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*Only for medical professionals to read for reference.
FcRn antagonists are expected to improve the unmet need for treatment of patients with myasthenia gravis
.
Myasthenia gravis (MG) is a chronic autoimmune disease, which was included in the "First List of Rare Diseases" jointly issued by five national ministries and commissions in 2018
.
Increased muscle weakness and involvement of the respiratory muscles can cause crisis.
If the treatment is not timely, it can endanger life, seriously affect the patient's quality of life and labor ability, and bring a heavy burden to the family and society
.
In June this year, the international authoritative medical journal "The Lancet Neurology" published the results of a phase III clinical study of neonatal Fc receptor (FcRn) antagonist efgartigimod, showing that it has a good effect on the treatment of adult systemic MG (gMG) And safety, which is of great significance to patients
.
Based on the above research progress, we are fortunate to invite Professor Lu Jiahong from Huashan Hospital Affiliated to Fudan University and Professor Yang Huan from Xiangya Hospital of Central South University to give a detailed interpretation of the latest progress in diagnosis and treatment of MG
.
"Not rare" rare diseases, need to pay attention to the differential diagnosis! MG is an autoimmune disease with acquired neuromuscular junction (NMJ) transmission disorder mediated by autoantibodies
.
Regarding the clinical manifestations of MG, Professor Lu mentioned that all skeletal muscles of MG patients can be affected.
The main manifestations are extraocular muscle involvement, eyelid drooping, and eye dysfunction.
They may also have difficulty chewing, swallowing and dysarthria, limb weakness, and even It will also affect breathing
.
The incidence of MG in China is about 0.
68 per 100,000* person-years, and all age groups can suffer from the disease
.
Talking about the pathogenesis of MG, Professor Lu pointed out that acetylcholine receptor (AChR) antibody is the most common pathogenic antibody of MG, accounting for more than 80%; in addition, it targets other components of the postsynaptic membrane, including muscle specificity.
Receptor tyrosine kinase (MuSK), low-density lipoprotein receptor-related protein 4 (LRP4) and other antibodies have also been found to be involved in the pathogenesis of MG
.
Professor Lu mentioned that the symptoms of MG are similar to other neuromuscular diseases, but the most prominent feature of MG is the fluctuating symptoms, manifested by fluctuating weakness and fatigue.
The symptoms are "light in the morning and heavy in the evening".
It can be aggravated later and relieved after rest
.
In MG, the ocular muscle type is a relatively common subtype, which needs to be distinguished from other neuromuscular diseases that affect the eye, such as chronic progressive external ophthalmoplegia (CPEO)
.
CPEO is also characterized by drooping eyelids and eye movement disorders, but there is no obvious symptom fluctuation, and the course of the disease is gradually worsening
.
If CPEO is suspected, a muscle biopsy can be performed to identify it
.
Eyelid spasm is also a common clinical disease, manifested by involuntary contraction of the orbicularis oculi muscle, leading to smaller eye fissures
.
But this is the contraction of the orbicularis oculi muscle, not the weakness of the levator palpebral muscle, so it needs to be distinguished from MG
.
In addition to fatigue test, neostigmine test, and repeated electrical stimulation tests, the examination of MG-related antibodies is also an effective method for diagnosing MG
.
Existing drugs cannot meet the needs of MG treatment, and the development of new drugs is urgently needed.
Common treatment options for MG may have certain risks and limitations, and the treatment effect is not satisfactory
.
Professor Lu mentioned that the more classic treatment of MG is symptomatic treatment, such as the use of brompistigmine
.
Brompistigmine has a certain effect in some early and milder ophthalmic MG patients, but for gMG patients, the drug alone cannot meet the treatment needs, and it is generally used in combination with hormones and immunosuppressants in clinical practice
.
However, hormone therapy has many side effects, such as leading to metabolic syndromes such as osteoporosis and obesity.
In the process of hormone reduction, symptoms may also recur
.
During the clinical application of glucocorticoids for the treatment of MG, some patients will experience short-term aggravation of symptoms in the early stage, and may even cause a crisis in individual patients
.
Regarding this situation, Professor Yang mentioned that in patients who have already had a threatened crisis or have aggravated new onset, if high-dose corticosteroids are used for pulse therapy, they are prone to myasthenia crisis
.
For some patients with mild to moderate disease and no serious infection, it is recommended to use the hormone in small doses, which is relatively safe
.
