Promising therapies for the treatment of myasthenia gravis

ABSTRACT

Introduction

Myasthenia gravis (MG) is an autoimmune condition targeting the neuromuscular junction, which manifests with neuromuscular symptoms of varying severity and significant morbidity. The mainstay of treatment in MG is mitigation of the immune cascade with steroids and non-steroidal immunosuppressive therapies. The therapeutic strategies in MG are transitioning from broad and indiscriminate immunosuppression to novel agents targeting key steps in MG pathogenesis, including T cell activation, B cell proliferation, complement activation, maintenance of pathogenic antibody production, and proinflammatory cytokine production.

Areas covered

In this review, an overview of the pathogenesis of MG and traditional MG therapies is presented, followed by a discussion of the novel MG drugs that have been evaluated in phase 3 clinical trials with an emphasis on those which have received regulatory approval.

Expert opinion

Novel MG therapeutics belonging to the classes of complement inhibitors, neonatal Fc receptor (FcRn) inhibitors and B cell depletors, as well as the other emerging MG drugs in the pipeline constitute promising treatment strategies with potentially better efficacy and safety compared to the conventional MG treatments. However, further long-term research is needed in order to optimize the implementation of these new treatment options for the appropriate patient populations.

KEYWORDS:

• Emerging therapies
• myasthenia gravis
• neuromuscular junction transmission disorders
• novel drugs
• phase 3 trials
• investigational therapies
• immunotherapy
• neuromuscular disorders

Article highlights

• Pathogenesis of myasthenia gravis (MG) involves a complex interplay between CD4+ cells, antibody-secreting plasma cells, antigen-presenting cells, and the proinflammatory cascade. Acetylcholine receptor (AChR) and muscle-specific tyrosine kinase (MuSK) antibodies differ with regard to which parts of this immune milieu [including immunoglobulin G (IgG) subclasses] are predominantly affected, which have therapeutic implications.

• Although relatively effective and tolerable, traditional MG therapies do not universally provide optimal disease control for MG patients and can cause significant adverse effects. Novel MG drugs provide a more targeted and precise approach to MG therapeutics by altering specific steps of the pathologic immune response.

• There are five new MG drugs that received U.S. Food and Drug Administration (FDA) approval in the last 5 years for use in generalized MG patients: complement inhibitors (eculizumab, ravulizumab, and zilucoplan) and neonatal fragment crystallizable receptor (FcRn) inhibitors (efgartigimod and rozanolixizumab). Rituximab is also being used off-label for refractory MG, particularly in those with MuSK-MG.

• Additional clinical studies for the evaluation of other therapeutic prospects in MG are underway, including but not limited to CD20 biologicals, anti-B-cell activating factor of the tumor-necrosis-factor family (BAFF) immunoglobulin, monoclonal antibodies against IL-6, IL-17, IL-23, JAK inhibitors, hematopoietic stem-cell transplantation (HSCT) and chimeric antigen receptor (CAR) and chimeric autoantibody receptor (CAAR)-T cell therapy.

• There is a need to consider a utility of combination MG immunotherapies targeting multiple steps of the immune cascade simultaneously. Additionally, further MG research should better capture traditionally underrepresented MG patient subgroups (such as those with ocular MG, seronegative MG, and MuSK-MG) as well as the cost/affordability aspects of the new therapies.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they have been involved in various clinical trials in Myasthenia Gravis and have been an advisory board member for several pharmaceutical companies linked to MG clinical trials. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This paper was not funded.