Prospective study of efgartigimod in severe myasthenia gravis exacerbations requiring ventilatory or enteral support

Abstract

Background and objectives

To evaluate the safety and clinical efficacy of efgartigimod in adults with severe generalized myasthenia gravis (MG) exacerbations requiring ventilatory or enteral support.

Methods

Prospective, single-arm, open-label study conducted between November 2024 and April 2025. Sixteen consecutive adults with AChR- or MuSK-antibody-positive generalized MG requiring invasive or non-invasive ventilatory support or enteral feeding were enrolled; all met 2016 MG Guidelines criteria for impending myasthenic crisis. MGFA classification included Class IIIb (n=14), IIIa (n=1), and IVb (n=1). The primary endpoint was clinically meaningful improvement (CMI) in MG Activities of Daily Living (MG-ADL), defined as ≥2-point reduction from baseline at weeks 4 and 8.

Results

All 16 participants (mean age 58.5±17.4 years; 8 women) completed eight weeks of follow-up. At week 8, 12 patients (75%; 95% CI 47–91%) achieved the primary endpoint. Median MG-ADL decreased from 11 (IQR 9–13) to 7 (IQR 6–9) (median change −5 points; p=0.003). Median QMG decreased from 21 (IQR 19–23) to 13 (IQR 11–16) (median change −7.5 points; p<0.001), with 56% meeting QMG-CMI by week 1. Among 12 participants receiving corticosteroids (mean starting dose 21.2 mg/day), 50% reduced or discontinued by week 8. No treatment-related serious adverse events occurred.

Discussion

Efgartigimod produced rapid, clinically meaningful improvement in severe MG exacerbations without safety concerns. FcRn blockade may represent a practical alternative to plasma exchange or IVIG in acute care settings. Findings are limited by the absence of a control arm, which precludes definitive attribution of clinical improvement to efgartigimod alone.

Clinical trials registration

NCT06688253.

Introduction

Myasthenia gravis (MG) is associated with the production of autoantibodies, primarily those targeting post-synaptic nicotinic acetylcholine receptors (AChR-Ab). It is associated with the production of autoantibodies, primarily those targeting post-synaptic nicotinic acetylcholine receptors (AChR-Ab). There is a wide range of clinical severity, with some patients experiencing only mild ocular impairment in the context of pure ocular MG while other patients who have generalized MG (gMG) experience life-threatening crisis, characterized by respiratory failure requiring ventilatory support. Current management of MG crisis primarily involves either plasma exchange (PE) or intravenous gamma-globulin (IVIg) ¹ which, while effective, have short-lived efficacy, and in the setting of plasma exchange, may not be readily available. The need for other therapeutic modalities for MG crisis is a recognized unmet need.

Several targeted therapies with quick onset of action have been approved for AChR-Ab positive generalized MG since 2017.^2,3 Rapid initiation of complement inhibitors in the clinical setting of myasthenic crisis is somewhat problematic due to the mandatory requirement to vaccinate for Neisseria meningitidis and provide coverage with prophylactic antibiotics for two weeks or longer. Such precautions are not confronted when initiating neonatal Fc receptor (FcRn) blockers.

Several agents that competitively inhibit IgG recycling via FcRn salvage pathways have been approved in gMG patients with uncontrolled disease and have demonstrated positive impact in the first 1-2 weeks after administration, but the trial programs did not enroll patients in MG crisis.^4,5 In this investigation, we prospectively assessed the therapeutic efficacy of an Fc fragment engineered to block the FcRn in patients experiencing MG crisis. Our study aims to provide the first prospective signal that efgartigimod may serve as a practical alternative in acute care and helps define feasibility, safety, and likely effect sizes to power a definitive trial. We designed this as a prospective, single-arm pilot to establish feasibility and a safety/efficacy signal in a high-acuity setting where randomization to delayed or deferred rescue would be difficult to justify.

Methods

This study was approved by the local and national IRB committee and each participant signed informed consent.

Study design ethical considerations, and study cohort

This is a prospective, single-arm, open-label study. The primary objective was to evaluate the safety and clinical efficacy of efgartigimod in patients with severe MG exacerbations. Patients presenting to emergency services or admitted to the hospital neurology department with clinically confirmed severe MG exacerbation were recruited and after informed consent treated with efgartigimod between November 15, 2024 and April 30, 2025.

