He Liping, chief reporter of The Paper
In January 2018, a dose of Milasen was injected into the sheath of 7-year-old mila through lumbar puncture, and human medicine reached a milestone: for the first time in the history of the FDA approved the design and development of an antisense nucleic acid drug for a patient, the concept of "single patient" (N-of-1) became a reality for the first time...
Although Mila eventually died, the girl, who suffered from a rare, lethal neurodegenerative disease, one of neuronal waxy liposcinosis 7 (CLN7, Barton's disease), was once sparked with hope of a life because of her tailor-made medications. For many patients with rare diseases, the lack of a cure is a reality that must be faced.
Chen Shifei, deputy director of the State Drug Administration, said at last year's China Rare Disease Conference that the research and development of rare disease drugs is difficult, the amplitude is high, and the cycle is long, and it has been difficult to meet the clinical needs of patients. In the field of domestic rare disease treatment, there are mainly key problems such as some rare diseases that are not available in the world, some rare disease drugs that have not yet been listed in China, the phenomenon of ultra-indication drugs, and the shortage of supply of some low-cost rare disease drugs.
However, in recent years, driven by the development of the entire domestic biomedical industry and the introduction of relevant national policies, in addition to the acceleration of the introduction of drugs that have been abroad and urgently needed by domestic patients, domestic enterprises concerned about rare disease drugs are gradually increasing.
"The country has a lot of policy inclinations, such as the introduction of a rare disease directory, the approval of drugs for rare diseases has also accelerated, and the country has gradually attached importance to the diagnosis and treatment of rare diseases, so we feel that this is a situation of time, location, people and people." Liang Yi, chief commercial officer and president of Zaiding Pharmaceutical and president of Greater China, said in an interview with the surging news (www.thepaper.cn) reporter that this prompted the company to pay more attention to the investment of rare diseases of autoimmune diseases.
Zai Ding Pharmaceutical is headquartered in Shanghai and was established in March 2014. Three years after its establishment, in September 2017, the company was listed on the NASDAQ in the United States and re-listed on the Hong Kong Stock Exchange in September 2020. It is worth mentioning that Dr. Du Ying, the founder, chairman and CEO of Zaiding Pharmaceutical, is one of the leaders of China's biological industry. The company, which already has four commercial products, sees the autoimmune field as a "shoulder-to-shoulder tumor."
On June 15, the ninth Myasthenia Gravis Care Day, the world's first FcRn antagonist efgartigimod landed in the Boao Lecheng International Medical Tourism Pilot Zone (hereinafter referred to as the "Lecheng Pilot Zone"), becoming a new breakthrough in the mainland's 30 years of myasthenia gravis drugs. In January 2021, Zaiding Pharmaceutical announced that it has acquired from argenx the right to exclusively develop and commercialize efgartigimod in Greater China, and argenx has received a total of $175 million in cooperative payments, while receiving a pro-rata share of efgartigimod's annual net sales in Greater China.
The world's first FcRn antagonist efgartigimod landed in the Boao Lecheng International Medical Tourism Pilot Zone.
In December 2021, efgartigimod was approved for marketing in the United States. The approval of efgartigimod is based on the results of the Global Phase 3 clinical study ADAPT, which was published in The Lancet Neurology, published in July 2021. The ADAPT study, a 26-week randomized, double-blind, placebo-controlled, global, multicenter clinical study designed to evaluate the safety and efficacy of efgartigimod in patients with gMG, enrolled a total of 167 adult gMG patients in North America, Europe and Japan.
Professor Zhao Chongbo, deputy director of the Department of Neurology of Huashan Hospital affiliated to Fudan University and director of the working group of Huashan Rare Disease Center, said in an interview with the surging news (www.thepaper.cn) reporter that after the new drugs of high-level evidence-based medicine such as efgartigimod enter the Chinese market, "it will produce a 'catfish effect', driving domestic research institutions and pharmaceutical companies to pay more attention to the disease of myasthenia gravis, and further develop safer and more effective drugs to treat this disease." ”
There are at least 200,000 patients with myasthenia gravis in China, affecting young adults
Droopy eyelids, ghostly things to see, unclear speech, drinking water will choke, chewing hard, looking up weakly, hands and feet are weak, a young adult can not even dress and brush his teeth, it may be difficult to stand up alone after squatting down...
There are a conservative estimate of 200,000 such patients in China, and the disease is one of the nearly 7,000 rare diseases in the world, namely myasthenia gravis (MG).
