PB2305: EFGARTIGIMOD: CLINICAL DEVELOPMENT OF A NOVEL FCRN ANTAGONIST IN THE TREATMENT OF AUTOIMMUNE DISEASES

Background: Immunoglobulin G (IgG) autoantibodies play a key role in the pathogenesis of various autoimmune diseases. 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 IgG. Therapeutic blocking of FcRn leads to reduction of all IgG subtypes without reducing other immunoglobulin types, making it a possible target for symptomatic treatment of autoimmune disorders, while maintaining normal immunological responses. Efgartigimod (EFG), an FcRn antagonist, is a human IgG1-derived Fc-fragment that outcompetes endogenous IgG binding, reduces IgG recycling, and increases IgG degradation. EFG is approved in the US and Japan for treatment of generalized myasthenia gravis (MG) in adult patients. Aims: This presentation provides an overview of EFG as a molecule and summarize the clinical development program to date. Methods: Studies in healthy volunteers and patients with autoimmune diseases are already completed. Phase 3 studies in immune thrombocytopenia (ITP; ADVANCE and ADVANCE SC) and phase 2/3 studies in chronic inflammatory demyelinating polyneuropathy (ADHERE), pemphigus vulgaris and foliaceus (ADDRESS), bullous pemphigoid (BALLAD), and myositis (ALKIVIA) are ongoing. Results: In a Phase 2 trial in patients with ITP, EFG (10 mg/kg given intravenously) reduced total IgG levels by 63.7% (from mean [SD] 10.6 g/L [5.1] at baseline to 4.1 g/L [2.0]) 3 days after the fourth weekly infusion. No changes in IgG levels were observed in patients treated with placebo during that time. These reductions led to clinically relevant increases in platelet counts; 46% of EFG patients vs 25% on placebo achieved a platelet count of ≥50 x109/L on ≥2 occasions. In a Phase 3 trial in MG (ADAPT), EFG rapidly reduced IgG without impacting IgM, IgA, or albumin levels while participants recorded statistically significant functional neurological improvements. In all studies to date, EFG was well tolerated, and adverse events were mainly mild to moderate. Summary/Conclusion: FcRn inhibition by EFG is a promising potential therapeutic option for several autoimmune diseases mediated by pathogenic IgG autoantibodies.