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At the end of last year, a targeted biological agent with good efficacy and safety, efgartigimod, was approved by the US FDA for marketing.
This innovative therapy has brought a new treatment option to patients with generalized myasthenia gravis (gMG).
At the 74th Annual Meeting of the American Academy of Neurology (AAN) held from April 2nd to April 7th this year, efgartigimod made another good news.
The latest results of ADAPT+ and other studies were announced for the first time at the meeting, which preliminarily proved the long-term treatment of efgartigimod.
gMG also has good efficacy and safety! There are limitations in the treatment of MG, and a combination of efficacy and safety is still needed.
Myasthenia gravis (MG) is an autoimmune disease with acquired neuro-muscular junction (NMJ) transmission disorders mediated by autoantibodies.
Disease 1 has been included in the "First Batch of Rare Disease List" by China in 2018 2
In the pathogenesis of MG, acetylcholine receptor (AChR) antibodies are the most common pathogenic antibodies, found in approximately 85% of patients 3
These autoantibodies can interfere with AChR aggregation, affect AChR function and NMJ signaling.
Some autoantibodies can also activate complement, destroy NMJ structural integrity, and cause neuromuscular signaling failure 1,4
It will eventually lead to systemic skeletal muscle involvement in patients, manifested as fluctuating weakness and easy fatigue, and in severe cases, death may occur due to respiratory failure, pulmonary infection, etc.
Currently, guideline-recommended MG therapies include glucocorticoids, acetylcholinesterase inhibitors, and non-steroidal immunosuppressants, which are nonspecific and cause many adverse reactions to patients, such as glucose intolerance, weight gain , osteoporosis, gastrointestinal problems, bradycardia, liver toxicity and renal dysfunction, etc.
Considering that immunoglobulin G (IgG) is central to the pathophysiology of MG, therapies that reduce IgG concentrations, such as plasma exchange (PE) and intravenous immunoglobulin (IVIG), have been shown to be effective in the treatment of MG
However, due to the low availability and the possibility of more adverse reactions, the current guidelines are only recommended for the treatment of patients with acute exacerbations 1
Therefore, the existing therapies still do not meet the treatment needs of MG patients, and safe and effective methods are needed to improve the treatment status
Efgartigimod: An innovative therapy targeting the pathogenic core of MG targeting the pathogenic core of MG, and another innovative approach to reduce the concentration of IgG, a neonatal Fc receptor (FcRn) antagonist, bringing the possibility of safe and effective treatment of MG
FcRn is a MHC class I molecule widely distributed in mammalian organs, tissues and cells
In vivo, FcRn can bind to IgG and protect it from degradation by lysosomes, thereby prolonging the half-life of IgG, resulting in increased pathogenic IgG concentrations 4
Therefore, blocking FcRn-mediated IgG recycling, thereby reducing the concentration of pathogenic IgG, can be used to treat autoimmune diseases caused by pathogenic IgG, including: MG, pemphigus vulgaris (PV), immune Thrombocytopenia (ITP), chronic inflammatory demyelinating polyneuropathy (CIDP),
Efgartigimod is a human IgG1 antibody Fc fragment, a natural ligand for FcRn
As an FcRn antagonist, it has a stronger affinity for FcRn than endogenous IgG, so it can competitively block the binding of endogenous IgG to FcRn, promote the degradation of IgG in lysosomes, and reduce the recycling of IgG ( Figure 1)
In addition, efgartigimod targets the reduction of all IgG subtype concentrations without affecting other Ig (eg, IgM, IgA) and albumin concentrations 5
Schematic diagram of the mechanism of action of Efgartigimod Phase III clinical study of Efgartigimod, the ADAPT study, has shown its good efficacy and safety in the treatment of gMG 5
Efgartigimod was also FDA-approved for the treatment of AChR antibody-positive adult gMG patients, becoming the first and currently only FDA-approved FcRn antagonist6, bringing new treatment options to MG patients
ADAPT+ Study Results First Announced: Preliminary Demonstration of Long-Term Efficacy and Safety of efgartigimod Treatment ADAPT Study 5 is a multicenter (56 neuromuscular academic and community centers in 15 countries in North America, Europe, and Japan), double-blind, randomized, placebo A dose-controlled, 26-week Phase III clinical study, and patients who complete the ADAPT study will enter the ADAPT+ open-label extension study (Figure 2)
The 3-year extension study was designed to evaluate the long-term safety, tolerability and efficacy of efgartigmod in patients with gMG
At this AAN conference, the data results of this study were published for the first time7
ADAPT+ Study Design Ninety-one percent of patients (151/167) in the ADAPT study entered the ADAPT+ study
Patients received efgartigimod (EFG) 10 mg/kg intravenously once a week for 4 weeks, with subsequent cycles initiated according to predefined criteria
The efficacy of each cycle was evaluated using the Myasthenia Gravis Activities of Daily Living Scale (MG-ADL) and the Quantitative Myasthenia Gravis Scale (QMG)
As of February 2021, 106 AChR antibody positive (AChR-Ab+) and 33 AChR antibody negative (AChR-Ab-) patients (including 66 patients in the placebo [PBO] arm of the ADAPT study) had received at least 1 open-label dose efgartigimod treatment
The mean (SD) duration of the study was 363 (114) days
The results showed: ➤ In terms of efficacy 7: AChR-Ab+ patients observed clinically meaningful improvement (CMI) in each treatment cycle (up to 10 cycles) (Figure 3), and the degree of improvement was comparable to that of the first treatment cycle.