Zhao Chongbo introduced that from the pathogenesis point of view, myasthenia gravis is an autoimmune disease. The disease is an autoimmune disease in which acquired nerve-muscle junction (NMJ) transmission disorders mediated by autoantibodies are among them, of which acetylcholine receptor (AChR) antibodies are the most common pathogenic antibodies. "When this antibody binds to acetylcholine receptors on the surface of muscle cells, it blocks the receptors and activates complement, which affects the function of muscle cells and causes muscle cells to contract well."
Professor Zhao Chongbo, Deputy Director of the Department of Neurology, Huashan Hospital, Fudan University, and Director of the Working Group of Huashan Rare Disease Center.
In terms of clinical manifestations, the patient's skeletal muscles can be affected throughout the body, manifested by fluctuating weakness and fatigue, and the symptoms are "morning light twilight", which is aggravated after activity and can be alleviated after rest. Extraocular muscles are the most susceptible, presenting with symmetrical or asymmetrical ptosis and/or binocular diplopia, and are the most common presenting symptoms of myasthenia gravis, occurring in more than 80% of patients.
Zhao Chongbo used four words to vividly describe the disease, "going with the flow". "With" means that the muscles that are affected are moving at will, that is, skeletal muscles; "Wave" refers to the volatility of symptoms; "Step by step" means that the muscles it affects will gradually expand from the local to the whole body; "Flow" is to take turns, that is, muscle weakness can take turns, such as a patient for a period of time is the left eyelid falling, after a period of time is replaced by the left eyelid falling down, also known as alternating eyelid drooping.
According to the "Guidelines for the Diagnosis and Treatment of Myasthenia Gravis in China (2020 Edition)", written by the Neuroimmune Branch of the Chinese Society of Immunology, the global prevalence of myasthenia gravis is (150-250)/million, and the estimated annual incidence is (4-10)/million. The incidence of myasthenia gravis in the mainland is about 0.68/100,000, and the incidence is slightly higher in women; The residential mortality rate was 14.69 ‰, and the main causes of death included respiratory failure and lung infection.
From the perspective of the age of onset, children over 6 months old have a certain probability of being hit by this disease. "When the immune system is basically developed, as an autoimmune disease, myasthenia gravis will affect the patient's function." Zhao Chongbo said that although the disease can occur at all ages, around 30 years old and 50 years old show "double peaks of onset". In addition, the latest epidemiological surveys also show that there is still a "peak" in the incidence of the mainland around 70 years old.
As a chronic disease, myasthenia gravis is clinically treated, but it is still difficult to cure.
One of the treatment options is symptomatic treatment, using the cholinesterase inhibitor bromidestermine to increase the amount of acetylcholine delivered by the neuromuscular junction and improve the patient's condition in symptomatology. Bromidestigmine is also currently the most commonly used and is a first-line agent for the treatment of all types of myasthenia gravis, which can alleviate and improve the clinical symptoms of some patients with myasthenia gravis. However, Zhao Chongbo introduced, "It cannot cure the root cause, it can only cure the symptoms." ”
When it comes to treating the symptoms, it is still necessary to focus on the regulation of the immune system. The first treatment plan introduced by Zhao Chongbo is immunosuppressive therapy. At present, the commonly used drug for immunotherapy is glucocorticoids, "which is the first-line immunotherapy recommended by various guidelines and consensus at present." "Commonly used also include azathioprine, tacrolimus, cyclosporine, mycophenolate mofetil, cyclophosphamide and other oral non-hormonal immunosuppressants. In addition, for refractory patients, anti-CD20 monoclonal antibodies have been used more recently.
The third is salvage treatment, that is, improving the patient's condition in the short term. Zhao Chongbo introduced that this type of treatment takes the removal of pathogenic antibodies as the main goal, including plasma exchange, intravenous immunoglobulin, immunosorbent and so on. "These treatments have a relatively fast onset of action, but the disadvantage is that the time to maintain efficacy is relatively short, and there are issues of safety and accessibility." Accessibility here mainly refers to the fact that some hospital medical conditions are not allowed to be carried out, and the patient is financially unbearable.
