In January this year, China's first genetic clinical trial for late-onset Pompe disease was administered to the first subject in Huashan Hospital. The picture shows medical staff preparing patients with rare diseases before taking medication.
In the past two years, more and more developers and pharmaceutical companies have set their sights on the R&D of rare disease drugs. According to statistics, in 2023, at least 27 rare disease drugs will be approved for marketing by China's State Food and Drug Administration, covering 20 rare diseases.
At the same time, in the adjustment list of the medical insurance drug list announced by the National Health Insurance Administration at the end of 2023, a total of 15 drugs for rare diseases outside the list were successfully negotiated and bidd, covering 16 rare diseases, filling the gap ......in drug protection for 10 diseases
"Moon Child", "Glass Man", "Mermaid Baby" ......Behind these beautiful names, in fact, they correspond to albinism, hemophilia, and congenital lower limb deformities, all of which are included in the same disease - rare diseases.
The last day of February is International Rare Disease Day every year. The first International Day for Rare Diseases was launched on February 29, 2008, and was chosen to occur only once every four years to deepen public understanding and awareness of rare diseases. Today, February 29, once held every four years, is also the 17th International Day of Rare Diseases.
In China, rare diseases are defined as diseases with a prevalence of less than 1 in 10,000 in the population, or less than 1 in 10,000 newborns, and less than 140,000 in the total number of patients. According to statistics, there are currently more than 7,000 rare diseases in the world, and most of them are facing multiple problems such as "difficult to diagnose and difficult to diagnose". It is gratifying that Rare Disease Day, which is in its 17th year, is ushering in more and more new dawns, just like this spring.
Suffering from the rare "7 parts per million", unfortunately encountered again and again.
I'm very confident in the follow-up! Dandan (pseudonym) said. She was about to be discharged from the hospital, and in the past six months, she was in and out of the emergency room, and her life was in danger for a while.
Dandan is a young ** who suddenly had a fever and cough in October 2023, and even a high fever half a month later, with a body temperature of up to 401. Accompanied by thrombocytopenia, generalized edema, and multiple rashes, ......Unable to find out the cause at the local hospital, she was sent to the emergency department of Ruijin Hospital at the end of November last year. Because of severe infection and respiratory failure, she was admitted to the emergency ICU for emergency treatment and was given endotracheal intubation and ventilator-assisted ventilation.
What the hell is this? Because Dandan was complicated with renal failure and thrombocytopenia, Zhang Wen, director of the Rare Disease Diagnosis and Treatment Center and chief physician of the Department of Nephrology of Ruijin Hospital, Mao Enqiang, director of the Department of Emergency Medicine, Wang Xuefeng, director of the Department of Clinical Laboratory, and Shi Hao and Feng Xiaobei, deputy chief physicians of the Department of Nephrology, conducted consultations.
Based on the results of several tests, doctors concluded that Dandan was suffering from atypical hemolytic uremic syndrome (AHUS). The prevalence of this disease is about 71 million, and nearly 50 per cent of patients can develop end-stage renal disease, with a mortality rate of 25 per cent! In 2018, it was included in China's first batch of rare disease lists.
It was unfortunate to suffer from this dangerous rare disease, but fortunately, Dandan was diagnosed quickly in Ruijin Hospital and did not take any detours.
The data shows that in China, 7297% of patients with rare diseases have the experience of being misdiagnosed, and the average time to diagnosis is 43 years, before being diagnosed, an average of 297 hospitals.
In Shanghai, including Ruijin Hospital, Zhongshan Hospital, and Huashan Hospital, many tertiary general hospitals have set up rare disease centers in recent years, hoping to let patients who were originally scattered in various departments "seek answers" "find the right door".
For Dandan, there is also a "good fortune" that from January 1, 2024, the new version of China's national medical insurance drug list will be implemented, and the drugs she needs will be included in the new catalog.
