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Myasthenia gravis (MG) is an autoimmune disease
mediated by autoantibodies, with impaired transmission of acquired neuro-muscle junctions (NMJs).
。 Acetylcholine receptor (AChR) antibodies are the most common pathogenic antibodies; In addition, antibodies targeting other components of the postsynaptic membrane, including muscle-specific receptor tyrosine kinase (MuSK), low-density lipoprotein receptor-associated protein 4 (LRP4) and ranny base receptor (RyR), have been found to be involved in the pathogenesis of MG, which can interfere with AChR aggregation, affect AChR function and NMJ signaling
.
Currently, MG is still treated with cholinesterase inhibitors, glucocorticoids, immunosuppressants, intravenous immunoglobulin (IVIG), plasmapheresis (PE), and thymectomy1
.
However, these treatments have certain limitations, and there is a huge unmet clinical need, and there is an urgent need for innovative therapies that are safe and effective to improve the treatment outcomes and quality of life of
MG patients.
Breaking the ice: Efgartigimod becomes the world's first FDA-approved drug targeting neonatal Fc receptors
Efgartigimod is a human IgG1-derived Fc fragment that accelerates pathological IgG clearance
by antagonizing the binding of IgG to neonatal Fc receptors (FcRn).
。 In December 2021 and January 2022, Efgartigimod intravenous dosage form (VYVGART®) was approved by the US Food and Drug Administration (FDA) and the Japanese Ministry of Health, Labour and Welfare (MHLW), becoming the world's first FDA-approved targeted FcRn drug and the first approved therapy
specifically to reduce pathogenic immunoglobulin (IgG).
The emergence of Efgartigimod breaks the "deadlock" and is a new breakthrough in MG's innovative drugs for many years, bringing good news
to MG patients.
of Efgartigimod in patients with gMG 。 After 2 weeks of screening, 167 adult patients with gMG were finally enrolled, and the enrollment criteria: MGFA stage II-IV; positive or negative for AChR antibodies; MG-ADL (MG Activities of Living Scale) score ≥ 5, with at least 50% of the score coming from non-ocular muscle symptoms; Receiving at least one stable dose of gMG therapy
.
Patients were randomized to efgartigimod (10 mg/kg IV, n=84) and placebo (IV, n=83).
Each treatment cycle was 8 weeks, which included a weekly infusion of the test drug for a total of 4 times in the first 3 weeks, followed by 5 weeks
of follow-up.
All patients completed their first treatment cycle, followed by an individualized treatment cycle
based on clinical assessment.
The primary endpoint of the study was the proportion of patients who achieved an MG-ADL response (at least 2 points improvement over baseline MG-ADL overall score for at least 4 weeks, with the first reduction occurring within one week of the last infusion) in patients with AChR Ab+
.
Ultimately, the study confirmed that Efgartigimod can help patients with rapid onset of action, bringing significant and rapid clinical benefits:
- The overall response rate was 68% (MG-ADL response rate in the first treatment cycle Efgartigimod group was 68%);
- 84% of responding patients appeared in the first two weeks of treatment;
Again with great results: efgartigimod showed good benefit in the treatment of gMG patients in different subgroups
in Nashville, Tennessee.
At the meeting, efgartigimod showed sustained improvement in the treatment of gMG patients in different subgroups in the ADAPT study3:
- AChR-ab+ patients were divided into 3 groups according to the duration of the disease≤3 years, 3~6 years, and ≥6 years, and the proportion of patients with efgartigimod who achieved MG-ADL response in the three groups was significantly higher than that in the placebo group
.
Moreover, the response ratio of patients in the two groups with a disease duration of ≤ 3 years and 3~6 years was numerically higher than that of patients with a disease duration of more than 6 years (Fig.
1). - In addition, in the ADAPT study, patients were asked to maintain at least one stable dose of standard treatment for MG, so patients had concomitant medication
during the study.
