Young-A Heo
Efgartigimod Alfa in Generalised Myasthenia Gravis: A Profile of Its Use
Intravenous efgartigimod alfa (also known as efgartigimod alfa-fcab in the USA; Vyvgart®) is the first neonatal Fc receptor antagonist approved in several countries worldwide, including the USA and EU for the treatment of generalised myasthenia gravis (gMG) in adults who are anti-acetylcholine receptor (AChR) antibody positive, and in Japan for the treatment of gMG regardless of antibody status. In the double-blind, placebo-controlled phase 3 ADAPT trial in patients with gMG, efgartigimod alfa significantly and rapidly reduced disease burden and improved muscle strength and quality of life compared with placebo. The clinical benefits of efgartigimod alfa were durable and reproducible. Furthermore, in an interim analysis of the ongoing open-label phase 3 ADAPT+ extension trial, efgartigimod alfa provided consistent clinically meaningful improvements in patients with gMG. Efgartigimod alfa was generally well tolerated, with most adverse events being mild to moderate in severity. Supplementary Information The online version contains supplementary material available at 10.1007/s40263-023-01000-z.
Efgartigimod Alfa in Generalised Myasthenia Gravis: A Profile of Its Use

Intravenous efgartigimod alfa (also known as efgartigimod alfa-fcab in the USA; Vyvgart®) is the first neonatal Fc receptor antagonist approved in several countries worldwide, including the USA and EU for the treatment of generalised myasthenia gravis (gMG) in adults who are anti-acetylcholine receptor (AChR) antibody positive, and in Japan for the treatment of gMG regardless of antibody status. In the double-blind, placebo-controlled phase 3 ADAPT trial in patients with gMG, efgartigimod alfa significantly and rapidly reduced disease burden and improved muscle strength and quality of life compared with placebo. The clinical benefits of efgartigimod alfa were durable and reproducible. Furthermore, in an interim analysis of the ongoing open-label phase 3 ADAPT+ extension trial, efgartigimod alfa provided consistent clinically meaningful improvements in patients with gMG. Efgartigimod alfa was generally well tolerated, with most adverse events being mild to moderate in severity.

The online version contains supplementary material available at 10.1007/s40263-023-01000-z.





Generalised myasthenia gravis (gMG) is a rare, chronic, autoimmune neuromuscular disorder [1–3]. It is predominantly manifested by generalised skeletal muscle weakness and exercise induced weakness, which can have a significant negative impact on quality of life (QOL). The underlying pathophysiology of myasthenia gravis involves pathogenic autoantibodies impairing neuromuscular transmission by binding to postsynaptic acetylcholine receptor (AChR), muscle-specific tyrosine kinase (MuSK) or low-density lipoprotein receptor-related protein 4 (LRP4). In up to 85% of cases of gMG, immunoglobulin G (IgG) antibodies are directed against AChRs, often resulting in complement-mediated damage of the postsynaptic membrane and inducing accelerated internalization and degradation of AChRs. Pathogenic AChRs autoantibodies also impair the function of AChR by blocking the binding of acetylcholine to the receptor [1–3]. The treatment goal of gMG is to achieve a complete remission, pharmacological remission or minimal manifestation status (i.e. asymptomatic or no disease-related functional limitation) with minimal adverse events (AEs) [4, 5]. Conventional treatment options for gMG have been based on symptomatic therapy (e.g. acetylcholinesterase inhibitors), short-term rescue immunotherapy (e.g. plasma exchange and intravenous immunoglobulins) and long-term immunosuppressive therapy (e.g. corticosteroids and nonsteroidal immunosuppressants) [2, 4, 6]. Broad, non-specific immunosuppressants, such as corticosteroids, azathioprine, cyclosporine, mycophenolate and tacrolimus, have been effective in controlling disease symptoms; however, many patients fail to attain a complete or stable remission, with 10–20% of patients being refractory or intolerant to these agents [5, 7]. Moreover, broad, non-specific immunosuppressants may take several weeks to months to be effective and are frequently associated with burdensome AEs [5, 7]. Recently, several novel targeted therapeutic approaches have emerged to provide faster onset of action compared with oral immunosuppressants, favourable tolerability profile and the potential for sustained disease control for patients with gMG [1, 2, 4, 6, 7]. One such approach is inhibition of neonatal Fc receptor. The receptor plays a key role in prolonging the life-span of IgG by preventing antibodies (including pathogenic IgG autoantibodies) from lysosomal degradation and recycling them back into the circulation. Thus, inhibition of Fc receptor would lead to increased degradation of autoantibodies, and improvement in clinical symptoms in patients with gMG [1, 2, 4, 6, 7]. Intravenous efgartigimod alfa (also known as efgartigimod alfa-fcab in the USA; Vyvgart®) is the first neonatal Fc receptor antagonist approved for the treatment of gMG in multiple countries worldwide, including the USA [8], EU [9] and Japan [10]. Table 1 provides a summary of the prescribing information for efgartigimod alfa in the treatment of gMG in the USA, EU and Japan [8–10]. Consult local prescribing information for further details.