Eculizumab injection, the preferred drug required by Dandan**, has been used internationally in recent years, but it was previously high - 20,000 yuan for a needle, 3 injections a week, and it usually takes two or three months in a row. The ** fee of close to one million makes many patients prohibitive. Zhang Wen introduced that the drug is now not only reduced to 2,500 yuan per stick, but also included in the medical insurance, the patient's financial burden has been greatly reduced, and there is real hope.
One shot dropped from 700,000 yuan to 330,000 yuan, benefiting more and more patients.
The field of rare diseases** is like a piece of ice, and there are many medical problems to be overcome. In recent years, with the successive launch of new drugs, and the inclusion of a number of drugs in the national medical insurance catalogue through national negotiations, benefiting more patients, the dilemma of rare diseases is gradually "breaking the ice".
Wang Cuijin, a neurologist at Shanghai Children's Medical Center, was deeply touched by this. On January 28, 2022, Verlo, a boy with rare diseases who has attracted much attention in Shanghai, was injected with the first injection of the drug for spinal muscular atrophy (SMA) - nusinersen sodium injection at Shanghai Children's Medical Center. This is the world's first SMA** drug, which was launched in China in 2019 but is only used by a small number of patients. Because at that time, the cost of one shot was 700,000 yuan, and 6 injections were usually required in the first year.
In 2022, with the update of the new national medical insurance catalog, nusinersen sodium injection will be included in the medical insurance, and the price will be reduced to 330,000 yuan per shot. Willow is one of the first beneficiaries of the new drug after it was included in the medical insurance.
With the entry of this type of drug into the medical insurance, there are significantly more patients who come to see us, and there are nearly 30 cases in routine follow-up**. Wang Cuijin lamented that the guarantee of drugs has made SMA a "common disease among rare diseases" in this hospital.
Among the patients Wang Cuijin followed, the youngest was only 2 weeks old at the time of the first diagnosis, and the oldest was 15 years old.
As far as SMA is concerned, it is not yet possible to talk about **, because patients need to face many problems such as **. As the disease progresses, such patients will develop scoliosis, and they are also looking forward to a better plan, looking forward to whether the drugs can be cheaper and more insured. In an interview, Wang Cuijin cited such a data: there are more than 7,000 rare diseases in the world, more than 4,000 in pediatrics, 80% of which are hereditary diseases, 30% of patients die before the age of 5, only 5% have the best methods, and 95% of rare diseases lack drugs or have poor access to drugs......
We've got a lot of changes, but there's still a lot to look forward to. Wang Cuijin said.
Broaden the age of diagnosis and treatment, and meet the needs of patients.
For children with rare diseases, not only do they need medicines, but doctors are also crucial.
22-year-old Xiao Lu (pseudonym) is an "old patient" of Li Xihua, director of the Neuromuscular Molecular Pathology Diagnosis Laboratory at the Children's Hospital of Fudan University.
At the age of 7, Xiaolu was diagnosed with Duchenne muscular dystrophy (DMD), an X-linked recessive genetic disorder in which children typically develop muscle atrophy between the ages of 3 and 4 and are usually unable to walk before the age of 12 without timely intervention.
Li Xihua and the patient's family.
In the case of rare diseases, continuity of care is also important. "Previously, I had to be referred to ** hospital because I was out of the age range that could be diagnosed and treated in a pediatric hospital. Fortunately, with the implementation of a new regulation of the hospital, Xiaolu returned to the pediatric hospital he was familiar with.
Since last year, with the approval of the Shanghai Municipal Health Commission, the Children's Hospital of Fudan University, Shanghai Children's Medical Center and Shanghai Children's Hospital have been able to provide continuous medical services for patients with special diseases over the age of 18 and under the age of 35, mainly focusing on four types of diseases: childhood leukemia and solid tumor diseases, congenital structural malformations, congenital genetic metabolic diseases, and rare diseases.
