Clinical Information

Drug and target:

Eculizumab is a humanized monoclonal IgG2/4 kappa antibody therapeutic directed against complement component 5 (C5). 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.(1) The reference product for eculizumab is Soliris (Alexion Pharmaceuticals). Several biosimilars are US Food and Drug Administration (FDA)-approved, including eculizumab-aagh (Epysqli, Samsung Bioepis) and eculizumab-aeeb (Bkemv, Amgen).

Indications:

Eculizumab is FDA-approved for use in paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), generalized myasthenia gravis and neuromyelitis optic spectrum disorder (NMOSD). All indications require meningococcal vaccination prior to therapy. Pediatric approval only applies to PNH and aHUS.(1) Eculizumab is administered as an intravenous (IV) infusion. The dosing regimen varies by indication. Eculizumab prescribed dosing 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, and 900 mg every 2 weeks thereafter. 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.(1, 2) 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 high risk of recurrence.(3-7)

Pharmacokinetic highlights:

As an IV infusion, the bioavailability of the hybrid IgG2/IgG4 monoclonal antibody is estimated to be 100%. Eculizumab’s half-life ranges from 8 to 15 days across studies, hence the administration every 2 weeks. Steady state is achieved after 4 to 5 half-lives, or approximately 4 to 6 weeks of therapy. Before then, serum concentrations tend to vary significantly. Higher clearance is observed in pediatric patients.

Immunogenicity:

The formation of anti-drug-antibodies (ADA) to eculizumab is uncommon (clinical trials suggest <2% detection) and not routinely investigated in clinical practice, as none of the detected antibodies were neutralizing nor influenced eculizumab’s clinical response.(1) There are no clinical laboratory tests available to detect eculizumab ADA. Loss of efficacy is more often driven by underexposure, not formation of ADA.

Evidence for therapeutic drug monitoring:

There are two main uses for laboratory testing of eculizumab. The most used is the pharmacodynamic effect of eculizumab on complement blockage. Complement blockage studies can aid in determining if a therapeutic concentration of the drug has blocked the complement C5 function and subsequent production of sC5b-9.(8-10)

Measuring the concentration of eculizumab in serum is another use, most helpful when providers are considering personalized treatment decisions, such as therapy discontinuation or extending dose intervals beyond the standard every 2 weeks infusions, when patients are in remission states.(11-14) A panel that includes both eculizumab concentration and eculizumab complement blockage testing is available; see ECMP / Eculizumab Monitoring Panel, Serum.