Inclusion criteria were adult patients ≥18 years of age with a confirmed diagnosis of gMG documented as MGFA classification II-V with either positive AChR or MuSK antibodies (using validated CBA or ELISA). All patients required mechanical ventilation (invasive or non-invasive) or gastric/enteral feeding at presentation. All patients met criteria for impending myasthenic crisis as defined by the 2016 MG Guidelines: rapid severe worsening that in the clinician's judgment was likely to result in crisis within days to weeks. Baseline MG-ADL score demonstrating worsening from prior documented values (when available) or presentation severity score ≥8. Patients were classified by early onset (<50 years of age) and late onset (age> 50 years of age). ⁶

Determination of need for mechanical ventilation or gastric feeding: Need for mechanical ventilation was determined by the treating intensivist or neurologist based on clinical assessment including forced vital capacity <15 mL/kg, inability to clear secretions, declining oxygen saturation, or clinical signs of respiratory distress. Need for gastric/enteral feeding was determined based on inability to maintain adequate oral intake due to severe bulbar dysfunction with risk of aspiration, documented by clinical swallowing assessment (Figure 1).

Figure 1.

Flow chart diagram.

Exclusion criteria included contraindications to efgartigimod administration, prior exposure to efgartigimod, significant comorbidities affecting study participation such as renal or hepatic dysfunction, low baseline IgG levels (<600 mg/dL), active infections or other conditions responsible for MG exacerbation, and surgery in the last 12 months. We screened 25 patients and excluded 9 (seronegative on testing, n=5; MG-ADL did not show worsening from baseline, n=4) A research assistant approached all eligible patients, Figure 2). A plasma exchange (PLEX) or intravenous immunoglobulin (IVIg) comparator arm was not included at this stage. The lead author (S.S.) obtained written informed consent and collected clinical data. Patient exacerbations and current mediation or baseline prednisone use were not an exclusion criteria.Efgartigimod was administered intravenously according to the FDA approved dose of 10 mg/kg once weekly for 4 consecutive weeks. Clinical status is then generally monitored without further infusions for at least 4 weeks.

Figure 2.

Significant changes in MG-ADL scores across treatment timepoints 4 weeks (cycle 1) and 8 weeks (median at baseline = 11.5, median post-treatment = 7, p = 0.003). P-values were calculated using the paired Wilcoxon signed-rank test applied to MG-ADL scores measured at three timepoints for each patient showing continues improvement.

Outcome measures: The MG Activities of Daily Living scale (MG-ADL) is a patient-reported measure with 8 questions scored 0-3, with score range 0-24; higher scores indicate worse disease. The Quantitative Myasthenia Gravis score (QMG) is a 13-item physician-assessed examination scored 0-39; higher scores indicate worse disease. The MG Quality of Life 15-revised (MG-QOL15r) is a patient-reported quality of life measure scored 0-60; higher scores indicate worse quality of life.

Endpoint The primary endpoint for efficacy was clinically meaningful improvement (CMI) in the MG-ADL defined as a ≥2-point improvement from baseline post-treatment at 4 weeks and 8 weeks. The primary outcome assessment was conducted at the 4-week timepoint after efgartigimod initiation; additional follow-up at 8 weeks evaluated the persistence of clinical improvements. Secondary outcomes included: safety and tolerability of efgartigimod, QMG score (CMI was a reduction of ≥3 points), MG-QOL15r, bulbar subscore changes (sum of questions 1-3 on MG-ADL: speech, chewing, swallowing), time to extubation for mechanically ventilated patients, time to resumption of oral intake for patients requiring enteral feeding, need for additional therapies, corticosteroid dose changes, and number of recurrent exacerbations requiring rescue therapy during the 8-week observation period.

Patients were followed every week with MG-ADL recorded and monthly with QMG. Weekly follow-up included the assessments described, all performed by a research coordinator with MG-specific training. Adverse events were graded per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Investigators assigned relatedness using a 3-tier algorithm. Hospital stay duration and discharge MG-ADL scores were recorded for all patients.

