Erin M. Burns, PhD, MSPH

Inhibition of the neonatal Fc receptor (FcRn) is currently being explored as a novel treatment approach for myasthenia gravis (MG), a disease in which immunoglobulin G (IgG) autoantibodies form against acetylcholine receptors (AChRs), muscle-specific kinase (MuSK), and lipoprotein-related protein 4 (LRP4).

The pathophysiology of MG is associated with the type of auto-antibody present. AChR MG accounts for approximately 85% of cases and is characterized by the predominant expression of IgG1 and IgG3.

 These antibodies directly bind and selectively degrade the AChRs.

 Additionally, IgG1 and IgG3 activate the complement pathway, which has been implicated as the major source of destruction of the neuromuscular end plate and has been observed in both animal and human studies.

of cases and is characterized by binding of MuSK autoantibodies to an Ig-like region of MuSK, which blocks activation of the agrin-LRP4-MuSK complex and inhibits neuromuscular transmission.

 The MuSK autoantibody primarily consists of the IgG4 subtype, which is not normally associated with complement activation.

 The transmembrane protein LRP4 functions as a receptor for agrin; after binding, these 2 proteins form a complex with MuSK, leading to MuSK activation. MuSK activation is thought to be essential for AChR clustering and formation of the neuromuscular junction.

FcRn primarily functions as either a recycling receptor, maintaining high levels of albumin and IgG in the circulation, or a transcytosis receptor, responsible for the bidirectional transport of these ligands across polarized cellular barriers (FIGURE).

Efgartigimod (ARGX-113) is an investigational monoclonal Fc fragment of IgG1 that has been modified at 5 residues, using ABDEG (antibodies that enhance the degradation of IgG) technology, to increase its affinity for FcRn.

 Molecules that harbor the ABDEG mutations (M252Y/S254T/T256E/H433K/N434F) have been shown to block the function of FcRn.

 Efgartigimod engages with and occupies FcRn, stopping its interaction with and salvage of IgG in the circulation. A multicenter, double-blind, phase 2 trial was launched to evaluate the safety, efficacy, and pharmacokinetics of efgartigimod in 24 patients with MG and generalized muscle weakness.

 The study was based on the hypothesis that patients with MG who received efgartigimod would experience therapeutic benefit if the drug reduced their levels of anti-AChR autoantibodies, similar to the total IgG decrease observed in healthy volunteers during a previous phase 1 trial of the drug.

 Participants received 4 intravenous administrations of placebo or efgartigimod over a 3-week period, followed by 8 weeks of observation.

Frequently reported adverse events in those treated with efgartigimod included headache and reduced monocyte count, which were considered mild in severity, as well as a moderately severe 16 shingles episode reported by 1 patient treated with efgartigimod. Investigators reported a rapid and sustained reduction of IgG levels which paralleled the reduction of anti-AChR autoantibodies.

Clinical improvement was assessed using the Myasthenia Gravis Activities of Daily Living (MG-ADL), Quantitative Myasthenia Gravis, and Myasthenia Gravis Composite efficacy scales, as well as the 15-item Myasthenia Gravis Quality of Life scale.

 Clinical improvement was consistent with serum IgG and anti-AChR autoantibody levels, with effects noted 7 days after the initial infusion. Whereas IgG and autoantibody levels returned to approximate baseline levels by the study’s end, clinical scores indicated a sustained improvement throughout the study. Notably, for any point reduction level, a larger proportion of patients treated with efgartigimod experienced clinical improvement compared with those who received placebo. There was a clinically meaningful improvement in MG-ADL score for at least 6 consecutive weeks in 75% of patients treated with efgar- tigimod versus 25% in the placebo group.

A phase 3, randomized, double-blind, placebo-controlled trial is currently under way to evaluate the safety, efficacy, and tolerability of the drug in patients with MG and generalized muscle weakness.

 The trial includes 167 participants and will assess the percentage of MG-ADL responders among those who are anti-AChR antibody seropositive, in addition to several secondary end points. The trial is expected to reach completion in November 2020.

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An efficacy and safety study of ARGX-113 in patients with myasthenia gravis who have generalized muscle weakness (ADAPT). ClinicalTrials.gov. Updated January 27, 2020. clinicaltrials.gov/ct2/show/NCT03669588. Accessed February 3, 2020

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