Efgartigimod for generalized myasthenia gravis: A multicenter real‐world cohort study in China

Abstract Objective Efgartigimod, a neonatal Fc receptor antagonist, facilitates antibody degradation including pathogenic IgGs. The ADAPT study demonstrated the tolerability and efficacy of efgartigimod in the treatment of generalized myasthenia gravis (gMG). However, very limited evidence is available for the Chinese population, and it remains inconclusive about which kind of patients are selected to preferentially receive efgartigimod in real‐world settings. Methods This multicenter cohort study included gMG patients treated at 14 neuromuscular reference centers in China. The Myasthenia Gravis Activities of Daily Living (MG‐ADL) score, immunosuppressants, and the incidence of treatment‐emergent adverse events (TEAEs) were prospectively collected. Results Of the 1640 gMG admitted between September and December 2023, 61 (3.7%) received efgartigimod for at least one treatment cycle. Among them, 56 cases (92%) were anti‐AChR antibody‐positive, 4 were anti‐MuSK antibody‐positive, and 1 was seronegative. Thymoma‐associated myasthenia gravis accounted for most cases (44%, 27 out of 61). The principal causes of efgartigimod initiation included MG acute exacerbation (MGAE) (48%, 29 out of 61) and myasthenic crisis (MC) (15%, 9 out of 61). Clinically meaningful improvement was rapidly achieved in 97% (58 out of 61) of patients at 1.3 ± 0.7 weeks. By week 12, the MG‐ADL score reduced to 3.8 ± 4.1 (baseline:10.5 ± 5.2) for all participants, while it reduced to 4.0 ± 4.7 for MGAE and 3.8 ± 4.2 for MC, respectively. All but one TMG patient required no additional rescue therapies after efgartigimod initiation. 11.5% (7 out of 61) reported ≥1 TEAEs. Interpretation This multicenter cohort study demonstrated the efficacy of efgartigimod in rapid control of gMG. Patients with MGAE or MC would benefit from efgartigimod treatment.


Introduction
Myasthenia gravis (MG) represents an autoimmune disorder in which pathogenic immunoglobulin G (IgG) antibodies target the neuromuscular junction. 1Approximately 85% of MG cases are positive for anti-acetylcholine receptor (AChR) autoantibodies.Other MG-associated antibodies encompass anti-muscle-specific tyrosine kinase (MuSK) and anti-lipoprotein receptor-related protein 4 (LRP4) antibodies (2-5%). 1 About 80% of all MG patients develop generalized MG (gMG), 2,3 which is further categorized as thymoma-associated MG (TMG), AChR early-onset MG (EOMG), AChR late-onset MG (LOMG), MuSK-MG, and seronegative MG (SNMG) according to recent advances in the understanding of disease mechanisms in MG. 4 Even with the recommended therapies within the current treatment paradigm, gMG still imposes a heavy disease burden that is associated with unpredictable disease course and treatment process. 5Particularly, gMG cases with an active disease course have a greater risk of social disability and poor quality of life.Some patients present continuous symptoms with or without crisis or crisis-like deterioration, as well as resistance to therapy. 6This highlights unmet needs in the therapeutic field of gMG.
Efgartigimod is a human IgG1's Fc fragment engineered for enhanced affinity to FcRn compared with endogenous IgG, thereby reducing IgG recycling and increasing IgG degradation.It is the first-in-class FcRn antagonist approved in the USA, Japan, and Europe, for the treatment of gMG based on the ADAPT study. 7Efgartigimod in China is used as an add-on to standard therapy in adult gMG cases with anti-AChR antibody positivity.][10][11] However, TMG and gMG cases with high disease activity only accounted for a small proportion in recent cohort studies.Further, the features of gMG cases that would choose efgartigimod remain unclear.
The present multicenter study aimed to analyze the indications of efgartigimod for gMG cases in real-world practice in China.We hypothesized that efgartigimod would benefit gMG cases regardless of initiation status, acting for rapid disease control as well as maintenance therapy.

Patients and methods
Between September and December 2023, we followed 1640 gMG patients who were treated in Clinical status and disease severity were determined by the recommendations of the Myasthenia Gravis Foundation of America (MGFA) and German guidelines.TMG was defined as gMG with a history of thymoma including all ages.EOMG was AChR-positive generalized MG without thymoma, with onset age <50 years.LOMG was AChR-positive generalized MG without thymoma, with onset age ≥50 years.MuSK-MG was a generalized MG with positive MuSK antibodies.SNMG cases were individuals double-negative for AChR and MuSK antibodies.MG acute exacerbation (MGAE) was defined as worsening of MG symptoms, including dysphagia, dyspnea, and decline in general limb muscle strength requiring monitoring or treatment. 12Myasthenic crisis (MC) was defined as a rapid clinical decline in respiratory function requiring noninvasive ventilation or intubation with mechanical ventilation (MV).Maintenance therapies with intravenous immunoglobulin (IVIg) or therapeutic plasma exchange (TPE) were defined as repeated IVIg and/or TPE for the last 3 months.
All clinical data were collected after signed informed consent.The study protocol was specifically approved by the institutional review board of the ethics committee of each institution (Fudan University, Huashan Hospital, IRB 2023-1100).The clinical study followed the Declaration of Helsinki.