Similar magnitude of improvement was observed at week 3 (mean [SE] improvement: MG-ADL, -5.
34]; QMG: -4.
demonstrated that efgartigimod enabled patients to achieve sustained and reproducible improvements in MG-ADL and QMG over multiple cycles
Changes in MG-ADL and QMG Total Scores in the ADAPT+ Study In addition, the proportion of patients treated with efgartigimod in the ADAPT+ study improved in MG-ADL or QMG at Week 3 over multiple cycles than in the ADAPT Study at Week 1 of the treatment cycle.
There was also a significantly greater proportion of patients with improved MG-ADL or QMG at 3 weeks (Fig.
Proportion of patients with improved MG-ADL and QMG total scores in ADAPT vs.
ADAPT+ studies ➤ In terms of safety/tolerability 7: Incidence of adverse events (AEs) in the efgartigmod group in the ADAPT+ study versus the efgartigmod group in the ADAPT study The incidence of AEs was generally similar in the and placebo groups, and most AEs were mild to moderate
The most common AEs were nasopharyngitis, upper respiratory tract infection, and urinary tract infection (Figure 6)
In addition, the incidence of the most common AEs in the EFG-EFG group (continuous efgartigmod treatment group) and the PBO-EFG group (placebo-to-efgartigmod treatment group) in the ADAPT+ study was also similar: headache (15.
3%), nasopharyngitis (8.
6%) and diarrhea (6.
Indicates that long-term treatment with efgartigmod has a safety profile consistent with the ADAPT study
Overview of adverse events in the ADAPT and ADAPT+ studies.
Although 5 patients died in the efgartigmod treatment group in the ADAPT+ study, the causes of death were analyzed (acute myocardial infarction, COVID-19 pneumonia/septic shock, bacterial pneumonia/MG crisis, Malignant lung tumors and unknown [multiple cardiovascular risk factors at autopsy]), the investigators concluded that these were not related to efgartigmod treatment
The results of the ADAPT+ study can preliminarily demonstrate that long-term treatment with efgartigmod has good efficacy in both AChR antibody-positive and negative gMG patients, providing sustained and reproducible clinically meaningful improvements in function and strength, while maintaining good tolerance.
In terms of safety, long-term treatment with efgartigmod also has a good safety profile
In addition, efgartigmod's multinational Extended Access Program (EAP) study will address the treatment needs of patients with MG who have not been enrolled in clinical trials, or whose disease cannot be effectively controlled with currently approved therapies
The study included patients with established gMG, regardless of antibody status, with an MG-ADL score ≥5 at screening (non-ophthalmotype score >50%), and documented IgG in the month prior to screening Level>6g/L
After enrollment, patients will receive intravenous efgartigimod (10mg/kg) according to the individualized treatment cycle dosing mode
At this AAN conference, the baseline characteristics and demographic characteristics of some patients enrolled in the EAP study were published for the first time
As of September 24, 2021, 10 patients had participated in the EAP, most of them were women (n=8), and the median age was 75 years (range 32-73)
Six patients were AChRAb+, three were seronegative, and one was MuSKAb+
Six patients received eculizumab, rituximab, or a combination of the two on their previous gMG regimen (n=3, 1, and 2, respectively)
In addition, 4 patients were hospitalized for gMG within the first 12 months of screening
Conclusion MG is a rare disease that seriously affects the health and quality of life of patients.
Although there are many treatment options, there is still an unmet need for treatment, that is, there is a lack of drugs with good efficacy and safety
Efgartigmod, as a targeted biological agent that directly hits the pathogenic core of MG, has demonstrated its good efficacy and safety in clinical studies, and preliminarily showed that its long-term treatment can also benefit patients with good safety and tolerance
In the future, there will be more evidence-based evidence to support this therapy
Currently, efgartigmod has been approved by the FDA to bring new treatment options to MG patients
Of course, we also sincerely hope that this innovative therapy can be launched in my country as soon as possible to benefit more patients! References: 1.
Neuroimmunology Branch of Chinese Society of Immunology.
Chinese Journal of Neuroimmunology and Neurology.
Notice on the publication of the first batch of rare disease catalogues.
BehinA, et al.
https:// et al.