FormalPara Key Summary Points

The CHAMPION MG study was conducted to assess the effects of ravulizumab (Ultomiris) in patients with generalized myasthenia gravis (gMG).

The study researched whether ravulizumab improved symptoms, muscle strength and day-to-day life in patients with gMG, along with what side effects patients experienced.

The main study outcomes were changes from baseline in scores assessing ability to perform MG-related activities of daily living and muscle strength over 26 weeks of treatment with ravulizumab compared with placebo. At week 26, the improvements in both scores were significantly greater in the ravulizumab group than in the placebo group (see Fig. 1). The side effects of ravulizumab were generally mild and similar to placebo. They were also similar to those seen in studies of ravulizumab in other diseases.

Ravulizumab improved symptoms and muscle strength compared with placebo in patients with gMG who had acetylcholine receptor antibodies, and its side effects were mild in most patients.

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Introduction

Generalized myasthenia gravis (gMG) is a long-term condition that affects the muscles, making them become abnormally tired and weak after use. Symptoms include double vision, difficulty speaking, eating, and breathing, as well as tiredness and mobility problems. These symptoms can disrupt patients’ day-to-day lives. gMG is an autoimmune condition in which the body's immune system makes antibodies which attack healthy cells. In most people with myasthenia gravis, antibodies attack the acetylcholine receptor (AChR), a protein found on muscle cells. Antibodies against AChR trigger activation of the ‘complement cascade’ (a complex series of molecular events) leading to muscles not working properly.

Immunosuppressive therapies that are often used to treat gMG work by suppressing the immune response but do not directly target the complement system. Most immunosuppressive therapies have a slow onset of action and some are associated with serious side effects when used long-term. Ravulizumab is a humanized monoclonal antibody that works by blocking the last few steps of the complement cascade. It is given by intravenous injection every 8 weeks. This summary of research reports the CHAMPION MG study, which assessed the effects of ravulizumab in adult patients with gMG who had AChR antibodies [1].

Methods

Patients were treated with either ravulizumab or placebo for 26 weeks. Four assessments were completed, the first immediately before starting treatment and the others during treatment over the next 26 weeks. These assessments measured how well patients performed MG-activities of daily living (MG-ADL), such as brushing their teeth or chewing their food, the strength of the muscles affected by gMG, including neck, leg, and eyelid strength [using a muscle strength scale called the Quantitative Myasthenia Gravis (QMG) test], and the patients’ quality of life (QoL). The impact of gMG on QoL was measured both in general, to check how overwhelmed patients are by the disease, and in particular how tiredness affected QoL, such as being too tired to leave the house. MG-ADL, QMG, and QoL were assessed at different times after treatment started.

Changes in these measures were compared between patients treated with ravulizumab and patients receiving placebo to see if ravulizumab was more effective than placebo, and if these changes were statistically significant. Information on safety and side effects was also collected during the study. The trial protocol was approved by the independent ethics committee or institutional review board at each participating institution, and all patients provided written, informed consent.

Results

There were 175 patients in the study: 86 were treated with ravulizumab and 89 were treated with placebo; 51% of the patients in the study were women; and the average age was 56 years at the start of the study. The average time since diagnosis was 10 years. At the start of the study, patients had predominantly mild to moderate impairment of MG-ADLs and mild to moderate disease severity. Patient and disease characteristics were balanced between the ravulizumab and placebo groups.

After 26 weeks of treatment, the improvement in MG-ADL and QMG scores was statistically significantly better in the patients treated with ravulizumab compared with patients who received placebo (P < 0.001; Fig. 1). Improvements in both the MG-ADL and QMG scores were seen after the first week of treatment and lasted for the 26 weeks of the study in both the placebo and ravulizumab groups. Improvements in QoL were greater with ravulizumab than placebo, but the differences after 26 weeks of treatment were not statistically significant.

The proportions of patients on ravulizumab and placebo experiencing side effects were similar. In most cases, the side effects were mild and not considered by clinicians to be related to the treatment. The most common side effects were headache, diarrhea, and nausea, and these were seen in similar proportions of patients in the ravulizumab and placebo groups. Serious adverse events (e.g., life-threatening events or events leading to hospitalization) were reported for 20 patients (23%) in the ravulizumab group and for 14 (16%) in the placebo group, and were considered related to treatment in two ravulizumab patients and four placebo patients. There were no cases of meningococcal infection. There were two deaths in the ravulizumab treatment group (one due to COVID-19 infection and one to cerebral hemorrhage), both were considered not to be related to treatment.

Fig. 1
figure 1

Study outcome measures over time, and pre-specified responder analyses at 26 weeks. Changes from baseline in MG-ADL total score over time. Changes from baseline in QMG total score over time. Reprinted with permission [1]. Copyright 2022. Massachusetts Medical Society

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Discussion

The results of the CHAMPION-MG study show that ravulizumab improved symptoms and muscle strength more than placebo in patients with gMG who had AChR antibodies. Improvements were seen quickly (in the first week) in patients receiving ravulizumab and continued through to the end of the study (week 26). Some improvements were also seen in the placebo group, an effect that has been seen in other studies in myasthenia gravis. Importantly, when compared against the placebo group, improvements were greater in the ravulizumab group, and changes were statistically significant for the key measures, i.e., MG-ADL scores, which are based on how a patient feels about their symptoms, and QMG scores, which are based the clinician’s measurement of how strong each muscle is. Although QoL scores improved with ravulizumab, the difference from placebo was not statistically significant. This may be because the study was carried out during the COVID-19 pandemic, which was shown to adversely affect the QoL of patients with gMG, and so could have ‘masked’ the true effect of ravulizumab. The side effects of ravulizumab were generally mild and similar to those seen in studies with ravulizumab in other diseases; also, most of the side effects were not considered by the treating physician to be related to ravulizumab.

One strength of the study was that it included a wide range of patients, who varied in terms of their age at gMG diagnosis, time since diagnosis, and severity of symptoms. Another strength was the assessments used to compare ravulizumab and placebo; these measured both the opinions of patients (MG-ADL and QoL) and the assessments of their clinicians on the symptoms of the disease (QMG).

The impact of ravulizumab on the long-term management of the disease and its effects on ongoing treatments (e.g., use of corticosteroids) is being evaluated in an open-label extension study.

Conclusion

Ravulizumab improved symptoms and muscle strength in patients with gMG who had AChR antibodies compared with placebo. Effects were seen quickly and its effects continued through to the end of this 26-week study. The onset of action and long dosing interval of ravulizumab differentiates it from immunosuppressive therapies. Most side effects that patients had with ravulizumab were mild and similar to those in patients who had placebo. Overall, the results suggest that ravulizumab is a good treatment option for patients who have gMG with AChR antibodies.