For some newly-onset patients who are still in rapid progress, or those who have infections or hyperthyroidism that can cause exacerbations, hormones need to be used cautiously
.
As the current MG treatment has certain limitations and the therapeutic effect is not ideal, the development of new effective drugs has become an urgent need for the current MG treatment
.
Professor Yang Huan mentioned that MG is an antibody-mediated disease from the point of view of its pathogenesis.
Every aspect of antibody activation may become an effective therapeutic target
.
Complement inhibitors target the main immune mechanism involved in the destruction of the MG endplate, which can inhibit the activation of C3 and C5.
At present, some drugs for complement are undergoing clinical trials
.
B cell activation is an important part of antibody production.
By depleting B cells, the source of autoantibodies in MG patients can be reduced or eliminated
.
Rituximab can deplete B cells, but it also has a certain risk.
After B cells are depleted, it will increase the chance of serious infection
.
Targeting some factors that activate B cells, such as B cell activating factor (BAFF) and B lymphocyte stimulating factor (BLyS) on the surface of B cells, is also the direction of MG treatment
.
Some drugs for regulatory T cells, and other cytokines such as interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) are also under development
.
Plasma cells are the final link in the production of antibodies, and FcRn targeting plasma cells has been a hot spot in recent years
.
FcRn can transport and recycle IgG, avoid IgG degradation and prolong the half-life
.
The FcRn antagonist blocks the IgG circulation by binding to FcRn, causing rapid depletion of IgG antibodies in autoimmune diseases
.
In MG patients with severe symptoms, it is expected to replace plasma exchange and immunoglobulin treatments
.
Efgartigimod Phase III clinical data is good, bringing new hope to MG patients.
For the popular target of FcRn, there have been gratifying research progress recently.
On June 18, 2021, "The Lancet Neurology" published efgartigimod.
Results of Phase III clinical study (ADAPT study)
.
It shows that efgartigimod has good efficacy and safety in patients with gMG
.
As the world's first FcRn antagonist, Efgartigimod is an Fc fragment of a human IgG1 antibody that can treat autoimmune diseases mediated by pathogenic IgG antibodies, including MG
.
Professor Yang pointed out the advantages of FcRn antagonists: 1.
FcRn antagonists can target plasma cells, selectively inhibit IgG, and have a clear target
.
2.
From the data of the ADAPT study, FcRn antagonists are safer
.
3.
The antibody clearance rate of FcRn antagonist can reach more than 70%, and the curative effect is good
.
4.
It can comprehensively improve the patient's quality of life, and the patient's quality of life score and other objective scores can be improved
.
5.
It is expected to replace poorly accessible treatments [such as immunoadsorption, plasma exchange, intravenous immunoglobulin (IVIG)], so that more patients can receive effective treatment in time
.
Professor Yang said that the ADAPT study has brightened the eyes of clinicians and has given more hope to MG patients with severe symptoms
.
The research design of ADAPT has also brought a lot of enlightenment to the clinical research of MG new drug research and development
.
Efgartigimod, as an FcRn antagonist, has a clear mechanism of action
.
The study design is also very rigorous.
The primary endpoint uses the Myasthenia Gravis Activity of Daily Living Scale (MG-ADL), which can comprehensively evaluate the quality of life of MG patients
.
The secondary endpoints are based on the Myasthenia Gravis Quantitative Scale (QMG) and the Myasthenia Gravis Quality of Life Scale (MG-QOL) scores, which can evaluate the patient’s myasthenia and quality of life
.
These indicators can comprehensively reflect the therapeutic effect of the drug
.
Summary: MG traditional treatment programs often have certain limitations and fail to achieve satisfactory treatment results
.
As the world's first FcRn antagonist, Efgartigimod can safely and quickly eliminate pathological IgG antibodies in the body through its unique mechanism of action, thus becoming a new type of therapeutic drug for highly targeted IgG antibodies against antibody-mediated autoimmune diseases
.
The ADAPT study shows that efgartigimod has good efficacy and safety in the treatment of adult gMG, and provides important evidence-based medicine support for the treatment of adult gMG
.
It is expected that efgartigimod will be approved for marketing as soon as possible, bringing new treatment options for MG patients
.
