Summary written by Alicia Chenoweth, PhD, King’s College London
Antibody Engineering & Therapeutics, held in December 2022, offered many opportunities to hear exciting and informative presentations by experts in the field, including Dr. Hans de Haard, Chief Scientific Officer at argenx.
Dr. de Haard’s talk, Efgartigimod: A Novel FcRn Antagonist in the Treatment of Autoimmune Diseases, detailed the mechanism of action and clinical trial results of the FcRn antagonist efgartigimod. Efgartigimod is a human IgG1 Fc fragment with five “Abdeg” mutations (M252Y, S254T, T256E, H433K, N434F) to increase its affinity for FcRn at both low pH and neutral pH (1,2). It is designed to outcompete the binding of serum IgG for FcRn, leading to degradation of the unbound IgG and recycling of efgartigimod back to the surface of the cell to be released back into circulation.
Dr. de Haard discussed the findings of a recent publication in which the biochemical, structural, and in vivo properties of efgartigimod and a full-length antibody counterpart containing the same Abdeg mutations were compared (3). Crystallographic studies of FcRn in complex with the full-length antibody demonstrated that the antigen-binding fragment projects towards the membrane, leading to a potential steric clash hindering binding. This hypothesis was confirmed using a bioassay measuring receptor occupancy, showing that efgartigimod gave a better FcRn occupancy and had improved uptake compared to the full-length antibody. Furthermore, in cynomolgus monkeys, the Fc fragment gave a much faster clearance of tracer antibody and a more potent pharmacodynamic effect compared to full-length antibody. Thus, the Fc fragment was determined to be the better performing FcRn antagonist over the full-length antibody due to improved blocking of IgG recycling in vitro and the more potent PD effect in vivo.
Dr. de Haard then discussed the results of two clinical trials using efgartigimod, a Phase 3 trial in generalized myasthenia gravis (gMG) patients, and a Phase 2 study in pemphigus vulgaris (PV) and pemphigus follaceus (PF) patients. The Phase 3 ADAPT study (NCT03669588) included 167 gMG patients regardless of anti-acetylcholine receptor (AChR)-antibody status, with a Myasthenia Gravis Activities of Daily Living (MG-ADL) score ≥5 and IgG levels of ≥6 g/L, who were on a stable dose of a minimum of one gMG treatment. These patients were randomised 1:1 to receive weekly doses of 10 mg/kg IV efgartigimod alfa or placebo administered over four weeks and repeated as needed based on clinical response ≥ 8 weeks since initiation of previous cycle. The primary endpoint was AChR-Ab+ patients who were MG-ADL “responders” (≥ 2-point improvement for ≥ 4 consecutive weeks). Of patients in the efgartigimod-treated group, 67.7% were classed as MG-ADL responders, compared to 29.7% in the placebo group (4), with 40% of patients in the efgartigimod-treated group attaining minimal symptom expression (MG-ADL of 0 or 1) compared to 11% of the placebo group. The maximal decrease in clinical score was observed at the end of the four-week cycle of treatment, which correlated with the maximal decrease in total IgG levels and AChR-specific IgG levels. Despite a 60-70% decrease in total IgG levels, most adverse reactions in the efgartigimod-treated group were mild to moderate in severity. Recycling of albumin also occurs by FcRn binding, although the binding site for albumin is distinct to IgG, and a decrease in serum albumin can contribute to an increase in cholesterol and LDL levels, thus there was concern of potential cardiovascular events. However, no significant effect was observed on the levels of serum albumin, cholesterol, or LDL levels in healthy volunteers or patients treated with efgartigimod, indicating that efgartigimod is only an FcRn antagonist for IgG, and not for albumin. The results of this Phase 3 trial supported the approval for efgartigimod as a treatment for both AChR-Ab positive and negative patients in Japan, as well as for only AChR-Ab positive patients in the US and Europe.
In the Phase 2 trial (NCT03334058) of efgartigimod in PV and PF patients, four cohorts were used to evaluate different drug concentrations and maintenance cycles. In the cohort given the highest dosage (25mg/kg weekly), 9/15 patients achieved complete remission. In the patients with sustained clinical response, the levels of total IgG as well as pathogenic autoantibody levels decreased during the treatment period. However, unlike the total IgG level, which returned to baseline once the treatment was stopped, the pathogenic autoantibodies (anti-Dsg-1 and anti-Dsg-3) remained low 10 weeks after treatment. Consistent with the decrease in autoantibodies, the numbers of Dsg antigen-specific B cells also decreased in three patients with PV with sustained clinical response, indicating that FcRn inhibition may trigger an immunomodulatory effect on antigen-specific B cells beyond the blockage of IgG recycling (5).
In summary, Dr. de Haard outlined the increased uptake and FcRn receptor occupancy by efgartigimod compared to a full-length IgG with the same ABDEG mutations, as well as the efficacy and safety profile of efgartigimod in the Phase 3 ADAPT study of patients with generalised myasthenia gravis which led to its approval in US, Japan, and Europe. In addition, the Phase 2 study in patients with pemphigus identified that efgartigimod may induce sustained responses due to reduction of autoantibody-producing B cells.
(1) Vaccaro C et al. Engineering the Fc region of immunoglobulin G to modulate in vivo antibody levels. Nat Biotech 2005;23(10):1283-1288. doi: 10.1038/nbt1143.
(2) Ulrichts P et al. Neonatal Fc receptor antagonist efgartigimod safely and sustainably reduces IgGs in humans. J Clin Invest 2018;128(10):4372-4386. doi: 10.1172/JCI97911.
(3) Brinkhaus M et al. The Fab region of IgG impairs the internalization pathway of FcRn upon Fc engagement. Nat Commun 2022; 13:6074. doi: 10.1038/s41467-022-33764-1.
(4) Howard JF Jr et al. Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis (ADAPT): a multicentre, randomised, placebo-controlled, phase 3 trial . Lancet Neurol 2021;20(7):526-536. DOI:10.1016/S1474-4422(21)00159-9.
(5) Maho- Vaillant M et al. FcRn Antagonism Leads to a Decrease of Desmoglein-Specific B Cells: Secondary Analysis of a Phase 2 Study of Efgartigimod in Pemphigus Vulgaris and Pemphigus Foliaceus. Frontiers in Immunology 2022. DOI: 10.3389/fimmu.2022.863095.
