Recent advances in understanding and managing myasthenia gravis

Introduction

Autoimmune myasthenia gravis (MG) is a neuromuscular junction (NMJ) disorder marked clinically by fatigable muscle weakness and serologically by the presence of autoantibodies. Autoantibodies against acetylcholine receptors (AChRs), muscle-specific kinase (MuSK), and lipoprotein-related protein 4 (LPR4) have been proven to be pathogenic¹. Several other antibodies such as agrin, cortactin, fast troponin, ryanodine receptor, and myofibrillar proteins have been discovered but were not able to induce the MG phenotype². The pathophysiology of the disease is dependent on the type of autoantibody present. In AChR MG, which accounts for about 85% of the population of patients with MG, IgG1 and IgG3 predominate³. These antibodies bind directly and cause selective degradation of the receptors⁴. Importantly, these immunoglobulins also cause activation of the complement pathway, including the membrane attack complex. Complement activation has been implicated as the major destructor of the neuromuscular endplate and has been observed in both human and animal models of MG^5–7. In MuSK MG, which accounts for about 10% of the population of patients with MG, antibodies bind to the Ig-like region, blocking activation of the agrin–LRP4–MuSK complex and inhibiting neuromuscular transmission⁸. Interestingly, the MuSK antibody is composed mostly of the IgG4 subtype, which does not have a predilection for activation of the complement cascade⁹. LRP4 is a transmembrane protein, which functions as a receptor¹⁰. Agrin binds LRP4, forming a complex that leads to MuSK activation. This activation appears to be essential for NMJ formation, including the distribution or clustering of the AChR¹⁰.

The incidence of MG in the total population is rare; rates are estimated to be 5 to 30 cases per million person-years, and the prevalence of the disease is estimated to be 10 to 20 cases per 100,000 population¹¹. The annual average health-care cost in the US is estimated to be $20,190 per person¹², showing that although MG is rare, it can present a significant and chronic financial burden to those who carry the diagnosis. The mortality of those who carry a diagnosis has been decreasing¹³, and this can be attributed to continued medical advancements, including better treatment options as well as improvements in acute critical care. Current treatment for MG includes anti-acetylcholinesterase (pyridostigmine) for daily or chronic symptom control; immunomodulatory therapies (intravenous immunoglobulin [IVIG] and plasma exchange), which are typically used for acute exacerbation of disease but have also been used for chronic symptom control; and immunosuppressant medications (steroids, azathioprine, cyclosporine, mycophenolate, and methotrexate), which are used for maintenance therapy and typically take weeks to months to see effect. It should be noted that of the above-listed agents, only IVIG has demonstrated clear efficacy in randomized, double-blind controlled studies¹⁴. All other agents have failed to show significant improvement over placebo^15–17. In the past 2 to 3 years, the standard of care for the treatment of MG has undergone several changes. The objectives of this article are to outline the most important advancements in care and to discuss new treatments in the pipeline.

Recent changes in the treatment of myasthenia gravis

New drugs in the pipeline

Rozanolixizumab (UCB7665) is a humanized anti-human neonatal Fc receptor (FcRn) monoclonal antibody designed to reduce the levels of pathogenic IgG in autoimmune diseases. In prior studies, the drug was found to effectively reduce IgG in cynomolgus monkeys and was found to be safe in humans in a phase 1 study²⁷. Rozanolixizumab is currently in phase II trials for both MG and primary immune thrombocytopenia. In MG, this phase II trial will look at the effectiveness and safety of the drug as compared with placebo in patients with moderate to severe MG (ClinicalTrials.gov Identifier: NCT03052751).

Efgartigimod (ARGX-113), an FcRn monoclonal antibody, recently completed its phase II trial and will be continuing in a phase III study. Results of the phase II trial report that 75% of subjects had clinical improvement in MG activities of daily living (MG-ADL) scores in the 6-week period compared with 25% of placebo, with reduction of total IgG levels, and adequate tolerability. No severe or adverse events were reported during the study period²⁶.

Monarsen (EN101) is an antisense oligonucleotide which intermixes with the mRNA encoding for acetylcholinesterase, causing a reduction in production of the enzyme. A phase Ib, non-placebo-controlled, open-label study was completed in 2007. This study showed an improvement in QMG score of 87% of the participants (13 out of 15 participants), and no major adverse events were reported²⁸. In a phase II trial, 31 patients (23 of whom completed the study) showed improvement in QMG score while on the drug²⁹. Four adverse events were reported and one of these was death by cerebral hemorrhage. The study group did not think that these adverse events were related to the drug itself. There are no plans for further studies at this time.