Expert profile Professor Lu Jiahong, chief physician of the Department of Neurology, Huashan Hospital Affiliated to Fudan University; doctoral supervisor, deputy director of the department; expert of Shanghai Rare Disease Prevention and Treatment Foundation; deputy leader of the amyotrophic lateral sclerosis collaboration group of the Chinese Medical Association Neurology Branch, peripheral nerve Member of the collaboration group; member of the Academic Expert Committee of the National Neuromuscular Disease Diagnosis and Treatment Standard Training Center, director of the National Neuromuscular Disease Diagnosis and Treatment Standard Training Sub-center; member of the National Peripheral Neuropathy Standard Diagnosis and Treatment Training Center, and director of the National Peripheral Neuropathy Standard Diagnosis and Treatment Training Sub-center
.
Professor Yang Huan, Professor of Department of Neurology, Xiangya Hospital of Central South University; Chief Physician, Doctor of Medicine, Doctoral Supervisor; Currently Director of Neuroimmunology and Neuromyopathy Subspecialty of Department of Neurology, Xiangya Hospital of Central South University; Current Neuromuscular Branch of Chinese Medical Association Member of the disease group, member of the Peripheral Neuropathy Collaboration Group, executive director of the Hunan Society of Immunology, chairman of the Neuroimmunology Branch, executive director of the Hunan Rehabilitation Medicine Association, chairman of the Myopathy and Peripheral Neuropathy Professional Committee of the Hunan Rehabilitation Medicine Association, Hunan Neuropathy Member of the Science Professional Committee, Leader of the Neuroimmunology Group, Member of the Standing Committee of the Hunan Society of Rare Diseases, Member of the Standing Committee of the New Technology Professional Committee of the Hunan Society of Medical Education and Technology, Expert of the Professional Technical Review Working Group of Neurology of Hunan Province; "Chinese Journal of Neurology" , "Chinese Journal of General Practitioners", "Journal of Modern Medicine" and other journal editorial board, associate editor of SCI journal Journal of Neuroimmunology
.
Obtained projects including 6 National Natural Science Funds, 1 "New Century Excellent Talent Fund of the Ministry of Education", 2 Natural Science Funds of Hunan Province, etc.
.
Participated in the formulation of the US NIH "Guidelines for Preclinical Testing Standards for Myasthenia Gravis"
.
There are more than 60 papers by the first or corresponding author, including more than 30 by SCI journals such as JCI and JI
.
Participated in the compilation of 5 monographs and teaching materials
.
*This article is only used to provide scientific information to medical and health professionals, and does not represent the platform's views
FcRn antagonists are expected to improve the unmet need for treatment of patients with myasthenia gravis
.
Myasthenia gravis (MG) is a chronic autoimmune disease, which was included in the "First List of Rare Diseases" jointly issued by five national ministries and commissions in 2018
.
Increased muscle weakness and involvement of the respiratory muscles can cause crisis.
If the treatment is not timely, it can endanger life, seriously affect the patient's quality of life and labor ability, and bring a heavy burden to the family and society
.
In June this year, the international authoritative medical journal "The Lancet Neurology" published the results of a phase III clinical study of neonatal Fc receptor (FcRn) antagonist efgartigimod, showing that it has a good effect on the treatment of adult systemic MG (gMG) And safety, which is of great significance to patients
.
Based on the above research progress, we are fortunate to invite Professor Lu Jiahong from Huashan Hospital Affiliated to Fudan University and Professor Yang Huan from Xiangya Hospital of Central South University to give a detailed interpretation of the latest progress in diagnosis and treatment of MG
.
"Not rare" rare diseases, need to pay attention to the differential diagnosis! MG is an autoimmune disease with acquired neuromuscular junction (NMJ) transmission disorder mediated by autoantibodies
.
Regarding the clinical manifestations of MG, Professor Lu mentioned that all skeletal muscles of MG patients can be affected.
The main manifestations are extraocular muscle involvement, eyelid drooping, and eye dysfunction.
They may also have difficulty chewing, swallowing and dysarthria, limb weakness, and even It will also affect breathing
.
The incidence of MG in China is about 0.
68 per 100,000* person-years, and all age groups can suffer from the disease
.
Talking about the pathogenesis of MG, Professor Lu pointed out that acetylcholine receptor (AChR) antibody is the most common pathogenic antibody of MG, accounting for more than 80%; in addition, it targets other components of the postsynaptic membrane, including muscle specificity.
Receptor tyrosine kinase (MuSK), low-density lipoprotein receptor-related protein 4 (LRP4) and other antibodies have also been found to be involved in the pathogenesis of MG
.
Professor Lu mentioned that the symptoms of MG are similar to other neuromuscular diseases, but the most prominent feature of MG is the fluctuating symptoms, manifested by fluctuating weakness and fatigue.