Efgartigimod administration and prospective follow-up
Efgartigimod was administered intravenously at 10 mg/kg as a 1-h infusion in cycles of four weekly infusions.In the subsequent flexible cyclical period, efgartigimod was readministered as four weekly infusions at the discretion of the treating physician in case of acute worsening of MG-ADL.
Baseline parameters were retrospectively analyzed, including sex, age, disease course, serum antibody type, gMG subtypes (TMG, EOMG, LOMG, MuSK-MG, and ª 2024 The Author(s).Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.SNMG), history of thymectomy, treatments for MG before efgartigimod administration, prednisone dose, Myasthenia Gravis Activities of Daily Living (MG-ADL) score, MGFA classification, and the indications of efgartigimod as an add-on therapy.
After the initiation of efgartigimod administration, therapeutic response based on MG-ADL score and safety profile were prospectively recorded weekly for 12 weeks.Changes in prednisone dose and other immunotherapies were prospectively recorded at 4, 8, and 12 weeks after efgartigimod treatment initiation.Clinical meaningful improvement (CMI) was defined as ≥2-point reduction of MG-ADL score from baseline values.Minimal symptom expression (MSE) was defined as an MG-ADL score of 0 or 1. 13 Since baseline MG-ADL scores differ in MG subtypes, "change in MG-ADL" (average MG-ADL reduction/baseline ADL) was used to evaluate therapeutic response, instead of the absolute value.For those who initiated the second cycle of infused efgartigimod, the therapeutic response and safety profile were still collected weekly till 12 weeks.

Statistical analysis
Continuous variables were reported as mean (SD) and compared by independent t-test or one-way analysis of variance (ANOVA).Categorical data were reported as percentage (%) and compared by the chi-squared test.The rstatix package in R version 4.03 (R Foundation for Statistical Computing) was used for data analysis.Figures were generated with tidyverse, ggpubr, and ggprism, also in R version 4.03.

Efgartigimod in patients with distinct clinical subtypes
The time to achieve CMI was 1.3 AE 0.5 weeks and 1.4 AE 1.0 weeks for EOMG and TMG cases, respectively.By week 4, MSE was achieved in 57.1% and 37.0% of EOMG and TMG cases, respectively; however, by week 12, the proportion with MSE was reduced to 14.3% and 37.0%, respectively.Patients with LOMG had the mildest baseline severity, with an average MG-ADL score of Although MuSK-MG and SNMG cases had relatively high baseline MG-ADL scores (13.0 and 15.0, respectively), they achieved CMI within 1 week.By week 4, MuSK-MG cases had an average MG-ADL score of 1.0 AE 1.4, with 33.3% achieving MSE, while SNMG cases had an average MG-ADL score of 3.0.By week 12, the average MG-ADL score was reduced to 1.5 AE 1.9 for MuSK-MG, with 50% of patients having MSE, while it increased to 6.0 for the SNMG case (Fig. 1A).
The change in MG-ADL score was used to assess the subjective therapeutic response for each clinical subtype.MuSK-MG cases had 90.We also stratified the participants by clinical severity according to baseline MG-ADL score (Fig. 2).The proportion of gMG patients with high clinical severity (MG-ADL≥10) decreased from 45.9% at baseline to 9.8% and 8.5% by weeks 4 and 12, respectively.The proportion of gMG cases with MSE increased from 0% at baseline to 45.9% by week 4, versus 39.0% by week 12.Approximately 70% of all participants with baseline MG-ADL≥10 had a mild disease status, with MG-ADL≤4.

