Eculizumab for the treatment of myasthenia gravis

ABSTRACT

Introduction

Acetylcholine receptor antibody-positive generalized myasthenia gravis (gMG) is effectively treated with symptomatic and immunosuppressive drugs but a proportion of patients has a persistent disease and severe adverse events (AEs). The unmet medical needs are specific immunosuppression and AE lowering. Eculizumab blocks C5 protecting neuromuscular junction from the destructive autoantibody effects. Phase II (Study C08-001) and III (ECU-MG-301) studies, with the open-label extension (ECU-MG-302), demonstrated eculizumab efficacy and safety in refractory gMG patients.

Areas covered

We provide an overview of eculizumab biological features, clinical efficacy, and safety in gMG patients, highlighting our perspective on the drug positioning in the MG treatment algorithm.

Expert opinion

Eculizumab has the potential to significantly change the immunosuppressive approach in gMG offering the opportunity to avoid or delay corticosteroids’ use due to its speed and selective mechanism of action. Eculizumab prescription will depend on: 1. ability to modify the natural disease course; 2. sustainability in the clinical practice (cost/effectiveness ratio); 3. drug-induced AE reduction. At present we are missing a controlled study on its use as a first-line treatment. We think that immunosuppression in MG will change significantly in the next years by adopting more focused ‘Precision Medicine’ approaches, and Eculizumab seems to satisfy such a promise.

KEYWORDS:

• Biological drugs
• complement system
• eculizumab
• myasthenia gravis

Article highlights

• Eculizumab is an innovative biological drug blocking the human terminal complement protein C5 with promising activity for the treatment of AChR-positive refractory generalized MG, as demonstrated in REGAIN, a phase III randomized clinical trial.

• The open-label extension (OLE) study of REGAIN provided evidence for safety and long-term sustained efficacy of eculizumab in AChR-positive refractory generalized MG.

• Future studies are needed to comprehend the clinical and therapeutic role of Eculizumab: e.g. its ability to reduce conventional immunosuppressive therapies or its efficacy in corticosteroid-naïve MG patients.

• Eculizumab has gained attention due to its ability to target a specific MG pathogenetic mechanism (complement-mediated damage), and seems to be safe in a long-term follow-up.

• The discovery of complement-related clinical/molecular biomarkers to predict successful response to eculizumab in individual refractory MG patients, or defined patients’ subgroups, and the reduction of the drug costs (whenever possible) are crucial for the future drug positioning in the MG treatment algorithm.

This box summarizes key points contained in the article.

Box 1. Drug summary box

Table

Declaration of interest

R Mantegazza has received compensation for participating on Advisory Boards in relation to MG clinical trial design, Congress participations and research support in the last 5 years from: Alexion Pharmaceuticals, ARGENX Pharma, and Biomarin. P. Cavalcante has received a grant and was supported by the Italian Ministry of Health (Grant No: GR-2013-02358564 and Annual research funding) in the last 5 years. The authors have no other 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 apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Supplementary material

Supplemental data for this article can be accessed here.

Additional information

Funding

This paper is not funded.