The symptoms are "light in the morning and heavy in the evening".
It can be aggravated later and relieved after rest
.
In MG, the ocular muscle type is a relatively common subtype, which needs to be distinguished from other neuromuscular diseases that affect the eye, such as chronic progressive external ophthalmoplegia (CPEO)
.
CPEO is also characterized by drooping eyelids and eye movement disorders, but there is no obvious symptom fluctuation, and the course of the disease is gradually worsening
.
If CPEO is suspected, a muscle biopsy can be performed to identify it
.
Eyelid spasm is also a common clinical disease, manifested by involuntary contraction of the orbicularis oculi muscle, leading to smaller eye fissures
.
But this is the contraction of the orbicularis oculi muscle, not the weakness of the levator palpebral muscle, so it needs to be distinguished from MG
.
In addition to fatigue test, neostigmine test, and repeated electrical stimulation tests, the examination of MG-related antibodies is also an effective method for diagnosing MG
.
Existing drugs cannot meet the needs of MG treatment, and the development of new drugs is urgently needed.
Common treatment options for MG may have certain risks and limitations, and the treatment effect is not satisfactory
.
Professor Lu mentioned that the more classic treatment of MG is symptomatic treatment, such as the use of brompistigmine
.
Brompistigmine has a certain effect in some early and milder ophthalmic MG patients, but for gMG patients, the drug alone cannot meet the treatment needs, and it is generally used in combination with hormones and immunosuppressants in clinical practice
.
However, hormone therapy has many side effects, such as leading to metabolic syndromes such as osteoporosis and obesity.
In the process of hormone reduction, symptoms may also recur
.
During the clinical application of glucocorticoids for the treatment of MG, some patients will experience short-term aggravation of symptoms in the early stage, and may even cause a crisis in individual patients
.
Regarding this situation, Professor Yang mentioned that in patients who have already had a threatened crisis or have aggravated new onset, if high-dose corticosteroids are used for pulse therapy, they are prone to myasthenia crisis
.
For some patients with mild to moderate disease and no serious infection, it is recommended to use the hormone in small doses, which is relatively safe
.
For some newly-onset patients who are still in rapid progress, or those who have infections or hyperthyroidism that can cause exacerbations, hormones need to be used cautiously
.
As the current MG treatment has certain limitations and the therapeutic effect is not ideal, the development of new effective drugs has become an urgent need for the current MG treatment
.
Professor Yang Huan mentioned that MG is an antibody-mediated disease from the point of view of its pathogenesis.
Every aspect of antibody activation may become an effective therapeutic target
.
Complement inhibitors target the main immune mechanism involved in the destruction of the MG endplate, which can inhibit the activation of C3 and C5.
At present, some drugs for complement are undergoing clinical trials
.
B cell activation is an important part of antibody production.
By depleting B cells, the source of autoantibodies in MG patients can be reduced or eliminated
.
Rituximab can deplete B cells, but it also has a certain risk.
After B cells are depleted, it will increase the chance of serious infection
.
Targeting some factors that activate B cells, such as B cell activating factor (BAFF) and B lymphocyte stimulating factor (BLyS) on the surface of B cells, is also the direction of MG treatment
.
Some drugs for regulatory T cells, and other cytokines such as interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) are also under development
.
Plasma cells are the final link in the production of antibodies, and FcRn targeting plasma cells has been a hot spot in recent years
.
FcRn can transport and recycle IgG, avoid IgG degradation and prolong the half-life
.
The FcRn antagonist blocks the IgG circulation by binding to FcRn, causing rapid depletion of IgG antibodies in autoimmune diseases
.
In MG patients with severe symptoms, it is expected to replace plasma exchange and immunoglobulin treatments
.
Efgartigimod Phase III clinical data is good, bringing new hope to MG patients.
For the popular target of FcRn, there have been gratifying research progress recently.
On June 18, 2021, "The Lancet Neurology" published efgartigimod.
Results of Phase III clinical study (ADAPT study)
.
It shows that efgartigimod has good efficacy and safety in patients with gMG
.
As the world's first FcRn antagonist, Efgartigimod is an Fc fragment of a human IgG1 antibody that can treat autoimmune diseases mediated by pathogenic IgG antibodies, including MG
.
Professor Yang pointed out the advantages of FcRn antagonists: 1.
FcRn antagonists can target plasma cells, selectively inhibit IgG, and have a clear target
.
2.
