Prospective cohort study evaluating efficacy and safety of efgartigimod in Chinese generalized myasthenia gravis patients.

Background: Despite the efficacy of efgartigimod demonstrated in ADAPT phase 3 trial, data specifically derived from Chinese participants are not available. Therefore, we aimed to evaluate the efficacy and safety of efgartigimod in Chinese patients with generalized myasthenia gravis (gMG). Methods: This is a prospective cohort study conducted in 8 hospitals across China. gMG patients received weekly intravenous infusions of efgartigimod (10 mg/kg) under a named patient program (NPP). The present study is an 8-week study, consisting of 4 consecutive doses of efgartigimod administered over 3 weeks (one cycle), followed by a 5-week follow-up period to assess the tolerability of efgartigimod's therapeutic effects. The primary outcome was the mean change in MG activities of daily living (MG-ADL) total score from baseline to 4 weeks. MG-ADL responder was defined as a ≥ 2-point improvement that persisted for 4 weeks, starting by week 4. Safety evaluations encompassed the monitoring of adverse events (AE) and serious AE (SAE) throughout the study. Results: Between 5 July 2022 and 25 August 2023, a total of 14 gMG patients were included. The mean age was 57.7 years, with a mean MG-ADL score of 10.86 ± 3.32. At week 4, MG-ADL scores showed a mean reduction of 6 points, reaching a maximum decline of 13 points. Among the patients, 85.7% (12/14) achieved MG-ADL responder status after one cycle of treatment. The most significant reduction in quantitative MG (QMG) scores also occurred at week 4, with a mean decrease of 7 points. Notably, the improvements in MG-ADL and QMG scores persisted until week 8. During treatment and follow-up period, only two mild neck rashes occurred and resolved promptly. No infections or SAE were reported. Discussion: A single cycle of efgartigimod treatment demonstrates effectiveness and the tolerability through week 8, with no new safety signals observed in Chinese gMG patients.

Clinical Features and Prognostic Analysis of MuSK-Antibody-Positive Myasthenia Gravis versus Double-Seropositive Myasthenia Gravis: A Single-Center Study from Central South China.

Purpose: To decipher the discrepancies between muscle-specific kinase antibody-positive myasthenia gravis (MuSK-MG) and double-seropositive myasthenia gravis (DSP-MG), and to determine prognostic factors for minimal manifestation status (MMS) achievement in MG patients with MuSK autoantibodies (MuSK-Ab). Patients and Methods: A total of 34 MG patients seropositive for MuSK-Ab were enrolled in this study. The demographic and clinical features were compared between MuSK-MG (n = 28) and DSP-MG (n = 6) patients, and factors affecting MMS induction in all patients with MuSK-Ab were identified using Cox regression analysis. Results: Compared to MuSK-MG patients, those with DSP-MG had similar clinical characteristics, except that they had a lower frequency of bulbar muscle involvement at nadir (50% vs 92.9%; P = 0.029) and higher proportions of comorbidities with diabetes mellitus (33.3% vs 0%; P = 0.027) and thymic abnormalities (33.3% vs 0%; P = 0.027). Higher MG Activities of Daily Living (MG-ADL) scores (HR = 0.16, 95% CI: 0.037-0.7, P = 0.015) and axial muscle involvement at nadir (HR = 0.39, 95% CI: 0.16-0.94, P = 0.035) were negative prognostic factors for MMS achievement in patients with MuSK-Ab regardless of acetylcholine receptor antibody (AChR-Ab) positivity. Multivariable Cox regression analysis further established higher MG-ADL scores at the nadir (HR = 0.19, 95% CI: 0.04-0.94; P = 0.042) as an independent risk factor for MMS achievement. Conclusion: DSP-MG was comparable to MuSK-MG and could be considered a single entity in our cohort. In all MG patients with MuSK-Ab, a higher MG-ADL score at nadir may herald a lower chance of MMS achievement, with no observed potential effect of AChR-Ab presence.

Efficacy of ravulizumab in patients with generalized myasthenia gravis by time from diagnosis: A post hoc subgroup analysis of the CHAMPION MG study.