Efgartigimod alfa is a humanized IgG1 Fc fragment that has been engineered to increase its affinity to the neonatal Fc receptor [8, 9]. The drug binds to and inhibits the neonatal Fc receptor, thereby reducing the levels of circulating IgG and pathogenic IgG autoantibodies [8, 9], without altering other immunoglobulins (IgA, IgD, IgE or IgM) and without reducing albumin levels or increasing cholesterol levels [9]. In a mouse model for muscle-specific kinase myasthenia gravis, efgartigimod alfa rapidly reduced serum IgG levels, and improved muscle weakness and fatigability relative to control [11]. Intravenous efgartigimod alfa also rapidly and specifically reduced serum IgG levels in cynomolgus monkeys and in healthy volunteers [12]. In the phase 3 ADAPT trial in patients with gMG who are AChR antibody positive, four weekly intravenous infusions of efgartigimod alfa 10 mg/kg per cycle decreased serum IgG levels and AChR antibody levels from baseline [13]. One week after the last infusion in the first cycle, there were mean maximum decreases of 61.3% and 57.6% in total IgG and AChR antibody levels, respectively, from baseline. Total IgG and AChR antibody levels returned to baseline levels 7 weeks after the last infusion of the first cycle. Similar pattern was observed for all subtypes of IgG and during the subsequent cycles, with no reductions in albumin levels [13].

Efgartigimod alfa rapidly reduces disease burden and improves muscle strength and QOL in patients with gMG [13, 14]. These results were initially established in an exploratory, randomized, double-blind, placebo-controlled phase 2 trial [14]. In this trial, relative to placebo, four weekly intravenous infusions of efgartigimod alfa 10 mg/kg demonstrated a rapid, sustained disease improvement (as assessed by four efficacy scales) and some patients showed a prolonged effects of efgartigimod alfa [14]. On the basis of these findings, the 26-week, randomized, double-blind, placebo-controlled phase 3 ADAPT trial investigated the efficacy of efgartigimod alfa for the treatment of gMG [13]. The ADAPT trial enrolled patients with gMG who had a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of ≥ 5 (> 50% non-ocular) and were receiving stable doses of ≥ 1 myasthenia gravis treatment, such as acetylcholinesterase inhibitors, corticosteroids and/or non-steroidal immunosuppressive therapies (NSISTs) [13]. Randomized patients received four weekly intravenous infusions of efgartigimod alfa 10 mg/kg (n = 84) or placebo (n = 83) per cycle. After the first cycle, patients could receive subsequent cycles based on individual clinical response (i.e. MG-ADL score of ≥ 5 and when an MG-ADL responder no longer had a ≥ 2 point improvement in MG-ADL total score). Subsequent cycles were not commenced for ≥ 8 weeks after the initiation of the previous cycle. During the trial, vaccination with non-live vaccines was allowed ≥ 48 h before or after efgartigimod alfa infusions, whereas live or live-attenuated vaccines were not allowed. Enrolled patients largely reflected the general gMG population and baseline characteristics were similar between the treatment groups [13]. In AChR antibody positive patients, a significantly (p < 0.0001) higher percentage of efgartigimod alfa than placebo recipients were MG-ADL responders in the first cycle (primary endpoint; Table 2) [13]. MG-ADL responder was defined as a patient who had a ≥ 2-point improvement in MG-ADL score for ≥ 4 consecutive weeks, with the first improvement occurring no later than 1 week after the last infusion of the cycle. Among the 44 AChR antibody positive MG-ADL responders in the efgartigimod alfa group, the onset of response occurred by week 2 in 84% of patients, and the duration of response lasted ≥ 12 weeks in 34% of patients [13]. Efgartigimod alfa provided significant (p ≤ 0.0001) benefits over placebo for the first three hierarchically tested secondary endpoints: the percentage of Quantitative Myasthenia Gravis (QMG) responders in the first cycle, the percentage of MG-ADL responders in overall patient population in the first cycle and the percentage of time with clinically meaningful (i.e. ≥ 2-point) improvement in MG-ADL score up to day 126 (Table 2). However, there was no statistically significant between-group difference in the median time from day 28 to not having clinically meaningful improvement and thus, statistical significance for the percentage of early MG-ADL responder was not assessed. Of note, the median time from day 28 to not having clinically meaningful improvement and the percentage of early MG-ADL responder in the first cycle were numerically higher with efgartigimod alfa than with placebo (Table 2). Efgartigimod alfa was also associated with greater (p < 0.05) mean improvements in Myasthenia Gravis Composite (MGC) score and MG–Specific Quality of Life 15-item scale (MG-QOL15r) questionnaire than placebo in the first cycle [13]. Overall, a greater percentage of efgartigimod alfa than placebo recipients achieved higher levels of improvement in MG-ADL score (up to 9-point reduction) and QMG score (up to 10-point reduction), and attained a MG-ADL score of 0 or 1 (minimal symptom expression) [40% vs 11%; p < 0.0001] [13]. Significant (p < 0.05) differences from baseline in MG-ADL, QMG, MGC and MG-QOL15r scores following treatment with efgartigimod alfa were observed from week 1 and maintained through week 7, with the maximum improvement occurring at week 5 for MG-QOL15r and week 4 for the other scales [13]. The clinical benefits of efgartigimod alfa were durable and reproducible after a second and third cycle. For instance, in patients who received a second cycle, the percentage of MG-ADL responders was greater with efgartigimod alfa than with placebo (71% vs 26%) [13]. Predefined exploratory and post hoc analyses indicated that beneficial effects of efgartigimod alfa over placebo were evident regardless of weight [15], gender, age, baseline MG-ADL scores [13, 16], affected muscle domain (bulbar, ocular, respiratory and limb/gross motor) [17], concomitant medications (NSISTs, steroids and/or acetylcholinesterase inhibitors) [17] and a history of thymectomy [13]. However, in AChR antibody negative patients, the percentage of MG-ADL responder was similar between the treatment groups (68% with efgartigimod alfa and 63% with placebo) but the percentage of QMG responder was numerically higher with efgartigimod alfa than with placebo (53% vs 37%) [13, 18]. It should be noted that the placebo response in this subgroup was unexpectedly high and the trial was not designed to measure the significance of the efficacy of efgartigimod alfa in AChR antibody negative patients [13, 18].

