Introduction to Eculizumab

Eculizumab (trade name: Soliris) is a humanized monoclonal antibody that inhibits terminal complement activation. It was first approved by the FDA in 2007 and has since become a crucial treatment for several rare, life-threatening disorders characterized by complement-mediated thrombotic microangiopathy.

• Class: Complement inhibitor
• Type: Humanized monoclonal IgG2/4κ antibody
• Target: Complement protein C5
• Half-life: 11.3 days
• Route of administration: Intravenous infusion

Eculizumab's ability to effectively block terminal complement activation has made it a groundbreaking treatment for several rare disorders, particularly in hematology and nephrology.

Mechanism of Action

Eculizumab works through the following mechanisms:

1. Binding specifically to complement protein C5
2. Inhibiting the cleavage of C5 to C5a and C5b
3. Preventing the formation of the terminal complement complex C5b-9
4. Preserving early components of complement activation important for opsonization of microorganisms and immune complex clearance

The complement cascade in brief:

• The complement system is part of the innate immune response
• It can be activated through three pathways: classical, alternative, and lectin
• All pathways converge at C3, leading to the formation of C5 convertase
• C5 convertase cleaves C5 into C5a (anaphylatoxin) and C5b
• C5b initiates the formation of the membrane attack complex (MAC) or C5b-9
• Eculizumab prevents the formation of C5a and the MAC, thus inhibiting complement-mediated cell lysis

By inhibiting terminal complement activation, eculizumab effectively reduces complement-mediated hemolysis and thrombosis in conditions such as paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS).

Indications

FDA-approved indications:

• Paroxysmal Nocturnal Hemoglobinuria (PNH) to reduce hemolysis
• Atypical Hemolytic Uremic Syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy
• Neuromyelitis Optica Spectrum Disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive
• Generalized Myasthenia Gravis (gMG) in adult patients who are anti-acetylcholine receptor (AchR) antibody positive

Pediatric-specific indications:

• PNH in patients aged 18 years and older
• aHUS in pediatric patients of all ages

Off-label uses in pediatrics:

• Refractory membranoproliferative glomerulonephritis
• Catastrophic antiphospholipid syndrome
• Severe cold agglutinin disease
• Prevention of antibody-mediated rejection in sensitized kidney transplant recipients

Dosage and Administration

Dosing of eculizumab varies based on the condition being treated and the patient's body weight. Here are the general guidelines:

Condition	Patient Group	Induction Dose	Maintenance Dose
PNH	≥ 18 years	600 mg weekly for 4 weeks	900 mg at week 5, then 900 mg every 2 weeks
	< 18 years	Not FDA approved, clinical trials ongoing
aHUS	≥ 40 kg	900 mg weekly for 4 weeks	1200 mg at week 5, then 1200 mg every 2 weeks
	30 to < 40 kg	600 mg weekly for 2 weeks	900 mg at week 3, then 900 mg every 2 weeks
	20 to < 30 kg	600 mg weekly for 2 weeks	600 mg at week 3, then 600 mg every 2 weeks

Administration:

• Given as an intravenous infusion over 35 minutes in adults and 1-4 hours in pediatric patients
• Do not administer as an IV push or bolus injection
• Dilute to a final concentration of 5 mg/mL
• Use dedicated line for administration
• Monitor for at least one hour following infusion for infusion reactions

Adverse Effects

Common adverse effects (incidence ≥ 15%):

• Headache
• Nasopharyngitis
• Back pain
• Nausea
• Fatigue
• Upper respiratory tract infection

Serious adverse effects:

• Serious meningococcal infections (boxed warning): Life-threatening and fatal meningococcal infections have occurred in patients treated with eculizumab
• Other serious infections: Aspergillus, Streptococcus pneumoniae, Neisseria gonorrhoeae
• Infusion reactions: Including anaphylaxis
• Immunogenicity: Development of anti-eculizumab antibodies

Pediatric-specific concerns:

• Growth and development: Regular monitoring recommended
• Immunizations: Meningococcal vaccine required before starting treatment
• Long-term effects: Limited data on long-term use in pediatric populations

Precautions and Contraindications

Contraindications:

• Unresolved serious Neisseria meningitidis infection
• Patients who are not currently vaccinated against Neisseria meningitidis, unless the risks of delaying treatment outweigh the risks of developing meningococcal infection

Precautions:

• Meningococcal infection: Vaccinate at least 2 weeks prior to administration of eculizumab. If urgent treatment is required, administer vaccine as soon as possible and provide 2 weeks of antibacterial drug prophylaxis
• Other infections: Monitor for early signs of serious infections and treat promptly if they occur
• Monitoring disease manifestations after discontinuation: Disease may return after stopping eculizumab. Monitor patients closely for at least 12 weeks after discontinuation
• Thrombosis prevention: Anticoagulation management
• Pregnancy: Limited human data; may be used if clearly needed
• Lactation: No data on presence in human milk; consider developmental and health benefits of breastfeeding

Clinical Pearls

• Eculizumab is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) due to the risk of meningococcal infection
• Patients should carry a safety card informing any treating physician that they are on complement inhibitor therapy
• In aHUS, eculizumab has shown efficacy in improving renal function and hematological parameters, often allowing discontinuation of plasma exchange/infusion
• The optimal duration of eculizumab therapy in aHUS is not established; some patients may be able to discontinue treatment, but others may relapse and require re-initiation
• In PNH, eculizumab dramatically reduces intravascular hemolysis and the need for blood transfusions, and may reduce the risk of thrombotic events
• Breakthrough hemolysis can occur in PNH patients, often due to insufficient dosing or C5 polymorphisms
• Vaccination against meningococcus should cover serogroups A, C, W, Y, and B. Revaccination according to current medical guidelines is required
• Monitoring of CH50 or AH50 (alternative pathway hemolytic activity) can be used to assess the degree of complement blockade
• Eculizumab may interfere with the interpretation of certain laboratory tests that use complement-dependent hemolysis, including the direct Coombs test