INTRODUCTION/AIMS: The CHAMPION MG study demonstrated that ravulizumab significantly improved Myasthenia Gravis-Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) total scores versus placebo in adults with acetylcholine receptor antibody-positive generalized myasthenia gravis (AChR+ gMG). This post hoc analysis aimed to assess these outcomes by time from MG diagnosis. METHODS: Changes from baseline to week 26 in MG-ADL and QMG total scores were analyzed by time from MG diagnosis to study entry (≤2 vs. >2 years). Within each subgroup, least-squares (LS) mean changes for ravulizumab and placebo were compared using mixed models for repeated measures. RESULTS: In ravulizumab-treated patients, differences in LS mean (standard error of the mean) changes from baseline to week 26 were not statistically significant in the ≤2-years subgroup versus the >2-years subgroup for MG-ADL (-4.3 [0.70] vs. -2.9 [0.37]; p = .0511) or QMG (-4.3 [0.94] vs. -2.5 [0.50]; p = .0822) scores. No clear trends were observed in the placebo group. LS mean changes from baseline were significantly greater for ravulizumab versus placebo in both the ≤2 and >2 years from diagnosis subgroups for MG-ADL and QMG scores (all p < .05). The difference in treatment effect between the ≤2-years and >2-years subgroups was not statistically significant. No clinically meaningful between-subgroup differences in treatment-emergent adverse events were observed in ravulizumab-treated patients. DISCUSSION: Ravulizumab treatment improved clinical outcomes for patients with AChR+ gMG regardless of time from diagnosis. A numerical trend was observed favoring greater treatment effect with earlier versus later treatment after diagnosis. Further studies are required for confirmation.

The best and worst of times in therapy development for myasthenia gravis.

Within the last 5 years, the US Food and Drug Administration (FDA) has approved complement and neonatal Fc receptor (FcRN) inhibitors for treatment of generalized myasthenia gravis, and several other therapies are in late-stage clinical trials or under regulatory review. However, questions about which patients are most likely to benefit from which therapies, and the relative effectiveness of these very expensive drugs, has resulted in uncertainty around the place that they should occupy in the existing therapeutic armamentarium. MGNet (a Rare Diseases Clinical Research Consortium funded by the National Institute of Neurological Diseases and Stroke) held two meetings during the 14th International Conference of the Myasthenia Gravis Foundation of America to discuss the most critical needs for clinical trial readiness and biomarker development in the context of therapy development for myasthenia gravis. Herein we provide a summary of these discussions, but not a consensus opinion, and offer a series of recommendations to guide focused research in the most critical areas. We welcome ongoing discussion through comments on this work.

Minimal Manifestation Status Indicates a Stable State in Myasthenia Gravis: A Quantitative Study.

Introduction: Minimal manifestation (MM) or better was recommended as the treatment goal for myasthenia gravis (MG). The sustainability of this status has not been described quantitatively in patients who had attained or are close to it. Methods: Patients who were with no or slight impact on daily living were recruited and followed at baseline and 3, 6, and 12 months. The included patients were classified into 3 post-intervention status (PIS) categories: remission (R), MM, and slight impact (SI). The proportion of patients belonging to real-time (not considering the intervals between assessments) and sustained (considering the intervals between assessments) PIS categories was compared at each follow-up. A sensitivity analysis (SA) cohort was established by including patients with PIS categories in all four follow-ups. The QMGS, MG-ADL, and MG-QOL15 scores in patients belonging to each PIS category at each follow-up were compared. The sustainability of the R/MM status was examined and correlated with real-time R/MM status at follow-ups. Results: At baseline, 376 patients could be classified, including 55 as R (14.2%), 209 as MM (54.0%), and 112 as SI (28.9%). In the whole cohort, 68.8-89.7%, 71-76.7% and 19.8-77.1% of the patients classified into real-time R, MM, and SI categories remained unchanged in each follow-up compared with the previous follow-up. The proportion of patients belonging to each real-time or sustained R/MM status at the three follow-ups was 89.7-92.1 or 60.8-67. In the SA cohort, at least 86.4% of the baseline R/MM patients remained in R/MM status till 12 months. There were no differences in keeping real-time R/MM status at 6 or 12 months between patients with and without sustained R/MM status at 3 and 6 months. There were differences in the QMGS, MG-ADL, and MG-QOL15 scores among patients belonging to each real-time category at baseline and follow-ups, ranking as R < MM < SI. The same trend was observed in patients belonging to each sustained PIS category with smaller scores than the same items of real-time categories. Conclusion: The sustainability of the R/MM status was confirmed. The R/MM status indicated a stable state of MG. The QMGS, MG-ADL, and MG-QOL15 scores may provide a quantitative reference for these PIS.

