According to a 2020 update of the International Consensus Guidance for Management of Myasthenia Gravis, eculizumab, a humanized monoclonal antibody against the terminal C5 complement molecule, should be considered in the treatment of severe, refractory, acetylcholine receptor positive myasthenia gravis (AChR-Ab+ MG). The role of eculizumab in the treatment of MG is suggested to evolve over time, but until further data become available to allow comparisons of cost and efficacy with other treatments, eculizumab should be considered after trials of other immunotherapies have been unsuccessful in meeting treatment goals. Recommendations of the Advisory Committee on Immunization Practices or other local guidelines regarding immunization against meningococcal meningitis should be followed prior to treatment with eculizumab. Vaccination against Neisseria meningitidis (both meningococcal conjugate Men ACWY and serogroup B or MenB) is required at least 2 weeks before starting treatment with eculizumab. Antibiotic coverage, for at least 4 weeks after immunization, is recommended if eculizumab is started before the 2-week period after vaccination. It is recommended that future research include assessment of the duration of eculizumab therapy necessary to achieve and maintain treatment goals, its efficacy in other MG populations (i.e., MG with thymoma and seronegative MG), and in other stages of disease (i.e., MG crises, exacerbations, and early therapy in non-refractory AChR-Ab+ MG). [1], [2]
This guideline update also provides a review of data regarding the use of eculizumab for treatment of MG. Through its prevention of the formation of the membrane attack complex, eculizumab reduces damage caused by complement-fixing acetylcholine receptor antibodies. In a phase II crossover randomized controlled trial (RCT) of 14 patients with refractory generalized AChR-Ab+ MG, 6/7 (86%) of eculizumab-treated patients achieved the primary end-point of a 2 point reduction in the quantitative MG score (QMG score) at the end of the first treatment period, compared to 57% with placebo. Additionally, a repeated measures mixed model of data from all visits found significant differences in the QMGS favoring eculizumab. Eculizumab treatment was also well tolerated. [1]
While there was no difference in the primary outcome measure of change in the MG-activity of daily living (MG-ADL) score from baseline to week 26 between eculizumab and placebo in a phase III, international, multicenter RCT of patients with generalized nonthymomatous AChR-Ab+ MG (REGAIN trial); the QMG score change on worst-rank analysis of covariance, and all prespecified secondary endpoints, and multiple sensitivity analyses showed a significant benefit for eculizumab (see Table 1). Participants who completed the 26-week REGAIN study were followed in an open-label extension (OLE) within 2 weeks of completing REGAIN (see Table 2). A preplanned interim analysis of the OLE at 22.7 months of median follow-up found a reduction in MG exacerbations by 75% compared with the year before REGAIN, and 56% of patients achieved minimal manifestation status or pharmacologic remission. Eculizumab was well tolerated despite one case of meningococcal meningitis occurring that was successfully treated. [1]
A 2019 network meta-analysis compared and ranked immunotherapies including immunosuppressant agents or monoclonal antibodies for MG. A total of 14 studies (N= 808 MG patients) were included for analysis. In a traditional pairwise analysis, eculizumab had a significant mean reduction of QMGS versus placebo of -0.8 (95% confidence interval [CI] -1.37 to -0.23). In the surface under the cumulative ranking curve (SUCRA) analysis, eculizumab was ranked second with a significant reduction in QMGS versus placebo of -0.75 (95% CI -1.33 to -0.3). Cyclosporine A was ranked first with a significant reduction in QMGS versus placebo of -1.18 (95% CI -1.81 to -0.59). After controlling for the intervention periods, eculizumab reached a significant reduction in QMGS of -1.5 (95% CI -2.81 to -0.18) versus placebo. Eculizumab and belimumab were ranked the most tolerable therapies causing the least counts of adverse events. This analysis is limited due to the overall quality of included studies being moderate to low; however, the authors suggest eculizumab represented the most effective therapeutic alternative to improve QMGS while maintaining good tolerability. Eculizumab may be recommended for refractory MG patients. [2]
Another recent meta-analysis aimed to evaluate drug efficacy and identify associated factors that affect QMGS and MG-ADLs in patients with MG. A total of 13 trials (N= 673) that evaluated immunosuppressants and targeted therapies (i.e., eculizumab) were eligible for analysis. A pharmacodynamic model found eculizumab to have the highest efficacy in reducing QMGs scores (3.66 points); however, efgartigimod had the highest efficacy in reducing MG-ADLs scores (1.97 points). [3]
Finally, a 2019 network meta-analysis compared and ranked immunotherapies including immunosuppressant agents or monoclonal antibodies for MG. A total of 14 studies (N= 808 MG patients) were included for analysis. In a traditional pairwise analysis, eculizumab had a significant mean reduction of QMGS versus placebo of -0.8 (95% CI -1.37 to -0.23). In the surface under the cumulative ranking curve (SUCRA) analysis, eculizumab was ranked second with a significant reduction in QMGS versus placebo of -0.75 (95% CI -1.33 to -0.3). Cyclosporine A was ranked first with a significant reduction in QMGS versus placebo of -1.18 (95% CI -1.81 to -0.59). After controlling for the intervention periods, eculizumab reached a significant reduction in QMGS of -1.5 (95% CI -2.81 to -0.18) versus placebo. Eculizumab and belimumab were ranked the most tolerable therapies causing the least counts of adverse events. This analysis is limited due to the overall quality of included studies being moderate to low; however, the authors suggest eculizumab represented the most effective therapeutic alternative to improve QMGS while maintaining good tolerability. Eculizumab may be recommended for refractory MG patients. [4]