ravulizumab

**Mechanism of action** - Humanized IgG monoclonal antibody that binds complement C5 with high affinity. - It inhibits cleavage of C5 into C5a (an anaphylatoxin and chemoattractant) and C5b. This prevents assembly of C5b-9, the membrane attack complex (MAC), and therefore terminal complement-mediated lysis. - It is a second-generation anti-C5 agent derived from eculizumab. Amino acid substitutions increase endosomal pH-dependent dissociation from C5 and binding to the neonatal Fc receptor (FcRn), so the antibody is recycled. This extends its half-life to about 50 days, versus about 11 days for eculizumab. Dosing is every 8 weeks (IV), compared with every 2 weeks for eculizumab.

**Indications** - **PNH:** Acquired clonal hematopoietic stem cell disorder with a somatic PIG-A mutation (X-linked). This causes deficiency of GPI-anchored proteins, including CD55 (DAF) and CD59 (MIRL, which blocks MAC formation). The result is complement-mediated intravascular hemolysis. Classic findings are hemoglobinuria (dark morning urine), a Coombs-negative hemolytic anemia, and thrombosis at unusual sites (hepatic vein/Budd-Chiari, cerebral veins). Thrombosis is the leading cause of death. Diagnosis is by flow cytometry showing absence of CD55/CD59 (or FLAER). Aplastic anemia and pancytopenia are associated, and there is a risk of evolution to AML. - **Atypical HUS (complement-mediated TMA):** Caused by dysregulation of the alternative pathway (factor H, factor I, or MCP/CD46 mutations; C3 or factor B gain-of-function). It presents with microangiopathic hemolytic anemia, thrombocytopenia, and AKI, without Shiga toxin and with normal ADAMTS13 activity. - **Generalized myasthenia gravis (anti-AChR antibody positive)** - **NMOSD (anti-AQP4 antibody positive)**

**Adverse effects and key warnings** - **Boxed warning: life-threatening meningococcal (Neisseria) infections.** The terminal complement components (C5b-9) are essential for lysis of Neisseria. Patients need meningococcal vaccines (MenACWY and MenB) at least 2 weeks before starting, and often antibiotic prophylaxis if therapy cannot be delayed. Access is through a REMS program. Risk of other encapsulated organisms (S. pneumoniae, H. influenzae) is also increased. - Other effects: headache, infusion reactions, upper respiratory infections, and hypersensitivity. - If the drug is stopped in PNH, patients may have severe hemolysis, so they need monitoring.

**Pharmacology comparisons (high-yield)** - **Eculizumab (Soliris):** The first anti-C5 antibody, with the same indications and risks. It has a shorter half-life and is dosed every 2 weeks. - **Pegcetacoplan (Empaveli):** A C3 inhibitor. It also addresses extravascular hemolysis in PNH, which C5 inhibitors can leave unaddressed because C3b opsonization of red cells leads to splenic or hepatic clearance. This can cause residual anemia on anti-C5 therapy. - **Iptacopan:** An oral factor B inhibitor that acts on the alternative pathway. - **Crovalimab:** An anti-C5 antibody that can be given subcutaneously. - **Naming:** The suffix "-zumab" indicates a humanized monoclonal antibody.

**Clinical pearls** - PNH hemolysis is intravascular, with high LDH, low haptoglobin, hemoglobinuria, and hemosiderinuria. The Coombs test is negative. - Anti-C5 therapy does not treat the underlying clonal defect. Bone marrow transplant is the only curative option and is rarely used. - Complement deficiencies of C5-C9 (terminal components) also predispose to recurrent Neisseria infections. Ravulizumab is a pharmacologic version of this deficiency. - Primary answer for "What drug treats PNH?" is a C5 inhibitor (eculizumab or ravulizumab).