Quantitative evaluation of drug efficacy in the treatment of myasthenia gravis.

OBJECTIVES: This study aimed to quantitatively evaluate placebo effect and drug efficacy characteristics and identify associated factors that affect quantitative myasthenia gravis (MG) score (QMGs) and MG activities of daily living score (MG-ADLs) in patients with MG. METHODS: Randomized placebo-controlled clinical trials were comprehensively searched in public databases (PubMed, EMBASE, and Cochrane Library databases).A model-based meta-analysis was developed to describe time-course about drug efficacy and placebo effect. RESULTS: Twelve articles including 13 trials (673 participants) that were eligible for this study evaluated four immunosuppressants (tacrolimus, cyclosporine, prednisone, and mycophenolate mofetil) and five targeted therapy drugs (eculizumab, belimumab, zilucoplan, efgartigimod, and iscalimab). The pharmacodynamic model showed that eculizumab had the highest efficacy in reducing QMGs scores (3.66 points), and efgartigimod had the highest efficacy in reducing MG-ADLs scores (1.97 points). The placebo effect of QMGs and MG-ADLs increased apparently with time and reached 52% and 90% of their maximum effect in 12 weeks, respectively. In addition, this study found that the activities of daily living ability increased with the increase of the proportion of patients undergoing thymectomy. CONCLUSION: This study analyzed the efficacy characteristics of nine drugs. The present findings provide necessary quantitative information for drug development of MG.

Sensitivity of MG-ADL for generalized weakness in myasthenia gravis.

BACKGROUND AND PURPOSE: Myasthenia gravis activities of daily living (MG-ADL) is a commonly used questionnaire in MG trials. To investigate whether MG-ADL is equally sensitive to oculobulbar and generalized weakness, its correlation with the oculobulbar and generalized domain of the quantitative myasthenia gravis (QMG) score was analyzed (QMGob and QMGgen, respectively). To test whether the sensitivity of MG-ADL for generalized weakness could be improved, the additional value of ACTIVLIM on top of MG-ADL in the prediction QMGgen in was investigated. METHODS: MG-ADL, QMG and ACTIVLIM, an ADL questionnaire focusing on generalized weakness, were analyzed in a prospective cohort of 112 MG patients. A generalized linear model was used to calculate the correlation of MG-ADL with QMGob and QMGgen and to assess the additional value of ACTIVLIM on top of MG-ADL for its correlation with QMGgen. RESULTS: MG-ADL had a higher correlation with QMGob than with QMGgen (B = 0.68, P < 0.001, and B = 0.38, P < 0.001, respectively). A similar trend was found for changes in the scores (B = 0.68, P = 0.132, and B = 0.39, P = 0.492, respectively). ACTIVLIM had a significant additional value on top of MG-ADL in the prediction of QMGgen, both cross-sectionally (B = -0.61, P < 0.001) and for changes within individual patients (B = -0.93, P = 0.041). CONCLUSION: MG-ADL has a lower sensitivity for generalized weakness than for oculobulbar weakness. Adding questions on generalized weakness would improve the sensitivity of the MG-ADL for generalized weakness.

Physician- and self-assessed myasthenia gravis activities of daily living score.

INTRODUCTION: The Myasthenia Gravis-Activities of Daily Living (MG-ADL) profile scale is a simple-to-use instrument. We aimed to validate this scale in the Korean language and compare physician- and self-assessed MG-ADL scores (pMG-ADL-K and sMG-ADL-K). METHODS: pMG-ADL-K and sMG-ADL-K and MG Composite (MGC) scores were obtained from patients. The correlation between pMG-ADL-K and MGC and the relationship between the pMG-ADL-K and sMG-ADL-K were assessed using the Cronbach α and the Spearman coefficient. By intraclass correlation coefficient (ICC), the reliability of each sub-item of pMG-ADL-K and sMG-ADL-K was evaluated. RESULTS: We included data from 40 patients. The pMG-ADL-K score showed a strong correlation with the MGC score (rho = 0.80, P < 0.01). The Cronbach α was 0.98 between pMG-ADL-K and sMG-ADL-K, and sub-items showed good consistency (ICC 0.684-0.985, P < 0.001). DISCUSSION: The MG-ADL-K is a valid tool and the sMG-ADL-K shows excellent correlation with pMG-ADL-K. Both the pMG-ADL-K and sMG-ADL-K can be used to measure MG severity. Muscle Nerve 57: 419-422, 2018.