From the data of the ADAPT study, FcRn antagonists are safer
.
3.
The antibody clearance rate of FcRn antagonist can reach more than 70%, and the curative effect is good
.
4.
It can comprehensively improve the patient's quality of life, and the patient's quality of life score and other objective scores can be improved
.
5.
It is expected to replace poorly accessible treatments [such as immunoadsorption, plasma exchange, intravenous immunoglobulin (IVIG)], so that more patients can receive effective treatment in time
.
Professor Yang said that the ADAPT study has brightened the eyes of clinicians and has given more hope to MG patients with severe symptoms
.
The research design of ADAPT has also brought a lot of enlightenment to the clinical research of MG new drug research and development
.
Efgartigimod, as an FcRn antagonist, has a clear mechanism of action
.
The study design is also very rigorous.
The primary endpoint uses the Myasthenia Gravis Activity of Daily Living Scale (MG-ADL), which can comprehensively evaluate the quality of life of MG patients
.
The secondary endpoints are based on the Myasthenia Gravis Quantitative Scale (QMG) and the Myasthenia Gravis Quality of Life Scale (MG-QOL) scores, which can evaluate the patient’s myasthenia and quality of life
.
These indicators can comprehensively reflect the therapeutic effect of the drug
.
Summary: MG traditional treatment programs often have certain limitations and fail to achieve satisfactory treatment results
.
As the world's first FcRn antagonist, Efgartigimod can safely and quickly eliminate pathological IgG antibodies in the body through its unique mechanism of action, thus becoming a new type of therapeutic drug for highly targeted IgG antibodies against antibody-mediated autoimmune diseases
.
The ADAPT study shows that efgartigimod has good efficacy and safety in the treatment of adult gMG, and provides important evidence-based medicine support for the treatment of adult gMG
.
It is expected that efgartigimod will be approved for marketing as soon as possible, bringing new treatment options for MG patients
.
Expert profile Professor Lu Jiahong, chief physician of the Department of Neurology, Huashan Hospital Affiliated to Fudan University; doctoral supervisor, deputy director of the department; expert of Shanghai Rare Disease Prevention and Treatment Foundation; deputy leader of the amyotrophic lateral sclerosis collaboration group of the Chinese Medical Association Neurology Branch, peripheral nerve Member of the collaboration group; member of the Academic Expert Committee of the National Neuromuscular Disease Diagnosis and Treatment Standard Training Center, director of the National Neuromuscular Disease Diagnosis and Treatment Standard Training Sub-center; member of the National Peripheral Neuropathy Standard Diagnosis and Treatment Training Center, and director of the National Peripheral Neuropathy Standard Diagnosis and Treatment Training Sub-center
.
Professor Yang Huan, Professor of Department of Neurology, Xiangya Hospital of Central South University; Chief Physician, Doctor of Medicine, Doctoral Supervisor; Currently Director of Neuroimmunology and Neuromyopathy Subspecialty of Department of Neurology, Xiangya Hospital of Central South University; Current Neuromuscular Branch of Chinese Medical Association Member of the disease group, member of the Peripheral Neuropathy Collaboration Group, executive director of the Hunan Society of Immunology, chairman of the Neuroimmunology Branch, executive director of the Hunan Rehabilitation Medicine Association, chairman of the Myopathy and Peripheral Neuropathy Professional Committee of the Hunan Rehabilitation Medicine Association, Hunan Neuropathy Member of the Science Professional Committee, Leader of the Neuroimmunology Group, Member of the Standing Committee of the Hunan Society of Rare Diseases, Member of the Standing Committee of the New Technology Professional Committee of the Hunan Society of Medical Education and Technology, Expert of the Professional Technical Review Working Group of Neurology of Hunan Province; "Chinese Journal of Neurology" , "Chinese Journal of General Practitioners", "Journal of Modern Medicine" and other journal editorial board, associate editor of SCI journal Journal of Neuroimmunology
.
Obtained projects including 6 National Natural Science Funds, 1 "New Century Excellent Talent Fund of the Ministry of Education", 2 Natural Science Funds of Hunan Province, etc.
.
Participated in the formulation of the US NIH "Guidelines for Preclinical Testing Standards for Myasthenia Gravis"
.
There are more than 60 papers by the first or corresponding author, including more than 30 by SCI journals such as JCI and JI
.
Participated in the compilation of 5 monographs and teaching materials
.
*This article is only used to provide scientific information to medical and health professionals, and does not represent the platform's views
