Additional Analyses of the Phase 2 Efgartigimod Study in Myasthenia Gravis (4484)

Objective: Report on additional analyses from a randomized, double-blind phase 2 study of efgartigimod in generalized Myasthenia Gravis (gMG) Background: gMG is mediated by pathogenic IgG autoantibodies causing acetylcholine receptor (AChR) blockade, accelerated receptor degradation and complement activation. The neonatal Fc receptor (FcRn) recycles IgG, rescues it from degradation, and is therefore responsible for the long half-life of IgGs. Blocking FcRn function to reduce IgG autoantibody levels is a logical potential therapeutic approach for MG. Efgartigimod is a human IgG1 antibody Fc-fragment, a natural ligand of FcRn, engineered for increased, pH-dependent, FcRn affinity. Efgartigimod outcompetes endogenous IgG binding, preventing recycling, increasing IgG degradation. Design/Methods: 24 patients with gMG, MG-ADL ≥ 5, were randomized to receive 4 weekly IV infusions of 10mg/kg efgartigimod, or placebo, plus their established MG therapy. The primary endpoint was safety; secondary endpoints included change in MG-ADL, QMG, and pharmacodynamics. Results: Efgartigimod resulted in targeted reduction of all IgG subtypes, reduced AChR-antibodies, without impacting levels of other immunoglobulin isotypes or albumin. Clinically meaningful and sustained improvements in symptoms across four MG scales were seen with efgartigimod. 75% of efgartigimod patients achieved ≥2-point reduction in MG-ADL for ≥6 consecutive weeks versus 25% for placebo (p=0.039). Further analyses found 6/12 efgartigimod patients maintained clinically meaningful improvement of MG-ADL score 8 weeks after last dose (end of study), suggesting sustained effect beyond IgG reduction. Minimum Symptom Expression (MG-ADL 0 or 1) at any time during study was achieved by 5/12 (42%) efgartigimod and 1/12 (8%) placebo. No safety concerns identified. Additional pharmacodynamic, safety and efficacy data will be presented. Conclusions: Efgartigimod reduced IgG and AChR-antibodies, and improvement in gMG symptoms was sustained to end of study with no safety concerns identified. It may be an innovative approach to gMG management. A global phase 3 study is ongoing. Disclosure: Dr. Howard holds stock and/or stock options in Johnson & Johnson, Pfizer, and General Electric. Dr. Howard has received research support from Alexion Pharmaceuticals, Argenx BVBD, and Ra Pharmaceuticals. Dr. Bril has nothing to disclose. Dr. Mantegazza has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alexion Pharmaceuticals, Argenx Pharma, Biomarin. Dr. Mantegazza has received research support from Alexion Pharmaceuticals, Argenx Pharma, Biomarin. Dr. Beydoun has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Grifols,Shire, CSL, Alexion, Mitsubishi Tanabe, Akcea, Alnylam. Dr. Beydoun has received research support from Argenx, Pfizer, Mallinckrodt, UCB, Catalyst. Dr. De Rivera Garrido has nothing to disclose. fees for clinical trials (serving as Chair of data monitoring committee with Parexel). Research grants (Genzyme, Merck KGaA, and Novartis) and fees for clinical trials (serving as Chair of data monitoring committee with Parexel).Dr. Rottoli has nothing to disclose. Dr. Van Damme has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Cytokinetics, CSL Behring, Pfizer, Biogen. Yes - I have served as consultant and/or on speaker bureau for Alexion, ARGENX, Allergan, Mitsubishi Tanabe Pharma, CSL Behring, BPL, and UCB Yes - I serve as site PI for multicenter clinical trials sponsored by Alexion, Ra, ARGENX, UCB, CSL Behring, Biogen, Mallinckkrodt, Amylyx, Cytokinetics, Orion, NEALS, Baxter, and Grifols.Dr. Ulrichts has nothing to disclose. Dr. Guglietta has nothing to disclose. Dr. Beauchamp has nothing to disclose. Dr. de Haard has nothing to disclose. Dr. Verschuuren has nothing to disclose.