Eculizumab: A Review in Generalized Myasthenia Gravis

According to the international consensus guidelines, the aim of treatment in MG is to achieve at least Minimal Manifestation Status (i.e. no symptoms or functional limitations from MG but have some weakness on examination of some muscles) with no more than grade 1 AEs [12]. The acetylcholineesterase inhibitor pyridostigmine is recommended as part of initial treatment in most patients with MG. Patients who do not achieve treatment goals with pyridostigmine should receive corticosteroids or IST, and when corticosteroids are contraindicated or refused, a nonsteroidal immunosuppressant should be used. For patients with refractory MG, in addition to the abovementioned treatment options, chronic PLEX, chronic IVIg, cyclophosphamide and rituximab are recommended by the international consensus guidelines. Chronic PLEX and chronic IVIg are also recommended for the management of myasthenic crises [12]. The Association of British Neurologists [36] and German Neurological Society [2] treatment guidelines have generally similar recommendations for the management of MG.

Research in recent years has focused on identifying new targets and developing novel therapies, particularly for patients with MG who are refractory to conventional therapies. These patients have unchanged or worse status after treatment with corticosteroids and at least two other immunosuppressive agents (used in adequate doses for an adequate duration) with persistent symptoms or side effects that limit functioning, as defined by patient and physician [12]. Patients with refractory disease continue to have symptoms, which adversely affect the ADL, and may experience frequent exacerbations, which can be life-threatening and require hospital care [24]. Eculizumab is one such novel therapy; it is the first targeted complement inhibitor approved for use in anti-AChR antibody-positive adults with gMG (USA) [16], refractory gMG (EU) [17] or gMG with symptoms that are difficult to control with high-dose IVIg or PLEX (Japan) [18]. Although treatment guidelines for MG were updated prior to the approval of eculizumab, current German Neurological Society guidelines include eculizumab as an option for use in patients with severe, refractory gMG [2].

Eculizumab is a recombinant humanized monoclonal antibody that binds to human C5 complement protein and inhibits the activation of terminal complement, thereby protecting the NMJ from the destructive effects of antibody-mediated complement activation (Sect. 2). The clinical benefit of treatment with eculizumab was demonstrated in the well-designed, 26-week REGAIN study in patients with anti-AChR-positive refractory gMG [24], with treatment benefits sustained during the 52-week extension study [25] (Sect. 3). Although the prespecified primary endpoint analysis for the change from baseline to week 26 in the MG-ADL score as measured by worst-rank ANCOVA did not show statistically significant difference between eculizumab and placebo recipients, prespecified and post hoc sensitivity analyses showed significant improvements in the ADL with eculizumab relative to placebo, regardless of background IST (Sect. 3.1). Prespecified sensitivity and secondary analyses were included in the analysis plan to assess the treatment effect comprehensively (reflecting both the patients’ and physicians’ perspective), as the use of the worst-rank analysis would have made it difficult to generalize the results to clinical practice [24].

Failure to meet the primary endpoint appears to be related to the worst-rank analytical approach used for assessment, according to which all patients who discontinued therapy were assigned to the poor outcome group, regardless of the reason for discontinuation [24, 27]. Significant treatment benefit seen in the post hoc analysis of the primary outcome illustrated the importance of differentiating between patients with poor outcomes related to MG and those with poor outcomes unrelated to MG at the time of treatment discontinuation [24]. In addition, the sample size of the study may have been inadequate for the use of the worst-rank analytical approach [24].

Other outcomes, including muscle strength (QMG score) and HR-QOL measures (MG-QOL15 and Neuro-QOL Fatigue scores) improved significantly with eculizumab relative to placebo, supporting the efficacy of eculizumab in patients with anti-AChR-positive refractory gMG (Sect. 3.1). Responder analyses (a particularly important outcome in rare diseases [24]) from REGAIN showed that significantly more eculizumab than placebo recipients had clinically meaningful improvements (based on thresholds above the established criteria) in MG-ADL and QMG scores (Sect. 3.1). Up to 40% of placebo recipients also had clinically meaningful improvement in these outcomes (Sect. 3.1), which, according to the study authors, may reflect the known effect of responsiveness with placebo in patients with neurological symptoms, variability of myasthenic symptoms in the short term or greater potential for variability in patients with refractory disease [24].

Immunomodulatory therapies, such as IVIg and PLEX, act rapidly, while ISTs targeting autoantibody production (including commonly used agents that are considered steroid-sparing) may require several months to provide clinical benefit [37]. Eculizumab also acts rapidly, with treatment benefits seen within 4 weeks of initiating treatment in REGAIN, maximal effects generally seen within 12 weeks (Sect. 3.1) and clinical benefits maintained during the ongoing 52-week extension (Sect. 3.2) [24]. However, the overall duration for which eculizumab treatment may be required remains to be determined [38] and may depend on the mechanism of disease. Further research is needed to determine if the formation of MAC and destruction of the NMJ would restart after discontinuation of complement inhibition.

Eculizumab itself appears to have a steroid-sparing effect, as evidenced by a greater proportion of eculizumab recipients reducing their daily dose of IST or stopping IST than those increasing their daily dose of IST or starting new IST (63 vs. 29%; Sect. 3.2). However, as eculizumab does not target the autoantibody component of the disease, it is unlikely that patients with gMG will be able to discontinue all other therapies.

Eculizumab was generally well tolerated in patients with anti-AChR-positive refractory gMG during ≥ 78 weeks’ therapy in REGAIN and its extension, with a tolerability profile generally similar to that seen previously in other indications and no new safety concerns identified (Sect. 4). The tolerability and efficacy of eculizumab during long-term therapy remains to be established, and final results from the extension of REGAIN are awaited with interest.

Although the REGAIN study did not include patients with thymoma, treatment with eculizumab is expected to be beneficial in these patients, as their autoantibody-profile is similar to that of the REGAIN study population [38]; confirmatory studies in this subgroup of MG patients would be helpful, although patient numbers could be limiting. By contrast, eculizumab is not expected to be effective in patients with anti-MuSK IgG4 antibody-positive MG, as this IgG subclass inhibits complement activation [38].

In addition to the efficacy and tolerability, cost-effectiveness is an important consideration when choosing a therapy. Currently there are no pharmacoeconomic analyses of eculizumab in patients with gMG; well-designed studies assessing the cost-effectiveness of eculizumab are needed, especially considering the high acquisition cost [39] of eculizumab.

To conclude, eculizumab is the first targeted complement inhibitor to be approved for use in anti-AChR antibody-positive adults with gMG or refractory gMG. In the well-designed REGAIN study, although a statistically significant benefit of eculizumab over placebo in the prespecified primary endpoint analysis was not formally demonstrated, preplanned and post hoc sensitivity analyses of this outcome and other secondary outcomes, as well as data from an extension study supported the efficacy of eculizumab in this indication. Eculizumab was generally well tolerated, with a tolerability profile generally similar to that reported previously in other indications. Although several questions remain, such as duration of treatment, cost effectiveness and long-term efficacy and tolerability, current evidence indicates that eculizumab is a valuable emerging therapy for patients with refractory gMG.