The fourth treatment option is mainly thymus resection. It is worth noting that 80% to 90% of patients with myasthenia gravis are accompanied by thymic abnormalities, that is, thymus hyperplasia or thymoma. Zhao Zhongbo said that patients with thymoma need to be removed as soon as possible, while patients with thymos hyperplasia should look at the control of myasthenia gravis, "If the control is difficult, for systemic patients with positive acetylcholine receptor antibodies, the existing high-level evidence-based medical evidence also shows that the removal of the thymus is very helpful for the long-term control of such patients and the combined reduction of hormone use." ”
Zhao Chongbo concluded that at present, doctors have more "weapons" to help patients with myasthenia gravis control their condition and restore them to a close to normal working or living state as much as possible.
The world's first FcRn antagonist landed in the Lecheng Pilot Zone
However, better disease control does not mean that the quality of life of patients with myasthenia gravis improves. This is almost a common paradox in the patient population.
Zhao Chongbo said that from the questionnaire survey of the daily life scale, although the patient's muscle strength has improved significantly, there has been no corresponding obvious improvement in the quality of life. "A large part of the reason is the side effects of patients' long-term use of immunotherapy drugs, including glucocorticoids and other immunosuppressants."
For patients with chronic diseases, the body shape fat, osteoporosis, hypertension, diabetes, acne, hairy skin, and other side effects such as leukopenia and liver function impairment after long-term use of non-hormonal immunosuppressants are difficult for patients with myasthenia gravis to accept, so that they are "very dissatisfied" with the existing treatment plan.
Zhao Chongbo concluded that although myasthenia gravis is a treatable disease and has obtained good control results, there are also multiple pain points.
First, there are still 15%-20% of patients who do not respond well to existing treatments; Second, 20% of patients with generalized myasthenia gravis may develop a myasthenia gravis crisis, which fluctuates between 3.5% and 11% globally, and higher in poorly treated places; Third, the drugs currently used to treat myasthenia gravis, including glucocorticoids and immunosuppressants, have certain side effects, and rescue treatments with rapid onset such as plasma exchange may have an impact on the innate immune system due to the removal of other macromolecular substances, etc. Although immunoglobulins are safer, they are more expensive and economically difficult to bear; Fourth, the disease affects a large number of young adults, who are the main force of social development and will have a greater impact on productivity.
Zhao sees 2016 as a watershed year for the treatment of myasthenia gravis. "Before the 2016 MGTX study results were released, they were basically based on low-level evidence-based medical evidence, coupled with the opinions of experts, because it lacked RCT (randomized controlled studies) support for high-level evidence-based medicine."
One reason is that it is naturally difficult to conduct RCT studies for myasthenia gravis disease, "the difficulty lies in the disease itself, which has its own fluctuations and fluctuations that will offset the observation of an active drug." In addition, the design of the study may have been inexperienced and flawed before, so it could not produce a positive result. ”
After 2016, with the advent of several blockbuster high-quality RCT studies around the world, the treatment of myasthenia gravis evidence-based medicine was rewritten. "These two bio-targeted drugs against complement C5 or antagonists against FcRn are effective in treating myasthenia gravis and have been approved for U.S. FDA indications."
Take efgartigimod, for example, a human IgG1 antibody Fc fragment that targets the neonatal Fc receptor (FcRn). FcRn has been shown to bind to IgG and protect it from lysosomal degradation, the half-life of IgG is extended to about 21 days compared to IgM or IgA (half-life of about 5 days), FcRn is not involved in the recycling of IgA and IgM. As a bioengineered modified IgG antibody Fc fragment, efgartigimod has a high affinity with FcRn, can compete with IgG to bind FcRn and reduce overall IgG recycling, thereby reducing the overall level of IgG, including pathogenic AChR antibodies present in myasthenia gravis.
Preclinical and clinical studies have demonstrated that efgartigimod can rapidly and consistently reduce IgG levels without affecting IgM, IgA, or albumin.
The ADAPT study, published in The Lancet Neurology, aimed to achieve individualized treatment modalities, including initial treatment cycles and follow-up cycles based on clinical evaluation, reached the primary study endpoint, showing that significantly more patients with positive acetylcholine receptor antibodies after efgartigimod treatment were responders to the Myasthenia Gravis Daily Living (MG-ADL) score (68% versus 30%); p < 0.0001)。 Respondents were defined as at least 2 points improvement in MG-ADL scores for a duration of at least 4 weeks during the first treatment cycle. In addition, the response rate of quantitative myasthenia gravis (QMG) in patients after efgartigimod treatment was also significantly higher than that of placebo. Respondents were defined as at least 3 points improvement in QMG scores and duration of at least 4 weeks during the first treatment cycle. This clinical study also confirmed that efgartigimod has a good safety profile in gMG. The most common adverse reactions are respiratory infections, headaches, and urinary tract infections.
