Clinical Information

Eculizumab (Soliris, Alexion Pharmaceuticals), a humanized monoclonal IgG2/4 kappa antibody therapeutic directed against complement component C5, has been heralded as a breakthrough treatment for paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). More recently, eculizumab has been approved to treat aquaporin-4 (AQP4) IgG positive neuromyelitis optica spectrum disorder and generalized myasthenia gravis. By association with C5, eculizumab inhibits the terminal complement pathway through simultaneous blockade of the generation of the potent prothrombotic and proinflammatory molecule, C5a, and the formation of membrane attack complex initiator, C5b.

Eculizumab is administered as an intravenous infusion and the dosing regimen prescribed for an average adult diagnosed with PNH is 600 mg weekly for the first 4 weeks, followed by 900 mg for the fifth dose 1 week later, then 900 mg every 2 weeks thereafter. Eculizumab has been evaluated in aHUS patients through 2 prospective, open-label, single-arm studies (C08-002 and C08-003) as well as a single-arm retrospective study. In aHUS, it is prescribed for an average adult at 900 mg weekly for the first 4 weeks, followed by 1200 mg for the fifth dose 1 week later, then 1200 mg every 2 weeks thereafter. Eculizumab was generally well tolerated, and no significant adverse effects were attributed to drug treatment; some adverse reactions included upper respiratory tract infections and diarrhea in prospective and retrospective studies, hypertension, headache, and leucopenia (C08-002/C08-003), and fever (C09-001R). Additional case reports suggest that eculizumab may prevent post-transplantation recurrence of aHUS, even in those patients harboring CFH/CFHR1 hybrid gene variants who are at very high risk of recurrence. Further research is needed to determine the duration of eculizumab therapy in the context of the genetic background of aHUS cases and risk of disease relapse.

Therapeutic drug monitoring of eculizumab is helpful when providers are considering personalized treatment decisions such as therapy discontinuation or extending dose intervals when patients are in remission states. In PNH, a minimum therapeutic concentration is expected to be above 35 mcg/mL and in aHUS, the therapeutic concentrations are expected to be above 50 to 100 mcg/mL of eculizumab. Complement blockage studies can aid in determining that a therapeutic concentration of the drug has blocked the complement function and subsequent production of sC5b-9. Here we offer a panel of eculizumab concentration plus alternative pathway function to monitor eculizumab therapy efficacy.