Patients were divided into AChEI alone, any hormonal patients, and any immunosuppressants based on concomitant medication (Figure 2), with overlapping patients in the latter two groups
.
Subgroup analysis showed that the proportion of patients who achieved an MG-ADL response was significantly higher in the efgartigimod group than in the placebo group, regardless of the patient's concomitant medication (Figure 2). - In addition, based on the patient's previous drug history, the patients were divided into 4 groups, including whether they had previously undergone thymectomy and whether they had previously used immunosuppressants, and the results showed that regardless of whether the patients had received thymectomy or whether they had used immunosuppressants before, the proportion of patients who achieved MG-ADL response in the efgartigimod group was significantly better than that in the placebo group (Figure 3).
- QMG (MG quantitative score) responses followed a similar pattern, with consistent responses
across subgroups.
Figure 1: Proportion of patients who achieved MG-ADL response in the EFG group and PBO group in the subgroup of patients diagnosed earlyFigure 2: Proportion of patients who achieved MG-ADL response in the EFG group and PBO group in the subgroup of patients with concomitant medication Figure 3: Proportion of patients who achieved MG-ADL response in the EFG group and PBO group in the subgroup of patients with different previous surgical and drug history
Although there were no comparisons between each subgroup, the duration of disease was relatively short, the drug history and surgical history were not complicated, i.e.
, patients in the early stages of the disease could achieve a higher proportion of MG-ADL responses with efgartigimod
.
Similar views have been made in other drugs, such as Brauner et al.
4 who point out that the use of rituximab to achieve remission in patients with new-onset MG is shorter
than that of refractory patients.
The study suggests that anti-CD20 biologics consume immature B cells, memory B cells, and plasma blasts
.
In the early immune response of MG disease, antibodies are mainly derived from plasmablasts
.
After long-term continuous antigen stimulation, the main antibodies are produced
by long-lived plasma cells.
The accumulation of antibody-producing plasma cell banks in patients with shorter duration of disease is less than in patients with
longer duration of disease.
Therefore, it is speculated that the early efficacy of rituximab is related
to the accumulation of plasma cell pools that produce antibodies.
This suggests that antibody production is not the same in the
early stages of MG disease.
Studies have found that there are antibodies secreting anti-AChR antibodies, unique antibodies and anti-unique antibodies in MG, and there are also T cells that are autoreactive to human AChR, unique antibodies and anti-unique antibodies, forming a centralized unique network
of AChR.
The concentration of anti-unique antibody in the early stage of the disease is relatively higher than that of receptor antibody, and the concentration advantage of unique antibody changes
with the progression of the disease.
The natural function of anti-unique antibodies is to downregulate autoantibody responses through cross-linking of cell surface immunoglobulins and their surface Fc receptors on autoantibody-producing cells6
.
Clinical improvement in MG patients is associated with changes in autoreactive T cells, which cannot be detected in patients who achieve remission, while the unique antibody/anti-unique antibody response can still be detected
.
However, after 6 months of follow-up in patients with the same disease severity, the unique/anti-unique-type antibody response was undetectable7
.
Given that efgartigimod competitively binds to FcRn to all types of antibodies, the early use of efgartigimod may break the AChR unique type network, thereby promoting symptom improvement
.
However, more basic and preclinical studies are
needed.
Pathophysiology also seems to explain the higher
response rate in patients early in the disease.
It has been suggested that in MG as the disease progresses, the postsynaptic membrane is damaged due to repeated targeting by the immune system, the synaptic cleft expands, and the amount of available AChR decreases
.
As the muscle membrane deforms the postsynaptic membrane permanently changes, the membrane structure changes the amount of AChR available on the membrane surface and reduces the number of voltage-gated channels, increasing the action point threshold8
.
This can also be explained
from the perspective of muscle biopsy.
AChR-positive patients have shown fibroneurogenic features and muscle atrophy in skeletal muscle, while MuSK-positive patients show significant mitochondrial dysmyopathy features9
.