In December 2021, efgartigimod was approved for marketing in the United States, becoming the world's first and currently the only approved FcRn antagonist and the first approved therapy to specifically treat systemic myasthenia gravis through endogenous reduction of pathogenic antibodies.
Zhao Zhongbo told the surging news reporter that the advantages of efgartigimod are mainly reflected in the fact that the onset of action is very fast, and some patients may have subjective improvement in the drug week, and the condition of the drug has improved significantly in two weeks, and the doctor can very clearly observe the obvious improvement of the patient's condition. In addition, the efficacy is maintained for a relatively long time, "in fact, after the discontinuation of chronic diseases, the vast majority of patients' conditions will rebound, but if efgartigimod is used effectively, the efficacy can continue to be maintained for several weeks after discontinuation, and even when the drug is stopped for 12 weeks, 33% of patients can maintain good control." ”
Zhao Chongbo added that because of the use of the drug, it is possible to achieve the precision treatment that has been discussed for patients with myasthenia gravis. "The patient now has symptoms, work life is affected, then start to administer, administer once a week, after four times the general condition is very well controlled, stop the drug, after stopping the patient can continue to work and life." He may have a 30% chance that his condition will be very stable for more than three months, and of course, there is a 70% chance that the condition will repeat within three months, and then come back to continue to give the second cycle of treatment. ”
Professor Huang Shixiong, director of the Department of Neurology of Hainan Provincial People's Hospital, said, "The introduction of efgartigimod, the world's first innovative drug, into Lecheng has become a new breakthrough in the mainland's myasthenia gravis drugs in the past thirty years. As a rare disease, the treatment of myasthenia gravis involves multiple disciplines, in order for patients to be able to receive new drug treatment smoothly and safely, we have set up a special medical team including neurology, emergency department, ICU, etc., and the United Nations well-known experts in the field of internal neurology have established a special remote multidisciplinary consultation mechanism to maximize the quality of medical treatment for patients with myasthenia gravis. ”
Zhu Ning, director of the Hainan Provincial Food and Drug Administration, pointed out, "Thanks to the licensed pharmaceutical and equipment policy granted to Lecheng by the State Council, the provincial food and drug administration approved the use of international innovative drugs introduced by Zaiding Pharmaceutical to treat myasthenia gravis in Lecheng, bringing new hope to domestic patients with myasthenia gravis." She mentioned that in the four years since the implementation of the licensed drug and device policy, the Hainan Provincial Food and Drug Administration has continuously expanded the applicability and benefits of the licensed drug and device policy, and continued to promote the approval of licensed drugs and devices to achieve new results.
It is worth mentioning that as early as April 2020, the Lecheng Pilot Zone established a rare disease center, integrated the expert resources inside and outside the island, united with public hospitals to continue to provide medical services for rare disease patients, and further explored and solved the problems of rare disease groups in diagnosis, treatment and access to drugs, and promoted more international innovative pharmaceutical devices to enter China. According to reports, as of now, the import of licensed pharmaceutical equipment varieties in lecheng pilot zone has exceeded 220 cases, including various new drugs for the treatment of rare diseases.
In addition, Liang Yi also told the surging news reporter that efgartigimod is a "Product-in-a-Pipeline", "that is to say, this is a blockbuster new drug with multi-indication potential in a single product, and it is possible to become a new treatment for a variety of serious autoimmune diseases." ”
Liang Yi said that the efgartigimod's global key phase III clinical study in myasthenia gravis has been completed, and it has entered the stage of applying for registration in China. "In addition to myasthenia gravis, efgartigimod is also conducting global clinical studies in a number of autoimmune diseases such as CIDP (chronic inflammatory demyelinating polyradiculopathy), ITP (primary immune thrombocytopenia), PV (pemphigus)"
How will the disease treatment landscape change? "Three Levels"
It is worth noting that for rare diseases, the advent of a therapeutic drug with better efficacy is not only about the benefits it brings.
A well-known example in China is SMA (spinal muscular atrophy). SMA is an autosomal recessive disorder caused by mutations in the motor neuron survival gene 1 (SMN1), which leads to progressive, symmetrical muscle weakness and muscle atrophy in the proximal limb and trunk due to degeneration of the anterior horn of the spinal cord and bulbar motor neurons, ranking first among the fatal genetic diseases in children under 2 years of age.