Efgartigimod alfa provides longer-term treatment benefit in patients with gMG [19, 20]. Patients who completed the ADAPT trial were eligible to enter the ongoing, 3-year, open-label phase 3 ADAPT+ extension trial, in which patients received four weekly intravenous infusions of efgartigimod alfa 10 mg/kg per cycle. After the first cycle, patients received subsequent cycles based on clinical evaluation. Subsequent cycles were not commenced for ≥ 7 weeks after the initiation of the previous cycle [19, 20]. In an interim analysis (data cutoff 31 January 2022), of 145 patients who received ≥ 1 dose of efgartigimod alfa, 95 AChR antibody positive patients with ≥ 1 year of follow-up received a median of 5.0 treatment cycles per year [20]. In AChR antibody positive patients, the mean change in MG-ADL and QMG scores after the first cycle of efgartigimod alfa was − 5.0 and − 4.7, respectively, and clinically meaningful improvements in MG-ADL (i.e. ≥ 2-point reduction) and QMG (i.e. ≥ 3-point reduction) scores with efgartigimod alfa were maintained in each cycle for up to 10 cycles. Efgartigimod alfa consistently decreased IgG and AChR antibody levels over multiple cycles [20]. Across all cycles, the clinical benefits associated with efgartigimod alfa correlated with the maximal reductions in total IgG and AChR antibody levels, and the efficacy profile of efgartigimod alfa in AChR antibody negative patients was generally similar to that observed in AChR antibody positive patients [19].

Intravenous efgartigimod alfa is generally well tolerated in patients with gMG, as demonstrated in the ADAPT and ADAPT+ trials, with most AEs being mild to moderate in severity [13, 19, 20]. In the ADAPT trial, AEs occurred in 77% of 84 efgartigimod alfa recipients versus 84% of 83 placebo recipients. The most common (≥ 10%) AEs with efgartigimod alfa occurring at a higher nominal rate than placebo included headache (29% vs 28%), upper respiratory tract infections (11% vs 5%) and urinary tract infections (10% vs 5%) [13]. Overall, serious AEs occurred in 5% and 8% of patients in the efgartigimod alfa and placebo groups, respectively, and 4% of patients from each group discontinued treatment due to an AE. There were no deaths during the trial [13]. Infection-related AEs occurred in 46% of efgartigimod alfa recipients and 37% of placebo recipients, with most being mild to moderate in severity, except three severe events (influenza and pharyngitis with efgartigimod alfa, and upper respiratory tract infection with placebo) [13]. In addition, infusion-related reactions occurred in 4% and 10% of patients in the efgartigimod alfa and placebo groups, respectively, with all being mild in severity. There were no clinically meaningful mean changes in haematology or chemistry parameters (including albumin levels), electrocardiograms or vital signs with efgartigimod alfa [13]. Moreover, efgartigimod alfa was not associated with hypertriglyceridemia or high cholesterol [21]. Longer term, the tolerability profile of efgartigimod alfa in the ongoing ADAPT+ trial revealed no new safety signals [19, 20, 22]. Over 217.55 patient-years (PY) of follow-up (data cutoff 31 January 2022), AEs occurred in 85% of 145 patients who received ≥ 1 dose of efgartigimod alfa, with most being mild or moderate in severity [20]. The most common AEs were infections (55% of patients; 0.8 events/total PY of follow-up), headache (25%; 0.5), infusion-related reactions (10%; 0.1) and diarrhoea (10%; 0.1) [20] Overall, 15.5–31.4% of efgartigimod alfa recipients experienced incidental decreases in lymphocyte, neutrophil and white blood cell counts [22]. However, no clinically relevant changes in mean lymphocyte, neutrophil or white blood cell counts were observed over time and there were no increases in infections in patients with incidental decreases in haematological parameters [22]. As with all therapeutic proteins, efgartigimod alfa has a potential for immunogenicity. In the ADAPT trial, anti-drug antibodies (ADA) were detected in 20% of efgartigimod alfa recipients, with 7% of patients developing neutralizing antibodies [8, 9]. The presence of ADA did not appear to impact the pharmacokinetics, efficacy and safety of efgartigimod alfa; however, the available data are limited to draw definitive conclusions [8, 9].

