Myasthenic crisis (MC) is a complication that suddenly aggravates the condition of patients with myasthenia gravis (MG) and seriously threatens the patient's life during the course of the disease, mainly manifested as severe involvement of respiratory muscles, respiratory failure, and the need for non-invasive or endotracheal intubation ventilator-assisted ventilation, which is the main factor of death in MG and will lead to a significant increase in the patient's hospitalization costs1,2. Therefore, the idea of "prevention is better than cure" is particularly important in MG patients, and it is urgent to strengthen the prevention of MC risk factors.
Prevention is better than cure, focusing on long-term symptom control of MG
A retrospective study conducted at 7 neurology centers in mainland China showed that in the case of treatment with traditional drugs (including steroids, azathioprine, mycophenolate mofetil, tacrolimus, etc.), MG patients had unstable symptom control and 24.1% of patients experienced relapse during treatment (Figure 1), thus increasing the likelihood of MC developing3.
Figure 1
In addition, a history of previous MC, respiratory tract infection, presence of thymoma, positive muscle-specific receptor tyrosine kinase (MuSK) antibodies, and high disease severity at diagnosis (Myasthenia Gravis Foundation [MGFA] IIIb and above) are the five risk factors for MC4-7. For patients with the above high-risk factors, long-term good disease control is required to avoid the occurrence of crisis.
A 15-year cohort study in South Korea showed a 2.49-fold reduction in all-cause mortality and a 3.14-fold reduction in MC risk in patients with MG with well-controlled symptoms compared with those with poor symptom control (Figure 2)8. Therefore, clinicians recommend close monitoring in the early stages of MG and timely treatment regimens to ensure stable symptom control and improve long-term prognosis.
Figure 2
Newer biologics may lead to better symptom control and reduce the risk of recurrence and MC
In recent years, with the advent of FcRn antagonists, the treatment of gMG has entered the era of biological targeting. Compared with traditional treatments, the new targeted biologics can achieve minimal symptom expression (MSE, Myasthenia Gravis Scale of Daily Living [MG-ADL] 0 or 1 points) in a higher proportion of patients in a shorter period of time (Fig. 3), helping patients better control symptoms and reduce recurrence.
Figure 3
Agamod is the first biologic to achieve positive results from the primary endpoint of a Phase 3 enrollment study in MG (ADAPT study) with confirmed efficacy and a favorable long-term safety profile.
Strong efficacy – Agamod helps more patients achieve MSE quickly
The results of the ADAPT study were published in the July 2021 issue of the journal Lancet Neurol. The study was a randomized, double-blind, placebo-controlled, global, multicenter Phase 3 clinical study of 167 adult patients with gMG who were randomized to either egamod (n=84) or placebo (n=83), with primary results showing 9:
➤ Higher proportion of patients with a ≥2-point improvement in MG-ADL in the first cycle of treatment in the egamod group: 77.8%
➤ The proportion of patients who achieved MSE in the first cycle of treatment in the egamod group was about 40% compared with placebo: 40% (P<0.0001)
Another multicenter real-world clinical study in Israel included 22 patients with anti-AChR-positive gMG treated with agamod, all of whom were treated with other immunosuppressive (IS) therapies. The results show 10:
➤ The proportion of patients in the egamod group who achieved MSE after the first cycle of treatment was as high as 54.5%
Long-term stability – long-term use of agamod avoids relapse and risk of MC
To further explore the incidence of hospitalizations and exacerbations after long-term treatment with agamod, the investigators conducted a post-hoc analysis of ADAPT and showed significant benefits from long-term use of agamod11:
➤ Reduced the risk of exacerbations (proportion of patients with a quantitative myasthenia gravis scale [QMG] above baseline ≥3 points) by 52.3%
➤ Reduce the risk of MG-related hospitalization by 67%
In addition, a single-center, real-world study in Italy with 14 months of follow-up showed a significant effect of agamod on disease course12: long-term use of agamod compared to pre-treatment
➤ Reduced hospitalization rate from 42% to 0% in patients with gMG
➤ Reduced plasmapheresis (PLEX)/intravenous immunoglobulin (IVIG) therapy from 79% to 5% (1 patient only)
➤ Reduced ICU occupancy from 16% to 0%
Safe tolerability – up to 3 years of studies have shown a favorable safety profile for long-term treatment with agamod
In terms of long-term safety, the three-year ADAPT+ study (open-label, single-arm, multicenter, Phase 3 expansion study, enrolled in 151 patients who completed ADAPT) showed no increase in adverse events (TEAEs) and serious TEAEs in long-term treatment with egamod, and a downward trend with prolonged administration (Figure 4)13.
Figure 4
Expert Profile
Prof. Huiyu Feng
- Director of ICU, Department of Neurology, The First Affiliated Hospital of Sun Yat-sen University
- Chief Physician, Professor, Doctoral Supervisor
- Deputy head of the Neuroimmunology Professional Group of the 8th Committee of Neurology of the Chinese Medical Association
- Deputy head of the Neurocritical Care Group of the Committee of the Neurology Branch of the Guangdong Medical Association
- Research interests: neuroimmune diseases and neurological diseases, published more than 50 related papers, participated in and presided over a number of provincial and national projects, and participated in the compilation of 6 monographs
Expert commentary
Control recurrence and avoid crisis
MC is the most severe clinical state in MG patients, significantly increasing the risk of mortality and disease burden. Studies have shown that poorly controlled symptoms increase the risk of MC8, and disease recurrence is one of the important manifestations of poorly controlled MG symptoms. Therefore, controlling recurrence is an important intervention to avoid MC. In contrast, for patients with the five major risk factors for MC (i.e., previous MC history, respiratory tract infection, presence of thymoma, positive MuSK antibody, and high disease severity [MGFA IIIb and above] at diagnosis)4-7, long-term strong symptom control is more necessary to reduce the risk of disease recurrence and thus avoid the occurrence of MC.
In recent years, the treatment of gMG has entered the era of biological targeting, and new biotargeted preparations represented by agamod have pushed the treatment goal of gMG to a higher height and helped more patients achieve MSE in a shorter time. Studies have shown that agamod has excellent performance in long-term symptom control, prevention of recurrence and avoidance of MC in MG, which is of great significance for the prevention of MC. It is expected that in the future, more clinical studies will provide more evidence-based evidence and reliable guidance for the management of MC, and bring comprehensive improvement in the quality of life of patients.
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