PB0347 - Efgartigimod: A Novel FcRn Antagonist in the Treatment of Autoimmune Diseases

Background: Immunoglobulin G (IgG) autoantibodies play a key role in the pathogenesis of immune thrombocytopenia (ITP) and other autoimmune diseases, such as myasthenia gravis (MG), chronic inflammatory demyelinating polyneuropathy (CIDP), pemphigus vulgaris (PV) and foliaceus (PF), bullous pemphigoid (BP), and myositis. The neonatal Fc receptor (FcRn) is the central regulator of IgG homeostasis, rescuing IgG (including pathogenic autoantibodies) and albumin from lysosomal degradation and is responsible for the long half-life of IgGs.

Aims: Therapeutic blocking of FcRn has been shown to lead to reduction of all IgG subtypes without reducing other immunoglobulin types, making it a rational target for treatment of autoimmune disorders while maintaining normal immunological responses.

Methods: Efgartigimod (EFG), an FcRn antagonist, is a human IgG1-derived Fc-fragment that outcompetes endogenous IgG binding, reduces IgG recycling, and increases IgG degradation. In healthy volunteers, EFG reduced IgG by 50–75%.

Results: In a Phase 3 study in MG (ADAPT), EFG rapidly reduced IgG without impacting IgM, IgA, or albumin levels while participants recorded statistically significant functional improvements. In a Phase 2 trial in ITP, EFG dosed at 5 and 10 mg/kg weekly for 4 weeks reduced IgG by ~60%, leading to clinically relevant increases in platelet counts (46% of EFG patients vs 25% on placebo achieved a platelet count of ≥50 × 109/L on ≥2 occasions). Phase 2/3 studies in CIDP (ADHERE), PV/PF (ADDRESS), BP (BALLAD), and myositis (ALKIVIA) are ongoing. In all studies to date, EFG was well tolerated, and adverse events were mainly mild to moderate. EFG is approved in the US and Japan for treatment of generalized MG in adult patients. Phase 3 studies in ITP (ADVANCE and ADVANCE SC) are ongoing.

Conclusion(s): FcRn inhibition by EFG is a promising potential therapeutic option for several autoimmune diseases mediated by pathogenic IgG autoantibodies.