Refractory generalised myasthenia gravis is a chronic, debilitating, rare disorder of severe muscle weakness resulting from autoantibody-mediated destruction of the neuromuscular junction. Patients with refractory generalised myasthenia gravis, representing approximately 10–15% of all patients with myasthenia gravis, do not respond to long-term treatment with corticosteroids or multiple steroid-sparing immunosuppressive treatments, or they have intolerable side-effects to these therapies or require ongoing treatment with either intravenous immunoglobulin or plasma exchange.1, 2 This heterogeneous patient population continues to have disease symptoms and persistent morbidities, despite substantial use of immunosuppressive treatments, including difficulties with speech, swallowing, and mobility, impairment of respiratory function, and extreme fatigue, with substantial negative effects on activities of daily living and quality of life.1, 3 Patients with refractory generalised myasthenia gravis might also have frequent exacerbations, which can be life-threatening and require admission to hospital or intensive care, and cause episodes of respiratory failure that require mechanical ventilation. A recent US-based claims analysis reported that the frequency of myasthenic gravis crises and exacerbations, admissions to hospital, and emergency room visits was three times higher in patients with refractory generalised myasthenia gravis than in patients in the overall generalised myasthenia gravis population.4
Research in context
Evidence before this study
We searched MEDLINE, Embase, and PubMed databases up to July 23, 2017, for relevant clinical studies in refractory myasthenia gravis on the use of eculizumab, a terminal complement inhibitor, with no date or languge restrictions. The search terms used were “randomised controlled trial”, “eculizumab”, and “refractory myasthenia gravis”. We did not identify any reports of masked, placebo-controlled, randomised studies testing the use of eculizumab in refractory myasthenia gravis, except for a pilot phase 2 study of eculizumab in patients with anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis published in 2013 that was funded by the same source as this study.
Added value of this study
Current immunosuppressant therapies have not been rigorously assessed in the setting of a prospective, randomised, placebo-controlled, clinical, phase 3 study in patients with refractory generalised myasthenia gravis. REGAIN is the only study in patients with anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis. Eculizumab was well tolerated for more than 26 weeks, with few adverse events. The primary endpoint of the Myasthania Gravis-Activities of Daily Living score did not differ significantly between patients who received eculizumab and those who received placebo. Additional prespecified sensitivity and secondary analyses suggested efficacy of eculizumab.
Implications of all the available evidence
This study used several validated myasthenia gravis-specific, physician-reported and patient-reported outcome measures to capture a detailed picture of the patient population with refractory myasthenia gravis and the effects of eculizumab therapy. The data suggest that complement inhibition might be an approach to the treatment of anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis, and should stimulate additional research.
Approximately 74–88% of patients with myasthenia gravis produce autoantibodies to the acetylcholine receptor.5, 6, 7, 8, 9, 10 These autoantibodies are directly pathogenic at the postsynaptic membrane of the neuromuscular junction by initiating several processes, including accelerated endocytosis and degradation of acetylcholine receptors, and complement-mediated membrane damage and inflammation.11, 12, 13, 14, 15, 16
The role of complement in damage to the neuromuscular junction is supported by animal models of myasthenia gravis in which inhibition of formation of the membrane attack complex or use of complement-knockout animals has been shown to preserve the function of neuromuscular junctions in induced or passively transferred myasthenia gravis.17 Additionally, evidence showing that functional blockade of the complement protein C5 protects against severe disease in preclinical studies18, 19 suggests that complement inhibition might be a potential therapeutic approach for myasthenia gravis. Further support for the role of complement is derived from clinical studies in which complement activation proteins were identified at the site of damage to neuromuscular junctions, and the presence of the membrane attack complex correlated with the site of the damage in patients with myasthenia gravis.20, 21, 22 There are currently no approved therapies for refractory generalised myasthenia gravis that specifically target the complement system; inhibition of terminal complement activation represents a novel, targeted approach that might prevent damage at the postsynaptic membrane of the neuromuscular junction in patients with anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis.
Eculizumab is a humanised monoclonal antibody that specifically binds with high affinity to human terminal complement protein C5, inhibiting enzymatic cleavage to the proteins C5a and C5b and preventing C5a-induced chemotaxis of proinflammatory cells and formation of C5b-induced membrane attack complex.23, 24 Eculizumab is currently approved for the treatment of two life-threatening, complement-mediated diseases: paroxysmal nocturnal haemoglobinuria (in nearly 50 countries) and atypical haemolytic uraemic syndrome (in nearly 40 countries, including the USA, European Union, and Japan).25, 26, 27 It is also approved for refractory generalised myasthenia gravis in 28 countries with applications pending in the USA and Japan. Eculizumab's mechanism of action suggests that it might also be effective in the management of patients with anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis, a hypothesis supported by results from a pilot phase 2 study28 in which clinically meaningful improvements occurred in patients treated with eculizumab. We therefore did a phase 3 study (eculizumab for refractory generalised myasthenia gravis; REGAIN) to confirm the results of the pilot study and provide a comprehensive assessment of the safety and efficacy of eculizumab in this patient population.