Statistical analysis

Statistical analysis used in the prospectively enrolled efgartigimod group was based on the ability to detect proportions of patients showing improvement of MG-ADL scores at 4 and 8 weeks at a significance level of 0.05 and power of 0.80. We compared proportions using the chi-square test as appropriate. We calculated p-values for MG-ADL scores at each timepoint using mixed models for repeated measurements to analyze the data collected at multiple time points. For continuous variables comparing QMG and ADL, we used Pearson or Spearman correlation, as appropriate.

We used the CONSORT reporting guidelines, ⁷ study was registered with ClinicalTrials.gov [NCT06688253].

Results

A total of 16 patients with generalized myasthenia gravis were enrolled and included in the analysis. The mean (SD) age was 58.5 (17.4) years; 8 patients (50.0%) were women. Early-onset MG (EOMG) was observed in 7 patients (43.8%); the remaining 9 patients (56.2%) had late-onset MG (LOMG). Fourteen patients (87.5%) were acetylcholine-receptor antibody positive and the remaining (n=2; 12.5%) were MuSK antibody positive. Most patients had been classified as MGFA class IIIb (n=14; 87.5%); 1 patient (6.3%) was class IIIa, and 1 patient (6.3%) was class IVb. Other demographic information is found in Table 1.

Table 1.

Demographics and baseline characteristics.

Age (median [IQR])	64.50 [39.00, 73.25]
Sex F (%)	8 (50%)
AChR positive	14 AChR positive
MuSK positive	2 MuSK positive
Thymoma (%)	6 (37.5)
Thymic removal (%)	Yes 7(43.8)
MG-ADL baseline (median [IQR])	11.00 [9.75, 14.00]
QMG baseline (median [IQR])	21.00 [18.75, 23.25]
MGQOLr15 (median [IQR])	22.50 [17.75, 25.00]
Diabetes (%) type 1	1 (6.2)
Diabetes (%) type ii	5 (31.2)
Hyperlipidemia (%)	5 (31.2)
Hypertension (%)	8 (50.0)
Obesity (%)	4 (25.0)
History of thyroid Dysfunction (%)	2 (12.5)
History of liver disease (%)	1 (6.2)
Peripheral vascular disease (%)	2 (12.5)
Coronary disease (%)	6 (37.5)
Myocardial Infarction (%)	2 (12.5)
History of Atrial fibrillation (%)	3 (18.8)

Treatment regimens

All patients received four weekly infusions of efgartigimod. During the acute exacerbation, corticosteroids (prednisone) were initiated in 12 patients (75%) at a mean starting dose of 21.2 mg daily (SD 6.4 mg, range 5-30 mg). Pyridostigmine was prescribed in 10 patients (62.5%). Steroid-sparing immunosuppressive agents were started in 8 patients (50%), including azathioprine (n=7, 43.8%) and tacrolimus (n=1, 6.3%).

Outcome assessment

At week 4, 12 of 16 patients (75%) achieved a clinically meaningful improvement (CMI) in MG-ADL scores. Rapid clinical improvement was observed as early as one week after the first infusion, with improvements in both MG-ADL and QMG scores (Figures 2–4). During the first week, the mean MG-ADL improvement was 3.4 points (Figure 2), and 7 patients (43.8%) experienced an improvement of 4 or more points.

Figure 3.

Change in MG-ADL score from baseline over time. The plot shows the mean change in MG-ADL scores from baseline at each follow-up time point. MG-ADL was measured at baseline, week 2, week 3, week 4, and post-treatment (8 weeks). Each point represents the average difference in MG-ADL score compared with baseline. A negative change reflects clinical improvement.

Figure 4.

QMG score following treatment. Boxplots display quantitative myasthenia gravis (QMG) scores at baseline and post-treatment. A significant reduction in QMG score was observed following treatment (P = 0.0019, paired test), indicating clinical improvement. Lower QMG scores reflect reduced disease severity.

At 8 weeks, 12 of 16 patients (75%) either maintained or further improved their MG-ADL scores, indicating sustained efficacy after four weekly infusions. The median (IQR) improvement in MG-ADL was 5.0 (4.0–6.0) points (p = .003, Figure 2), and the median improvement in QMG was 7.5 points (p = .001, Figure 4). Among the 12 patients who achieved CMI in MG-ADL at 4 weeks, 10 (83.3%) maintained this response at 8 weeks.

Both anti-MuSK MG patients showed substantial improvement following 8 weeks of FcRn blockade, with MG-ADL scores decreasing by 4 and 7 points respectively.