This is a great benefit for both doctors and patients, and the broadening of the age of diagnosis and treatment has allowed the diagnosis and treatment needs of patients with rare diseases to be met. Li Xihua bluntly said that especially for DMD patients, the older they are, the more challenges they face. "Before the Spring Festival this year, Xiaolu told me that his condition had worsened, and he couldn't sleep at night and couldn't lie down and panicked. ”
This is a typical DMD progression that leads to a series of chain reactions in the heart, respiratory, spine, etc. Li Xihua responded quickly, and her DMD-MDT team involved neurology, cardiology, respiratory, orthopedics, nutrition, **, intensive care medicine and other disciplines.
In addition to the diagnosis and treatment of rare diseases, another thing that worries Li Xihua is fertility blockage.
At present, more than 600 drugs for rare diseases have been developed worldwide, but only about 5% of rare diseases are covered. Breakthrough medical technologies and means for rare diseases are still very limited, so it is of great significance to prevent them at the source.
Li Xihua often cooperates with Sun Luming, director of the fetal medicine department of Shanghai First Maternity and Infant Health Hospital, to reduce the occurrence of tragedies by reading the genetic "book of heaven".
Sun Luming is undergoing surgery.
At present, there are still about 300 cases of DMD children born in China every year, which also reminds us that there is still a long way to go to do a good job in primary prevention. She suggested that couples who wish to have children should receive formal genetic counseling and genetic testing before pregnancy to stop the occurrence of rare diseases from the source.
After 30 years of exploration in the field of DMD, for Li Xihua, there are times of difficulty and loss, but more of joy and hope. During the interview, she talked to the reporter about a detail, many years ago she looked through the foreign DMD clinical ** guidelines, the entries were detailed, and even related to how to guide patients to reintegrate into society.
At that time, Li Xihua thought, "How is this possible?" "After all, according to the current situation of diagnosis and treatment in China at that time, there were many patients who died of heart failure at the age of twelve or thirteen. Now, she understands that none of this is impossible. "Sometimes, parental optimism and rationality are more effective than special drugs. ”
For now, hormones** remain the most cost-effective way to delay DMD in the world. Nearly ten years ago, Li Xihua did a survey, and the hormone use rate of children with DMD in China was only 259%, and today, this proportion is rising, and it is close to the rate of hormone use among patients in EU countries.
The attitude of the parents of the children has changed greatly, they no longer feel sorry for themselves, and many of them will actively cooperate with the doctor and consult the literature at home and abroad. In Li Xihua's clinic, a parent told her that even if she can't ** the disease, she must find ways to delay the progression of the disease, "I believe that we can always wait for the special drug to be marketed."
She was also pleased to find that many 14 or 5-year-old children did not give up their studies because of illness, and they walked freely and went to school. "Some children asked me whether I should go to secondary school to learn a trade or continue to study in high school and go to university. She was so happy that the child was starting to think about her future.
There is no doubt that rare diseases are inseparable from the support of family and society. With the increase of social attention, more rare diseases have been "seen", and DMD, as a "common disease among rare diseases", has also given more and more patients and families hope.
The R&D side makes efforts to move towards the "unknown".
In the past two years, more and more developers and pharmaceutical companies have set their sights on the R&D of rare disease drugs. According to statistics, in 2023, at least 27 rare disease drugs will be approved for marketing by China's State Food and Drug Administration, covering 20 rare diseases. At the same time, in the adjustment list of the medical insurance drug list announced by the National Health Insurance Administration at the end of 2023, a total of 15 drugs for rare diseases outside the list were successfully negotiated and bidd, covering 16 rare diseases, filling the gap ......in drug protection for 10 diseases
In Shanghai Ruijin Hospital, with the promotion of policies such as the launch of new drugs and the update of the medical insurance catalog, all departments of the hospital work together to ensure the use of relevant drugs in the hospital as soon as possible. Bian Xiaolan, director of the Pharmacy Department of Ruijin Hospital, said that since 2020, Ruijin Hospital has been equipped with nearly 40 drugs for rare diseases. In January this year, with the inclusion of agamod injection, a rare disease drug for generalized myasthenia gravis, into the medical insurance, the Department of Neurology of Ruijin Hospital ushered in the first batch of patients with medical insurance.