QMG and MG-ADL correlations: Study of eculizumab treatment of myasthenia gravis.

INTRODUCTION: A phase 2 study of eculizumab for treating myasthenia gravis (MG) used the quantitative myasthenia gravis score (QMG) and myasthenia gravis activities of daily living profile (MG-ADL) to evaluate baseline disease severity and treatment response. Correlations were then analyzed between these assessments. METHODS: Patients were given eculizumab or placebo during the first 16-week treatment period of the crossover study, with treatment assignments reversed for the second treatment period following a 5-week washout. QMG and MG-ADL scores at baseline and endpoint of each treatment period generated correlation coefficients for baseline status and treatment response during eculizumab therapy. RESULTS: Correlation strength between QMG and MG-ADL scores was higher for treatment response (R = 0.726; 95% confidence interval, 0.264-0.907; P = 0.0036) than for assessing baseline disease status (R = 0.552; 95% confidence interval, -0.022-0.839; P = 0.0495). CONCLUSIONS: MG-ADL may be more sensitive for assessing treatment response than point-in-time disease status. Muscle Nerve 56: 328-330, 2017.

Late-onset myasthenia gravis is predisposed to become generalized in the elderly.

OBJECTIVE: The continuous increase in the number of patients presenting with late-onset myasthenia gravis (LOMG) underscores the need for a better understanding of the clinical course and the establishment of an optimal therapeutic strategy. We aimed to clarify factors associated with clinical outcomes in LOMG. METHODS: We retrospectively reviewed the clinical profiles of 40 patients with early-onset MG (EOMG) (onset age: 49 years or younger), 30 patients with non-elderly LOMG (onset age: 50-64 years), and 28 patients with elderly LOMG (onset age: 65 years or older) and compared the subgroups according to onset age and thymus status. The evaluated parameters were MGFA classification before treatment, MG-ADL score, complicating diseases, antibody titer, treatment, and MGFA post-intervention status. RESULTS: Elderly LOMG patients showed transition to generalized symptoms at a higher frequency and underwent thymectomy less frequently than EOMG and non-elderly LOMG patients (p < 0.001). The frequencies of crisis and plasmapheresis were significantly lower in thymectomized LOMG patients without thymoma than in thymectomized LOMG patients with thymoma or non-thymectomized LOMG patients (p < 0.01, P < 0.05, respectively). However, the outcome was not significantly different. All of the thymectomized LOMG patients without thymoma presenting with hyperplasia or thymic cyst had a favorable clinical course. CONCLUSIONS: Our study showed that elderly LOMG patients are more prone to severity, suggesting that they require aggressive immunomodulatory therapy.

Salbutamol therapy in congenital myasthenic syndrome due to DOK7 mutation.

INTRODUCTION: Salbutamol is a selective B2-adrenergic agonist, which has previously been described to be associated with partial improvement of myasthenia gravis and congenital myasthenic syndromes (CMS). In this study, we analyzed the effect of salbutamol in five patients with Dok-7 CMS. METHODS: We studied 5 patients (2 male and 3 female), with a mean age of 27±11.06 years, who harbored c.1124_1127dupTGCC, p.G64R and/or p.S45L mutations in DOK7 gene. Salbutamol was given at a dose of 2mg three times daily (6 mg/day) to all patients. The response was assessed by QMG score at baseline, 3, 6, 9 and 12 months; ADL-MG score and 6 minute walk test at baseline and after 12 months during follow-up clinic visits. Side effect profile of salbutamol was also evaluated. RESULTS: We noted an increasingly positive response as measured by the QMG score after 3 months of salbutamol treatment. Improvement in specific subcomponents of the QMG score such as leg outstretched in 45° supine was most marked. In ADL-MG scores and 6 minute walk test, comparison between baseline and after 12 months revealed a clear beneficial response. Salbutamol was well tolerated in all patients. CONCLUSIONS: Salbutamol is an effective treatment in Dok-7 CMS. This study provides class IV evidence that salbutamol given at a dose 6 mg/day improves function as measured by the QMG score, ADL-MG score and 6 minute walk test.