Clinical profiles of patients with inadequate rapid response to efgartigimod
In this multicenter prospective cohort, 3 patients still did not achieve CMI by week 4 (4.9%).The clinical profiles and therapeutic responses of these patients are retrospectively reviewed below.
Patient 1 (TMG with acute worsening triggered by COVID-19 infection): a 46-year-old female with AChR antibody-positive gMG for 14 years.A thymectomy carried out in 2017 confirmed the pathology of thymoma B1.She experienced recurrent MC and was refractory to conventional immunotherapies.Rituximab was administered, resulting in stable disease with MSE since January 2023.Despite full vaccination, she had COVID-19 infection in August 2023 and developed acute worsening 1 month later.Pulmonary CT revealed no pneumonia, thymoma metastasis or relapse.At admission, the patient was administered efgartigimod infusions for one cycle from September 2023.However, she gradually developed MC, requiring intensive care and plasma exchange (five cycles), followed by repeated IVIg.By the latest visit at week 12, this patient was still on ventilation (Fig. 3A).
Patient 2 (Mild LOMG): A 73-year-old female with mild gMG for 4 months.She reported a recent exacerbation of ptosis of the left eyelid that impaired her quality of life (ADL = 3, with 2 points in ptosis, and 1 point in the upper limb).She declined a dose increase for daily oral prednisolone (40 mg) as well as other immunosuppressants as add-on therapies.Thus, one cycle of efgartigimod was administered.However, 1 point change was achieved in upper limbs with no improvement in ptosis (Fig. 3B).
Patient 3 (TMG with unresectable thymoma): A 64year-old female, anti-AChR antibody-positive, complained of acute worsening in limbs for 3 months.A thymectomy carried out in 2020 confirmed the pathology of thymoma B3.She had recurrent proximal limb weakness for the past 2 years, and lung metastasis was detected by lung CT during regular visits.Before she could be safely transferred for chemotherapy, the patient was administered one cycle of efgartigimod and an escalation in the daily dose of prednisolone.Although the patient did not achieve CMI by week 4, the MG-ADL score showed a progressive decrease from week 6 to a minimum score of 7.0 by week 12 (Fig. 3C).

Discussion
The current study analyzed the indications of efgartigimod in adult Chinese patients in real-world settings soon after its approval in China.The patients encompassed a majority of gMG cases with high disease activity including individuals with MGAE and MC, which were not adequately included in the ADAPT and ADAPT+ studies.This analysis also allowed a preliminary assessment of efgartigimod efficacy in gMG patients stratified by subtypes, and disease severity at initiation.The emergence of new biologics provides opportunities in the field of MG to move from conventional treatments to target-specific immunotherapies with less side effects and faster action.Eculizumab, a C5 inhibitor, as the first approved biologic for the treatment of AChR-subtype gMG, was indicated in only 0.9% of all patients with gMG within 1 year since its approval in Japan. 14As the second approved biologic for gMG treatment, efgartigimod was used in about 3.7% of all gMG treated in the 14 participating Chinese centers.The indicated patients encompassed not only cases with highly active gMG despite adequate disease-modifying and symptomatic therapies, but also those with a mild/moderate disease course with side effects or contradictions to conventional therapies.This represents a wide spectrum for efgartigimod in the treatment of gMG patients in real-world settings.
In comparison with participants in a US multicenter cohort, gMG cases in this study had a more severe clinical status as reflected by higher baseline MG-ADL scores (10.5 AE 5.2). 10 However, the therapeutic response to efgartigimod was better in the Chinese cohort if assessed by the proportion of cases achieving CMI (97% vs. 72%) or MSE (45.9% vs. 25%) after one cycle of efgartigimod treatment.The potential explanation for this difference is a relatively younger admission age (55.3 AE 16.4 vs. 65.56AE 14.74 years) and a higher proportion of thymectomy cases (45.9% vs. 18.9%) in this cohort.Further, a short disease duration (5.1 AE 8.2 years) from the disease onset to the efgartigimod initiation may have contributions in the better therapeutic response to efgartigimod from our cohort, as compared with the previous cohort studies and phase III ADAPT trial.Future cohort studies focusing on one particular gMG subtype are expected to explore the therapeutic response.
This analysis revealed beneficial effects for efgartigimod in gMG regardless of antibody type.Noticeably, MuSK-MG also achieved a satisfactory MG-ADL reduction after treatment, corroborating the ADAPT+ study and an Italian multicenter cohort study. 9,15AChR-MG follows a Th1 paradigm and is characterized by immunoglobulin G1 (IgG1) and IgG3 subclasses, which have effector functions that promote tissue damage at neuromuscular junctions (NMJ).There is a disconnect between disease severity and autoantibody titers.Conversely, MuSK MG relies on a Th2 response, which is largely governed by the IgG4 subclass that mediates pathological processes by physically blocking NMJ proteinprotein interactions. 16Despite the abovementioned immunopathological discrepancy between the AChR and MuSK subtypes, efgartigimod showed equal efficacy in clearing pathogenic IgGs in IgG1, IgG3, and IgG4.
Even in cases positive for anti-AChR antibodies, EOMG and TMG exhibited less favorable responses to efgartigimod as evidenced by a more pronounced MG-ADL score rebound by week 8. EOMG and TMG cases accounted for the majority of patients administered the second cycle of efgartigimod, with an interval of 40 days from the first cycle, in which thymic inflammation has a profound effect on immunopathogenesis.and correlates with intrathymic production of heterogeneous IgG autoantibodies targeting AChR.The MGTX trial reported a beneficial effect for thymectomy in adult nonthymomatous MG cases. 18,19As for the role of thymoma in the development of TMG, overgeneration and escape of Th cells from thymoma further induce B cells to produce autoantibodies against AChR in the periphery.Once this is initiated, skeletal muscle-derived AChR/autoantibody complexes present in regional lymph nodes perpetuate TMG even after thymoma removal. 20,21In this regard, further studies enrolling EOMG or TMG patients with larger samples and applying more infusion cycles are warranted to evaluate the efficacy of targeting biologics in these specific subtypes.
This retrospective analysis reported a TMG case who developed MC after COVID-19 infection despite timely initiation of efgartigimod treatment.This points to an exacerbated immune response to acute respiratory syndrome coronavirus 2 (SARS-CoV-2).Indeed, COVID-19-mediated autoimmunity is associated with cytopathic effects by macrophages, CD8 + T cells and inflammatory monocytes, 22 which may not be easily suppressed by conventional immunotherapies or a single cycle of rescue therapy.
This study had strengths.It included a relatively large sample size for a real-world study of Chinese gMG patients.This cohort study allowed a preliminary assessment of efgartigimod's indications as well as therapeutic responses stratified by MG subtype and initiation status based on disease activity.The limitations of this study included a short follow-up period.In addition, patients administered the second cycle of efgartigimod were limited during the observation period.The repeated measurement of serum biomarkers, for example, pathogenic antibody or IgG levels, was unavailable in this real-world study.