Hopes for SMA patients began in 2016. Mao Shanshan, chief physician of the Department of Neurology of the Children's Hospital Affiliated to Zhejiang University School of Medicine, leader of the multiscientific diagnosis and treatment team for spinal muscular atrophy (SMA-MDT), and leader of the SMA diagnosis and treatment expert group in Zhejiang Province, mentioned in an interview with the surging news (www.thepaper.cn) reporter that 20 years after the discovery of the pathogenic gene, SMA's first disease correction therapy (DMT) drug was approved. The so-called DMT refers to a treatment or intervention that affects the pathophysiological process of the disease and produces beneficial outcomes for the course of the disease. In December of that year, Northinalsan sodium injection was approved in the United States.
The first year of the "era of drug treatment" for SMA patients in China is 2019. In February of that year, Northinalsan sodium injection was officially approved by the State Food and Drug Administration, becoming the first drug in China to treat SMA. As of now, there are two drugs approved for the treatment of SMA in China. In addition to Thearnassant sodium injection, in June 2021, the State Food and Drug Administration approved the listing of the Class 1 innovative drug Risperolane oral solution declared by Roche Pharmaceutical Company through the priority review and approval procedure (Chinese trade name: Ai Manxin ®, English trade name: Evrysdi®) for the treatment of SMA in patients aged 2 months and above. Currently, risperolane is approved in the United States for the treatment of children of all ages and adult SMA patients.
Zhang Jinni, a negotiator for the National Medical Insurance Bureau, and others last year held a 90-minute "soul negotiation" to benefit more SMA patients with the former "sky-high drug".
In Mao Shanshan's view, the availability of drugs to treat is an important factor that has greatly increased the attention of SMA, "After Nocina sodium entered the medical insurance, the drug was suddenly much cheaper, which aroused the attention of the whole country, and this information spread throughout the whole society at once through the media." Previously, it was not recognized, mainly because there was no effective treatment plan, and many grassroots doctors did not know about the disease. ”
In just 5 months since the beginning of this year, the SMA patients treated by Mao Shanshan's team who received sodium norcinsum were "blowout", and a large number of previously untreated patients emerged. More importantly, as more patients with SMA try to treat, the overall quality of life of these patients will be increasingly valued.
The impact of efgartigimod on the treatment of myasthenia gravis in China will also have a multifaceted impact. In Zhao Chongbo's view, this new drug will bring three changes to the pattern of disease treatment.
First, from the perspective of the disease itself, there is no doubt that it provides doctors with a new therapeutic "weapon" that can help patients who do not have a good effect on other treatments, and can also help some patients who have certain economic conditions to use this drug and do not want to use hormones or other potential side effects of immunosuppressants. "Our 'healing arsenal' is increasing."
Second, new drugs with high-level evidence-based medical evidence will have a "catfish effect" after entering the Chinese market. "It will drive domestic research institutions and pharmaceutical companies to pay more attention to this disease and further develop innovative treatment drugs for myasthenia gravis." Zhao Chongbo stressed that after a new drug comes in, it not only drives the existing treatment pattern to change, but also injects vitality into the research and development of more new drugs for the disease in the future, "because everyone sees hope, so this value may be greater." ”
Third, after the emergence of new therapeutic drugs, this success of pharmaceutical companies will also promote the academic aspects of the disease. For example, Zhao Zhongbo said that the literature published in the PUBMED database on myasthenia gravis can be seen that before the publication of the REGAIN study in 2017 (Note: the FDA approved the publication of the complement inhibitor Ecolizumab for the treatment of systemic myasthenia gravis in a Phase 3 clinical trial), the number of research articles published each year was an order of magnitude, but after the REGAIN study and later the efgartigimod ADAPT study, There are significantly more myasthenia gravis research articles each year than before. "That is to say, the success of new drugs will lead to research in the field of this disease, and it will also lead to the development of more innovative drugs, which will bring more 'weapons' to the treatment of this disease."
However, given that the efgartigimod is only approved for use in the Lecheng Pilot Zone, and the drug is an injection, patients with myasthenia gravis who need it still need to go to the relevant treatment on their own. In this regard, Zhao Chongbo stressed, "The global new drugs that have not been listed in China have been put into use in the Lecheng Pilot Zone, which is itself an exploratory policy, taking the first step first, and slowly accumulating experience." ”
Editor-in-Charge: Li Yuequn
Proofreader: Ding Xiao