Two patients worsened: one developed severe pneumonia with influenza B confirmed by PCR 3 weeks after stabilization, requiring ICU admission, intubation, and five sessions of rescue plasma exchange. The second patient had morbid obesity with a BMI of 48.3 and showed minimal clinical improvement.

Corticosteroid requirements

Among the 12 patients who received corticosteroids during the acute exacerbation, 6 (50%) had dose reductions or discontinuation by week 8. Three patients discontinued corticosteroids entirely, and 3 patients had dose reductions (10 mg, 5 mg, and 5 mg respectively). Mean corticosteroid dose at week 8 was 13.8 mg (SD 9.8 mg, range 0-25 mg) compared to the starting dose of 21.2 mg (SD 6.4 mg). The remaining 6 patients (50%) maintained their corticosteroid dose without change throughout the 8-week period.

Quality of life and baseline comparisons

Clinical and ICU outcomes

No patient required invasive mechanical ventilation at enrollment; all who received ventilatory support were managed with non-invasive ventilation (NIV), and the remainder required enteral feeding only. Specific timing outcomes (time to NIV weaning, time to resumption of oral intake, hospital length of stay) were not captured in the study dataset and represent a limitation acknowledged below. With respect to outcomes that were captured: one patient (6.3%) required rescue plasma exchange during the 8-week follow-up period following influenza B pneumonia three weeks after initial clinical stabilization. No other patient required rescue therapy. One additional patient (6.3%) experienced transient clinical worsening managed at a neurology outpatient visit without rescue immunotherapy and ultimately met the primary endpoint. Twelve of 16 patients (75%) met the QMG clinically meaningful improvement threshold (≥3-point reduction) over the 8-week study period.

MG-QOL15r scores improved in 9 patients (56%; Figure 5) and were significantly correlated with MG-ADL (p = 0.0185) and QMG (p = 0.017) scores. No significant baseline differences were observed between responders and non-responders with respect to age, sex, anti-AChR serostatus, thymoma prevalence, thymectomy status, medication history, or baseline MGFA class, MG-ADL and QMG scores.

Figure 5.

Change in MG Quality of Life 15r scores from baseline to post-treatment. There was no statistically significant change before and after treatment. Lower scores reflect a better perceived quality of life.

Safety

Treatment-emergent adverse events occurred in 9 of 16 patients (56.3%), with all but one graded as CTCAE grade 2 or lower (Table 2). One patient experienced a recurrent crisis secondary to viral pneumonia 1 month after the initial crisis, representing the only treatment-emergent serious adverse event.

Table 2.

Adverse Events.

Adverse event	Number of patients	Percentage (%)
Headache	4	25
UTI	2	14.3
Muscle pain	5	31.25
Nausea	1	7.1
Pneumonia	1	7.1
Others*	4	25

*Others include Dizziness (n=1), Sore trout (n=1), Fatigue (n=2).

Discussion

This single-center investigation systematically evaluates an FcRn blocker in severe MG exacerbations requiring non-invasive ventilatory support or enteral feeding, including patients in impending myasthenic crisis. The study achieved three clinically important goals. First, efgartigimod produced a rapid, clinically meaningful benefit: 75% of patients achieved a ≥2-point MG-ADL improvement, with median gains of 5 points in MG-ADL and 7.5 points in QMG, emerging as early as one week after the initial infusion and sustained through 8 weeks. Second, treatment was accompanied by a substantial corticosteroid-sparing effect in half of subjects who were enrolled while on prednisone and in a relatively short time window of 8 weeks, highlighting the potential of FcRn inhibition to mitigate corticosteroid toxicity that often complicates MG management. Third, efficacy was observed across patients with heterogeneous demographic characteristics and disease manifestations, including both thymectomized and non-thymectomized patients.

No new safety findings were detected following the use of efgartigimod in the setting of impending or myasthenic crisis. Collectively, these findings position FcRn blockade as a rapid, well-tolerated, and logistically straightforward alternative to plasma exchange or IVIg, addressing a long-standing need for additional therapeutic approaches in the management of myasthenic crisis.

