Efgartigimod Provides Genuine Benefit For Myasthenia Gravis Disease
Overview
Efgartigimod, a neonatal Fc receptor inhibitor, has recently received approval for the treatment of myasthenia gravis (MG). This retrospective cohort study systematically evaluated the short- and long-term efficacy of efgartigimod in patients with refractory MG. Sixteen patients with autoimmune acetylcholine receptor MG, who were resistant to standard treatments, were included in the study. Data collection spanned from January 2021 to March 2023, assessing the Myasthenia Gravis Activities of Daily Living (MG-ADL), Quantitative Myasthenia Gravis score (QMG), Myasthenia Gravis Composite score (MGC), and the 15-item revised Myasthenia Gravis Quality of Life questionnaire (MG-QoL15r).
Results indicated a positive outcome in 56% of patients at the final measurement. Half of the patients responded favorably to the MG-ADL after the first treatment cycle. Within four weeks, a clinically significant improvement was observed across the MG-ADL, QMG, and MGC compared to baseline. The MG-QoL15r also showed a statistically significant enhancement from baseline to week four, with sustained improvement in MGC and MG-QoL15r up to the final assessment. By the last visit, all patients had adjusted their dosing intervals, transitioning from the initial four-week schedule to more frequent administrations every one, two, or three weeks. Additionally, the dosages of prednisolone (n=7), azathioprine (n=2), and intravenous immunoglobulin (n=9) were reduced, and the frequency of plasma exchange decreased in nine patients.
In conclusion, efgartigimod demonstrated efficacy in at least half of the patients with refractory MG. However, more frequent dosing was required compared to the phase 3 ADAPT trial. Importantly, 80% of the patients were able to reduce or discontinue concurrent medications, highlighting the potential of efgartigimod as an effective treatment option for refractory MG.
Introduction
In recent years, the neonatal Fc receptor has emerged as a key target for innovative therapies in various antibody-mediated autoimmune conditions, including myasthenia gravis (MG). In 2021, intravenous efgartigimod, a neonatal Fc receptor antagonist, was shown to be both effective and well-tolerated in patients with generalized MG. The treatment led to improvements in muscle strength and overall disease status, with most adverse events reported as mild to moderate. Interim findings from the ADAPT+ study have further confirmed the long-term safety and efficacy of efgartigimod in managing generalized MG. However, its effectiveness in patients with refractory MG remains unclear.
Refractory MG, which affects about 10% of patients with generalized MG, is characterized by inadequate response to standard therapies. These patients often require intensive treatment regimens, including multiple drugs, chronic intravenous immunoglobulin (IVIg), or plasma exchange, along with frequent adjustments in their medication dosages. Due to these complex treatment needs, patients with refractory MG are typically excluded from clinical trials.
Following the approval of efgartigimod by the European Medicines Agency, an expanded access program (EAP) was launched to provide the drug to patients before its official market release. This study reports on the long-term use of efgartigimod in a cohort of patients with refractory MG, offering insights into its potential benefits for this challenging patient population.
Methods
This retrospective cohort study examined the use of efgartigimod in treating patients with myasthenia gravis (MG) at Leiden University Medical Center in the Netherlands, between January 2021 and March 2023. Since efgartigimod was not yet approved in the Netherlands, it was provided through a named patient program, a regulatory mechanism allowing access to investigational drugs under strict oversight. Patients eligible for this Expanded Access Program (EAP) met specific clinical criteria, including a Myasthenia Gravis Foundation of America (MGFA) classification of II-IV, a minimum Myasthenia Gravis Activities of Daily Living (MG-ADL) score of 5 with non-ocular symptoms, and prior treatment with specified therapies.
Patients received efgartigimod intravenously at a dose of 10 mg/kg once weekly for four weeks, with adjustments based on clinical symptoms and IgG levels. Outcome measures included MG-ADL, QMG, MGC, and MG-QoL15r scores, collected weekly for the first four weeks and subsequently at each hospital visit. A meaningful clinical improvement was defined as a ≥2-point improvement in MG-ADL or a ≥3-point improvement in QMG and MGC scores.
Demographic and clinical data, including IgG levels and AChR antibody titers, were retrospectively collected. Chronic IVIg or plasma exchange was defined as treatments given periodically or at least four times in the previous year. Baseline IgG values were established before efgartigimod administration, excluding values influenced by recent plasma exchange or IVIg. A favorable outcome was characterized by significant improvement on at least two outcome measures, reduction or discontinuation of prednisolone or chronic plasma exchange/IVIg, and no use of rescue medication.
Statistical Analysis
Statistical analyses were descriptive, using paired t-tests to evaluate changes from baseline for each outcome measure, without imputing missing values. The study found that efgartigimod was generally well-tolerated, with clinical benefits observed in a subset of patients, as illustrated by Kaplan-Meier analysis of efgartigimod persistence over time. All data were collected during routine clinical care, and informed consent was obtained from all patients.
Result
Efgartigimod was evaluated in a cohort of 16 patients with a median follow-up period of 29.5 weeks. The study begins by detailing the patients’ demographics and baseline clinical characteristics, providing a comprehensive overview of their initial health status. Notably, before starting efgartigimod, four patients were receiving chronic intravenous immunoglobulin (IVIg) therapy, and five were undergoing chronic plasma exchange, indicating that these patients had already been on substantial immunomodulatory treatments.
Over the course of the study, 309 efgartigimod infusions were administered. Initially, patients followed a 4-weekly dosage cycle, but over time, all patients transitioned to more individualized treatment schedules, ranging from one to three weeks between infusions. This shift reflects a tailored approach to treatment, aiming to optimize therapeutic outcomes for each patient based on their specific needs and responses to the drug.
