary endpoints of their Phase 3 trials, giving indication that oral therapies may be strong competitors in the near-future.
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