Mechanism of Action of Vyvgart (Efgartigimod)
Efgartigimod is a human IgG1 antibody fragment that binds to the neonatal Fc receptor (FcRn), resulting in the reduction of circulating IgG antibodies, including pathogenic autoantibodies. 1
Detailed Mechanism
Efgartigimod works through a specific immunological pathway:
FcRn Binding: Efgartigimod is a human immunoglobulin G1 (IgG1)-derived Fc fragment that has been modified at five residues to increase its affinity for the neonatal Fc receptor (FcRn) 2
Blocking IgG Recycling:
- Normally, FcRn protects IgG antibodies from degradation by binding to them in endosomes
- When efgartigimod binds to FcRn with high affinity, it prevents this protective mechanism
- This leads to increased lysosomal degradation of circulating IgG antibodies
Reduction of Autoantibodies:
- In myasthenia gravis, efgartigimod reduces acetylcholine receptor (AChR) autoantibody levels by approximately 57.6% one week after the first treatment cycle 2
- Total IgG levels are reduced by approximately 61.3% during the same timeframe
Clinical Application in Myasthenia Gravis
Efgartigimod is FDA-approved for the treatment of generalized myasthenia gravis in adults who are anti-acetylcholine receptor (AChR) antibody positive 1. Its mechanism provides several clinical benefits:
- Rapid Onset: Clinical improvement can be observed as early as week 1 after treatment initiation 3
- Sustained Effect: The therapeutic effect typically lasts between 4-12 weeks after a treatment cycle 4
- Targeted Approach: By reducing pathogenic autoantibodies rather than broadly suppressing the immune system, it offers a more targeted approach to treating autoimmune conditions
Formulations
Efgartigimod is available in two formulations:
- Intravenous (IV): Original approved formulation (Vyvgart)
- Subcutaneous (SC): Newer formulation (Vyvgart Hytrulo) that provides similar efficacy with different administration route 5
Pharmacokinetic Properties
- Distribution: Volume of distribution is 15-20L 1
- Metabolism: Degraded by proteolytic enzymes into small peptides and amino acids 1
- Elimination: Terminal half-life is 80-120 hours (3-5 days) 1
- Excretion: Less than 0.1% of the administered dose is recovered in urine 1
Potential Applications Beyond Myasthenia Gravis
The FcRn antagonism mechanism makes efgartigimod potentially useful in other autoimmune conditions where pathogenic IgG antibodies play a role, including:
- Bullous pemphigoid
- Chronic inflammatory demyelinating polyradiculoneuropathy
- Immune thrombocytopenia
- Autoimmune myositis
- Pemphigus 6
This novel mechanism of action represents an important advancement in the targeted treatment of antibody-mediated autoimmune diseases, focusing on reducing pathogenic antibodies while potentially avoiding some of the broad immunosuppressive effects of conventional therapies.