The clinical effectiveness of efgartigimod was assessed after 4 weeks of treatment. At this point, one patient had received two infusions, while the others had completed four infusions. The results were promising, with 50% of the patients classified as MG-ADL responders, meaning they showed significant improvement in their Myasthenia Gravis Activities of Daily Living (MG-ADL) scores. Moreover, 56.3% of the patients met the criteria for a favorable outcome, indicating overall positive effects of the treatment. Interestingly, four patients who did not meet the criteria for a favorable outcome continued with efgartigimod because both they and their clinicians observed subjective clinical improvements, highlighting the importance of individualized treatment assessments beyond standardized outcome measures.
Significant clinical improvements were observed across various metrics. On average, patients experienced a 4.37-point improvement in MG-ADL scores, a 4.93-point improvement in Quantitative Myasthenia Gravis (QMG) scores, and a 7.60-point improvement in Myasthenia Gravis Composite (MGC) scores. Additionally, the Myasthenia Gravis Quality of Life 15-Item Revised (MGQoL15r) score improved by an average of 5.75 points, reflecting meaningful enhancements in patients’ quality of life. These improvements were statistically significant, with p-values indicating a high likelihood that these effects were not due to chance.
The study also looked at the sustainability of these improvements over time. The last measurements were taken at varying intervals, with median times of 28 weeks for MG-ADL, 16 weeks for QMG, 20 weeks for MGC, and 24 weeks for MGQoL15r. Sustained improvement was observed for MGC and MGQoL15r scores, but the improvements in MG-ADL and QMG scores, while still positive, were not statistically significant at the last measurement.
During the study, four patients discontinued efgartigimod treatment within the first 100 days, with three of these discontinuations due to perceived lack of efficacy. One patient discontinued for unspecified reasons. Additionally, five patients required rescue medications, including plasma exchange, IVIg, prednisolone, and various immunosuppressants like azathioprine, mycophenolate mofetil, rituximab, and eculizumab. The median time to the first use of rescue medication was 56 days, indicating that while efgartigimod was generally effective, some patients still needed additional treatment to manage their symptoms.
A noteworthy aspect of the study was the impact of efgartigimod on patients’ medication regimens. Among the 15 patients who were on medication at the start of the study, 80% were able to reduce their medication dosage, particularly corticosteroids like prednisolone and immunosuppressants such as azathioprine. This reduction in medication use is significant, as it suggests that efgartigimod may help decrease the need for other, potentially more burdensome treatments.
The study also monitored changes in IgG levels and acetylcholine receptor (AChR) antibody titers in nine patients. Despite the frequent dosing of efgartigimod, most patients maintained IgG levels above 2.0 g/L, which is within a safe range. One patient experienced a drop in IgG levels to 1.7 g/L, but this returned to above 2.0 g/L after discontinuing efgartigimod. Interestingly, patients who required weekly efgartigimod administrations tended to have higher AChR antibody titers throughout the treatment period compared to those on less frequent schedules. This observation suggests that more frequent dosing may be necessary for some patients to achieve optimal control of their condition.
Conclusion
This retrospective study evaluated the effectiveness of efgartigimod in patients with refractory myasthenia gravis (MG), finding that it was effective in over half of the participants, with 56% showing a favorable outcome at the final measurement. However, the proportion of patients achieving a significant MG-ADL response after four weeks of treatment was lower compared to the ADAPT phase 3 trial (50% vs. 68%), and even lower than the MG-ADL responder rate for patients with refractory MG in the ADAPT trial (67.5%).
Although other clinical outcome measures (such as improvements in MG-ADL, QMG, MGC, and MG-QoL15r) were similar to those observed in the ADAPT trial after four weeks, the long-term effectiveness of efgartigimod appeared to decline. Patients exhibited worsening symptoms after 8–12 weeks of treatment, which might indicate reduced effectiveness over time or could be linked to the discontinuation of concurrent medications. Interestingly, despite this decline, the long-term results for MG-QoL15r suggested a persistent effect, and a substantial proportion of patients (80%) were able to reduce their use of other MG treatments like prednisolone, azathioprine, plasma exchange, and IVIg. However, interpreting these long-term effects is challenging due to the decreasing number of patients contributing data over time, which makes the results less representative.
The study also found that patients required frequent dosing of efgartigimod, with all participants eventually switching to weekly, biweekly, or triweekly administrations by their final visit. With more frequent dosing, IgG levels remained stable, with no significant reductions below safety thresholds.
There are some limitations to this study. Adverse effects of efgartigimod were not systematically evaluated, though no major side effects were reported, and no patients discontinued the treatment due to adverse events, suggesting that the drug is well-tolerated. Additionally, several measurements were excluded from analysis because a significant number of patients (69%) had received plasma exchange or IVIg treatment in the month before starting efgartigimod, limiting the analyses of changes from baseline for both IgG levels and outcome measures. This study also did not frequently measure AChR antibody titers, preventing the correlation of these titers with IgG levels or clinical outcomes. Furthermore, the retrospective nature of the study meant that treatment outcome assessments were not mandatory, leading to missing data for a significant number of patients during follow-up and potentially introducing bias in estimating outcomes.
In conclusion, efgartigimod was found to be effective in a meaningful subset of patients with refractory MG, though they required more frequent dosing, and fewer patients achieved a significant improvement in MG-ADL response compared to the ADAPT trial. This study provides valuable insights into the long-term effectiveness of efgartigimod in patients with refractory MG.
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