Conclusion
This study provided the efficacy, safety, and tolerability data of efgartigimod in a Chinese multicenter real-world cohort with an elevated proportion of cases with high disease activity.As MG treatment is shifting toward target-specific biologicals, further prospective studies are warranted to examine if a given agent should be maintained or switched to another, as well as long-term safety profiles.

2216 ª 2024
The Author(s).Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.

Figure 3 .
Figure 3. MG-ADL score changes in 3 patients who did not exhibit rapid response to efgartigimod within 4 weeks.MG-ADL, Myasthenia Gravis Activities of Daily Living.
14 independenttertiary neuromuscular centers treating adult or adolescent MG from East, West, and South China.These hospitals were affiliated with Fudan University, Guangzhou University of Chinese Medicine, Hongkong University,

Table 1 .
Baseline clinical features for Chinese gMG patients who were treated with efgartigimod, total n = 61.The efficacy indexes in gMG are listed in Table 2.In the whole cohort, baseline mean MG-ADL score was 10.5 AE 5.2, and average prednisolone dose was 28.3 AE 23.0 mg.Under efgartigimod treatment, CMI was rapidly achieved in 97% (58 out of 61) of patients, with a mean time of 1.3 AE 0.7 weeks.By week 12, 39% (23 out of 59) of cases achieved MSE while MG-ADL was reduced to 3.8 AE 4.1.The change in MG-ADL reached 59.9 AE 53.7% by week 12, compared to baseline values.In patients on prednisone through efgartigimod treatment (n = 50), the average daily dose of prednisolone was reduced to 22.3 AE 19.0 mg by week 4, 19.1 AE 16.7 mg by week 8, and 15.7 AE 14.8 mg by week 12.
2214 ª 2024 The Author(s).Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.

Table 2 .
The efficacy profile of efgartigimod in gMG patients, total n a reduction of at least a two-point from the baseline MG-ADL score.Minimal symptom expression (MSE) was defined as an MG-ADL score of 0 or 1. "4w MG-ADL," "8w MG-ADL," and "12w MG-ADL" were defined as the average ADL score from the initiation of efgartigimod to the 4th week, 8th week, and 12th week after treatment, respectively."Change in MG-ADL" was defined as the average ADL reduction/baseline ADL.AE 3.8.MG-ADL scores decreased to 2.1 AE 2.9, with 60.0% achieving MSE, by week 12.
CMI, clinically meaningful improvement; MG-ADL, Myasthenia Gravis-Activities of Daily Living; MSE, minimal symptom expression.ª2024 The Author(s).Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.8.8 1,17A hallmark of EOMG is thymic follicular hyperplasia, which encompasses germinal centers and an increased number of B cells and plasma cells The proportion of gMG patients with different MG-ADL scores at baseline, 4 weeks, 8 weeks, and 12 weeks after efgartigimod initiation.gMG, generalized myasthenia gravis; MG-ADL, Myasthenia Gravis Activities of Daily Living.