Elsevier

The Lancet Neurology

Volume 16, Issue 12, December 2017, Pages 976-986
The Lancet Neurology

Articles
Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study

https://doi.org/10.1016/S1474-4422(17)30369-1Get rights and content

Summary

Background

Complement is likely to have a role in refractory generalised myasthenia gravis, but no approved therapies specifically target this system. Results from a phase 2 study suggested that eculizumab, a terminal complement inhibitor, produced clinically meaningful improvements in patients with anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis. We further assessed the efficacy and safety of eculizumab in this patient population in a phase 3 trial.

Methods

We did a phase 3, randomised, double-blind, placebo-controlled, multicentre study (REGAIN) in 76 hospitals and specialised clinics in 17 countries across North America, Latin America, Europe, and Asia. Eligible patients were aged at least 18 years, with a Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of 6 or more, Myasthenia Gravis Foundation of America (MGFA) class II–IV disease, vaccination against Neisseria meningitides, and previous treatment with at least two immunosuppressive therapies or one immunosuppressive therapy and chronic intravenous immunoglobulin or plasma exchange for 12 months without symptom control. Patients with a history of thymoma or thymic neoplasms, thymectomy within 12 months before screening, or use of intravenous immunoglobulin or plasma exchange within 4 weeks before randomisation, or rituximab within 6 months before screening, were excluded. We randomly assigned participants (1:1) to either intravenous eculizumab or intravenous matched placebo for 26 weeks. Dosing for eculizumab was 900 mg on day 1 and at weeks 1, 2, and 3; 1200 mg at week 4; and 1200 mg given every second week thereafter as maintenance dosing. Randomisation was done centrally with an interactive voice or web-response system with patients stratified to one of four groups based on MGFA disease classification. Where possible, patients were maintained on existing myasthenia gravis therapies and rescue medication was allowed at the study physician's discretion. Patients, investigators, staff, and outcome assessors were masked to treatment assignment. The primary efficacy endpoint was the change from baseline to week 26 in MG-ADL total score measured by worst-rank ANCOVA. The efficacy population set was defined as all patients randomly assigned to treatment groups who received at least one dose of study drug, had a valid baseline MG-ADL assessment, and at least one post-baseline MG-ADL assessment. The safety analyses included all randomly assigned patients who received eculizumab or placebo. This trial is registered with ClinicalTrials.gov, number NCT01997229.

Findings

Between April 30, 2014, and Feb 19, 2016, we randomly assigned and treated 125 patients, 62 with eculizumab and 63 with placebo. The primary analysis showed no significant difference between eculizumab and placebo (least-squares mean rank 56·6 [SEM 4·5] vs 68·3 [4·5]; rank-based treatment difference −11·7, 95% CI −24·3 to 0·96; p=0·0698). No deaths or cases of meningococcal infection occurred during the study. The most common adverse events in both groups were headache and upper respiratory tract infection (ten [16%] for both events in the eculizumab group and 12 [19%] for both in the placebo group). Myasthenia gravis exacerbations were reported by six (10%) patients in the eculizumab group and 15 (24%) in the placebo group. Six (10%) patients in the eculizumab group and 12 (19%) in the placebo group required rescue therapy.

Interpretation

The change in the MG-ADL score was not statistically significant between eculizumab and placebo, as measured by the worst-rank analysis. Eculizumab was well tolerated. The use of a worst-rank analytical approach proved to be an important limitation of this study since the secondary and sensitivity analyses results were inconsistent with the primary endpoint result; further research into the role of complement is needed.

Funding

Alexion Pharmaceuticals.

Introduction

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.

Section snippets

Study design and participants

We did a phase 3, randomised, double-blind, placebo-controlled study in 76 centres in 17 countries across North America, Latin America, Europe, and Asia (appendix). Independent ethics committees or institutional review boards provided written approval for the study protocol and all amendments.

Patients with anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis aged 18 years or older were eligible for the study if they had confirmed generalised myasthenia gravis,

Results

Between April 30, 2014, and Feb 19, 2016, 170 patients were screened, of whom 126 were randomly assigned to treatment and 125 received study drug (62 received eculizumab and 63 received placebo; figure 1). Of the 125 treated patients, 118 completed the study and seven dropped out prematurely. Discontinuation because of adverse events was the most common reason.

Treatment groups were generally well matched regarding demographic characteristics, disease status, and medical history (table 1,

Discussion

In this phase 3 study, the mean-ranked difference in change in MG-ADL between eculizumab and placebo was not statistically significant. Inhibition of terminal complement activation is a biologically rational approach to prevent damage at the neuromuscular junction in patients with anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis. REGAIN was designed to compare eculizumab, a terminal complement inhibitor, with placebo in these patients. However, the

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