Ravulizumab

Complement system activation plays an important role in innate and acquired immunity. Paroxysmal nocturnal hemoglobinuria (PNH) is a hematopoietic stem cell disorder characterized by hemolytic anemia, bone marrow failure, and thrombosis. It is caused by a genetic mutation, leading to complement-mediated hemolysis and deficiencies in glycosylphosphatidylinositol (GPI)-linked proteins such as those involved in fibrinolysis. Atypical hemolytic uraemic syndrome (aHUS) is a type of thrombotic microangiopathy also caused by complement dysregulation. It is associated with thrombocytopenia, microangiopathic hemolytic anemia, and end-organ damage. Myasthenia gravis, an autoimmune neuromuscular disease, also involves the immune system aberrantly attacking the muscles, causing progressive muscle damage.

Ravulizumab inhibits the terminal complement pathway by binding to C5 with high affinity: this inhibits the cleavage of C5 to C5a, which is a pro-inflammatory and pro-thrombotic anaphylatoxin, and C5b, an initiating subunit of the terminal complement complex (C5b-9), which promotes cell lysis. Since the generation of C5b is blocked, the formation of C5b-9 is also inhibited by ravulizumab. Ravulizumab inhibits terminal complement-mediated intravascular hemolysis in patients with PNH and complement-mediated thrombotic microangiopathy (TMA) in patients with aHUS. By blocking the complement system, ravulizumab ameliorates the extent of inflammatory and immune responses that play a role in the pathophysiology of myasthenia gravis.