Initial reports of efgartigimod in impending or manifest MG crisis employed the agent as an add-on to conventional first-line therapy with either PE.,^8–11 IVIg ¹² or both combined. ¹³ Improvement was generally observed within days to a few weeks. A retrospective multicenter Chinese study of efgartigimod in gMG documented a larger experience with 9 of 61 patients in MG crisis. ¹⁴ Of these 9 patients, 4 achieved minimal symptom expression at 4 weeks. Average MG-ADL scores fell prominently from 15.6 ± 5.2 to 5.8 ± 7.4 in 4 weeks and a further 2 points between weeks 4 and 12. ¹⁴

There are a growing number of reports using intravenous efgartigimod as the sole acute therapy to manage MG crisis. In a population of 10 MG crisis patients, all AChR-Ab positive except for one with MuSK antibodies, two received efgartigimod as first-line therapy while 8 had received prior PE or IVIg for the crisis episode but remained dependent on ventilatory support. All 10 subjects could be weaned from a ventilator at a mean of approximately 10 days. ⁹ After a standard cycle of 4 weekly efgartigimod infusions, MG-ADL scores fell by a mean of 12 points from a baseline value of 15.6. Proportions of regulatory and naïve T cell populations declined with efgartigimod therapy, illustrating a possible impact of efgartigimod on the role of FcRn in antigen presentation. Other CD4+ assays including Th1, Th2, and Th17 remained unchanged. In another report, two patients in manifest or imminent MG crisis who received efgartigimod without PE or IVIg improved rapidly in the first 3 to 7 days following the initial 10 mg/kg infusion. ¹⁰ Similarly, in a case report from Japan, a 70 year-old woman with AChR-Ab positive MG who developed crisis after non-compliance with her immunosuppressive medication regimen was successfully treated with a combination of efgartigimod and corticosteroids. ¹⁵ She was extubated 15 days into the crisis episode. IVIg was unavailable due to a supply shortage and plasma exchange could not be arranged. Subsequent cycles of efgartigimod were successful in managing disease activity while corticosteroids were tapered. Finally, subcutaneous efgartigimod 1000 mg was used successfully as the sole crisis therapy in a 54 year-old woman with AChR-Ab positive MG. ¹⁶ Within one day her vital capacity improved from 0.7 to 1.7 liters, and on discharge one week later her MG-ADL score had fallen from 10 to 3 and QMG from 18 to 3.

A retrospective analysis comparing efgartigimod to conventional rescue therapy in impending MG crisis has been completed. Of 19 patients in impending myasthenic crisis who were either given IVIg or efgartigimod, the 9 who received the FcRn blocker had a significantly better outcome at one week based on reduction in MG-ADL scores that persisted at week 4. ¹⁷ Only one adverse event was seen in the efgartigimod group, a mild upper respiratory tract infection that resolved in 6 days.

Our investigation has several important limitations. First, the sample was small (n=16) and drawn from a single center. Second, the design, although prospective, was an open-label, uncontrolled case series; without a parallel control arm, efgartigimod treatment effects cannot be discriminated fully from the natural course of crisis or the impact of ancillary care. Of particular importance, most patients received new or escalated corticosteroids (75%), pyridostigmine (62.5%), and/or steroid-sparing immunosuppressive agents (50%) concurrently with efgartigimod. In the acute care setting, where rapid clinical improvement may occur from ICU-level supportive care and multiple co-interventions, attributing the observed MG-ADL and QMG improvements specifically to efgartigimod is unavoidably confounded. These data should therefore be interpreted as preliminary, signal-generating evidence supporting the feasibility and safety of efgartigimod in this setting; a randomized controlled trial is required to establish treatment-specific efficacy. Third, most participants were receiving background immunotherapies, introducing potential confounders that could not be adjusted for in this small cohort.

In conclusion, this prospective series of patients with generalized myasthenia gravis experiencing crisis illustrated that administration of the FcRn blocker efgartigimod was associated with rapid clinical improvement in three-quarters of participants that was sustained for 8 weeks. The safety data from this study remains consistent with the known safety profile. The role of FcRn blockers as first-line management for myasthenic crisis and as a targeted treatment alternative to intravenous immunoglobulin and plasma exchange, the latter often not available in small to medium-sized acute care facilities, deserves further study.

Ethical considerations

We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Approval for this study was obtained by the Institutional Review Board at the Rambam Medical Centre and all patients provided written consent to participate.