Before the launch of Agamod injection, our clinical pharmacists followed up on its use in Ruijin Hainan Hospital. Today, pharmacists will continue to follow up on its use in Ruijin Hospital. In fact, we have accumulated a lot of experience in 'how to make good use of new drugs', and we look forward to more new discoveries in the future." Bian Xiaolan said that the diagnosis and treatment of rare diseases should be a complete closed loop, from the front-end diagnosis of rare diseases, the mid-end of rare diseases and drug security, to the back-end of the first post-efficacy evaluation and adverse drug reaction monitoring, etc., only by realizing the closed loop can we truly escort the health of the rare disease population.
There is also a medical team, which is moving towards an earlier and more front-end force. In January this year, China's first clinical trial of the A**gene for late-onset Pompe disease completed the first subject administration in the Rare Disease Center of Huashan Hospital. The trial was led by Professor Zhao Chongbo and Deputy Chief Physician Zhu Wenhua of the Department of Neurology of Huashan Hospital as researchers, and jointly implemented by a multidisciplinary team composed of experts in nursing, nutrition and other disciplines.
Zhao Chongbo (second from right) clinical trial team with the first subject.
The research drug is CRG003 injection, which is a gene substitution based on recombinant A** technology, using the viral capsid as the delivery vehicle to deliver the optimized gene expression cassette into the cell and continuously synthesize the active protein, in order to improve the clinical symptoms of patients with late-onset Pompe disease and achieve the effect of "single dose, long-term effectiveness".
It is equivalent to a small transformation of the body, and a factory has been built inside to continuously produce active proteins. Zhu Wenhua said vividly.
This is an investigator-initiated clinical study (IIT) that is earlier than the Phase 1 clinical study, with the goal of observing the tolerability and safety of the new drug, and the study period is expected to be 5 years.
The vast majority of rare diseases are genetic diseases, and many teams at home and abroad are seeking breakthroughs in the field of genetics, which is also one of the hot directions of new drug research and development for rare diseases. For example, in order to strictly demonstrate the safety of this study, the academic committee and ethics committee of Huashan Hospital collected a large number of materials and demonstrated them many times, which took almost half a year - which is significantly longer than the general new drug clinical trial application cycle.
Because it's so new, our out-of-town hospital also ran away, and there is no hospital to pick it up! The head of this enterprise told reporters.
Who will be the first person to eat crabs? How to give greater support to the exploration of innovation frontiers? Zhao Chongbo said frankly that the research and development of rare disease drugs is, to some extent, a race against time, because the lives of most rare disease patients are counting down.
The process of R&D of new drugs for rare diseases is also promoting the deep transformation of some hospitals into research-oriented hospitals, including the establishment of clinical research teams, the formation of scientific research-oriented awareness, and the standardization of operating procedures. Zhao Chongbo revealed that since 2020, Huashan Hospital has become increasingly active in the field of clinical research of rare diseases, such as in the field of diagnosis and treatment of myasthenia gravis, and has led several domestic or international multi-center clinical trials of biotargeted drugs. This year, the team is also initiating an IIT study targeting rare disease cells** and will partner with a biopharmaceutical company to use CART cells** to refractory myasthenia gravis.
New drug R&D is not achieved overnight, but without the first step, it is impossible to talk about the R&D transformation chain from biopharmaceutical companies, to research hospitals, and then to approval and marketing. Zhao Chongbo said.
Author: Tang Wenjia Li Chenyan.
Text: Tang Wenjia Li Chenyan Photo: Photo provided by the interviewee Editor: Tang Wenjia Li Chenyan Responsible editor: Fan Liping Jiang Peng.
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