Patients in the early stages of the disease are subject to fewer repeated targeted attacks by the immune system and fewer changes in the postsynaptic membrane
.
Symptom relief
is more likely to be achieved with medical therapy than in patients with prolonged disease.
Efgartigimod showed sustained improvement
in the treatment of gMG patients in different subgroups, including the early diagnosis subgroup.
efgartigimod has a more significant clinical benefit
for gMG patients in the early stages of the disease.
It is also expected that efgartigimod can be used in the Chinese group as soon as possible, bringing more benefits
to Chinese MG patients.
Expert profiles
Professor Huiyu Fung
Department of Neurology, The First Affiliated Hospital of Sun Yat-sen University, Director of Neurology ICU, Chief Physician, Doctoral Supervisor
.Deputy leader of the 8th Neuroimmunology Group of the Neurology Branch of the Chinese Medical Association, and deputy leader
of the Neurocritical Care Group of the 10th Committee of the Neurology Branch of the Guangdong Medical Association.He graduated from the Department of Clinical Medicine of Sun Yat-sen University School of Medicine (formerly Sun Yat-sen Medical University) in 1999, and has been working
in the Department of Neurology of the First Affiliated Hospital of Sun Yat-sen University after graduation.
He received his master's degree in 2005 and his doctorate degree in 2012, focusing on neuroimmune diseases and neurocritical diseases
.
He has published more than 50 related papers, participated in and presided over a number of provincial and national projects
.
Participated in the compilation of 6 monographs
.
Expert reviews
The results of the ADAPT study, presented at the 2022 Annual Meeting of the American Association for Neuromuscular and Electrophysiological Diagnostic Medicine (AAENM AM), suggest two important messages
.
First, the effect of Efagrtigimod in the treatment of AChR-Ab-positive gMG is certain, with fast onset (response within 2 weeks at the earliest) and long
maintenance time.
The emergence of Efgartigimod breaks the "deadlock" and is a new breakthrough in MG's innovative drugs for many years, bringing good news
to MG patients.
Second, Efgartigimod showed good benefits in the treatment of gMG patients in different subgroups, and the results provided us with new therapeutic ideas, especially early application can be more beneficial, subverting the traditional view
that "biologics are recommended for use in refractory MG".
Unfortunately, the subgroup analysis did not cover the efficacy of Efagrtigimod on extraocular muscle symptoms, and we look forward to the publication
of more subgroup results from ADAPT.
ZMCNNP20221119002 Expire Date 2023/11/19
References:
1.Neuroimmunology Branch of Chinese Society of Immunology.
Chinese Journal of Neuroimmunology and Neurology.
2021.
28(1):1-12 2.
J F Howard Jr, V Bril, T Vu, et al.
Lancet Neurol.
2021; 20(7):526-36.
3.
V Bril, T Vu, E Brauer, et al.
Myasthenia Gravis Foundation of America (MGFA) Scientific Session at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) Annual Meeting.
Poster 32.
4.
S Brauner, A Eriksson-Dufva, M A Hietala, et al.
JAMA Neurol.
2020; 77(8):974-81.
5.
A K Lefvert.
Ann Inst Pasteur Immunol.
1988; 139(6):633-43.
6.
G J Thorbecke, B S Bhogal, G W Siskind.
Immunol Today.
1984; 5(4):92-3.
7.
Q Yi, R Pirskanen, A K Lefvert.
Scand J Immunol.
1996; 44(6):630-7.
8.
J Mays, C L Butts.
Neuroimmunomodulation.
2011; 18(5):320-7.
9.
C Angelini.
Clin Drug Investig.
2011; 31(1):1-14.
Past Review
☑ Is there also benefit in patients with seronegative myasthenia gravis? One of the 2022 AANEM Essentials Hot Review Series
☑ Expert Comment/Efgartigimod can coexist with the body defense of patients with generalized myasthenia gravis! ——2022 AANEM Essence Hot Review Series No.
2