The treatment strategy of myasthenia gravis can be individualized based on disease severity and serological subtype [5]. Acetylcholinesterase inhibitors and long-term immunosuppressive therapy have been the standard of care for patients with gMG. However, recent advances in developing novel target-specific immunological agents, such as neonatal Fc receptor antagonists, complement inhibitors, direct and indirect B-cell depletors and CAR-T cell therapy [2, 7], may shift the treatment algorithm. Studies evaluating the potential use of newer agents, including efgartigimod alfa, as a first-line therapy in treatment-naïve patients, its use as a monotherapy or as an add-on therapy, and the method and timing of switching patients from other treatments would be of interest [2]. Furthermore, given the rapid clinical improvement provided with efgartigimod alfa, its potential use as a rescue therapy in combination with broad, non-specific immunosuppressants would be another area of interest for future study [7]. Being the first neonatal Fc receptor antagonist approved for the treatment of gMG, intravenous efgartigimod alfa is a novel, effective and generally well-tolerated targeted therapy for adults with gMG. Clinical evidence indicate that intravenous efgartigimod alfa, administered in cycles, significantly reduces disease burden and improves muscle strength and QOL compared with placebo in patients with AChR antibody positive gMG. The clinical benefits of efgartigimod alfa occurred early and were durable. Moreover, the individualized dosing approach of efgartigimod alfa based on clinical evaluation was effective, providing reproducible efficacy with subsequent cycles [8]. The drug continues to provide consistent, clinically meaningful improvements in patients with gMG for up to 1 year of treatment. The long-term efficacy profile of efgartigimod alfa in AChR antibody negative patients was generally similar to that observed in AChR antibody positive patients. The final results with up to three years of exposure in the ongoing ADAPT+ extension trial are awaited with interest. Efgartigimod alfa is generally well tolerated, with most AEs being mild to moderate in severity. Although efgartigimod alfa causes transient decrease in IgG levels, the frequency and severity of infections were generally similar between the efgartigimod alfa and placebo groups. Of note, preliminary data from clinical studies in multiple autoimmune diseases, including gMG, suggest that vaccination with non-live vaccines prior to, or during efgartigimod alfa treatment does not impair the ability to mount an immune response to vaccines [23]; immunisation with live or live-attenuated vaccines is not recommended during efgartigimod alfa treatment (Table 1) [8, 9]. In a risk-benefit analysis in patients with AChR antibody positive myasthenia gravis, efgartigimod alfa is associated with favourable clinical benefits and similar tolerability compared with other treatments for myasthenia gravis, such as eculizumab, ravulizumab and intravenous immunoglobulin [24]. In addition, results from a model-based and network meta-analysis comparing efgartigimod alfa with various NSISTs and monoclonal antibodies have been reported [25, 26]. However, given their indirect nature, these findings (i.e. efgartigimod alfa has the highest efficacy in reducing MG-ADL score [25]; no significant differences in reducing MG-ADL scores between efgartigimod alfa and other monoclonal antibodies [26]) should be interpreted with caution. Direct head-to-head trials comparing the efficacy of efgartigimod alfa with conventional and newer agents would be of interest. A semi-Markov model was used to evaluate the cost effectiveness of efgartigimod alfa in patients with gMG from the US healthcare system perspective [27]. Results suggest that, over a 2-year time horizon, 4-week treatment cycles of intravenous efgartigimod alfa added to conventional immunosuppressive therapy is not cost-effective compared with conventional immunosuppressive therapy alone, and the costs exceed typical willingness-to-pay thresholds, which may limit patient access [27]. Further data on pharmacoeconomic and real-world experience would be helpful to further clarify the position of efgartigimod alfa in the management of gMG.

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