Image source @ Visual China
Text | Cai Jiandao, author| Zhang Yuqi, Yang Yan, editor| Zan Liyong
On January 13, 2022, 57-year-old heart patient David Bennett successfully broke away from ECMO (extracorporeal membrane lung) after a swine heart transplant and is currently recovering well.
Prior to this, on January 7, the University of Maryland School of Medicine in the United States successfully transplanted the heart of a genetically modified pig into Bennett's body. After knocking out four genes, Bennett did not immediately experience internal rejection after the 7-hour surgery, ensuring that the donor survived in the human body.
For the medical community, this is undoubtedly an important node in the successful landing of "xenotransplantation" (transplanting animal organs into the human body).
The heart of the pig changes the heart of the person, the heart of the pig is worth gold, and a heart of the pig saves a life, which is undoubtedly a huge attempt. Before that, humans have tried more in the transplantation of the human body's own organs, the first human donor kidney transplant is only 68 years old, in 1967, Cape Town, South Africa, in the groping for the first heart transplant in human history, but the patient survived only 18 days due to lung infection.
Changing the heart, changing the lungs, or cutting the liver or changing the kidney is only the first step to solve the patient's problem. It will take more time after the transplant to allow the donor to fuse with the recipient, either to live or to die. In 1978, Dr. Zhang Shize of Shanghai Ruijin Hospital completed the first heart transplant in China, and although the transplant was successful, the patient survived only 109 days.
Not only that, taking anti-rejection drugs, anti-infective drugs, etc. may accompany patients for half a lifetime, or even for life. With vansevir (anti-CMV, or cytomegalovirus infection) in one hand and cyclosporine (an anti-rejection drug) in the other, I wanted to see if there was a choice, but none of the drugs could be put down.
For patients, the donor is the basis for survival in the present, and the rejection drug is the future of continuous survival. As the technology matures, will this drug market usher in spring? Is there a golden upstream and downstream demand behind the transplant?
01 Watershed Of Organ Transplantation: Technology Opens the Industrial Explosion Period?
Transplanting a pig's heart into a human body sounds like a crazy enough medical attempt.
The case itself is special. As the world's first party to try "pig heart transplantation", Bennett could only rely on the heart support system for nearly two months before receiving the transplant operation, and at the same time, because of the "previous crime" of not following the doctor's advice, the road to human organ transplantation was also blocked by him.
The critical situation, the absence of other options, and the patient's subjective willingness to cooperate are essential elements for this extremely risky surgery to be performed.
Of course, Bennett was also fortunate that for decades, scientists around the world and countless patients in need of organ transplants have been waiting for advances in xenotransplantation, and many people have not seen this day until their deaths. This time, under the emergency certification of the FDA and the promotion of the University of Maryland, this operation finally landed.
As this "xenograft" operation moves forward, the door to a new era of medicine is slowly opening.
If science and technology is the primary productive force, then a big step in the field of medicine often means a new opportunity for the upstream and downstream expansion of the industry.
When the news of "pig heart transplantation" swept around the world, Li Qiang began to plan to re-pick up the plan of a generic drug that he had previously shelved.
The name of the drug is vincervita, also called valganciclovir hydrochloride tablets. As early as 2018, Li Qiang and his friends were trying to open up the imitation production chain of this Roche original research drug.
It's not that hard. From the production point of view, 70% of the world's valgenciclovir tablets API is made of intermediates exported by Li Qiang's friend's pharmaceutical factory, and Roche's original drug patent has expired. On the fine processing capacity, impurities and yield requirements, this API factory can also properly meet the requirements of domestic and foreign pharmacopoeias.
From the price point of view, anti-rejection drugs are mostly more expensive, Roche's Wansaiwei 16500 yuan / box, Indian imitation version to 2300 yuan / box, and in hand holding the API they can control the cost at about 1% of the Indian price, the price advantage is still very obvious.
But from the perspective of input-output ratio, this is not easy. Valganciclovir hydrochloride tablets have two major indications, one is used as an anti-rejection drug for immunosuppression after organ transplantation, and the other is used for complications such as blindness caused by advanced optic neuropathy in AIDS patients.
At present, most of the AIDS patients in developed areas have a perfect free drug system, which rarely develops to the late stage, and the domestic organ transplant market has an annual total of about 10,000 cases of operation, and the volume is very fixed. In simple terms, valganciclovir tablets are aimed at a very rigid but small user group.
The small number of users means that the market sales are basically stable, while the cost of imitating a drug is not low. Li Qiang calculated an account, the cost of research and development of this drug is about 28 million, plus the production cost of the drug, the declaration of consistency evaluation, before and after the need for about 2-3 years, the initial investment in 35 million or so, is not a small amount. If you remove factors such as government subsidies, the initial investment will take at least 7 years to return the capital.
For many pharmaceutical investors, the initial investment is large, the late return on the capital is slow, and the annual profit is fixed, which is obviously closer to the public welfare than the business. After chatting about the fruitless pharmaceutical investors around him, Li Qiang helplessly shelved the imitation progress of this drug.
"Pig heart transplantation" has brought unattainable growth opportunities to the entire industry. If the pig heart can be successfully transplanted into a person, then whether it is a donor or a surgical patient, it will increase significantly.
The fog of the real market: the problem behind just need to be solved
Once the field of organ transplantation accumulates from qualitative change to quantitative change, then the gold mine of "immunosuppressants" will inevitably rise with it.
Heart transplant technology has been developed in China for 45 years. At present, China has carried out more than 100,000 organ transplants, making it the second largest organ transplant country after the United States.
What cannot be ignored is that in addition to technical difficulties, the huge supply and demand gap is a more difficult pain point to solve.
Taking heart transplant surgery as an example, according to the "China Cardiovascular Health and Disease Report 2019", the current number of cardiovascular disease patients is estimated to be 330 million, and the number of patients in the center of the decline is 8.9 million. For end-stage heart failure, heart transplantation is one of the most effective treatment methods, and there are not a few patients who need to have a heart transplant.
The latest edition of the "China Organ Transplant Development Report" shows that from 2015 to 2019, the number of waiting for liver and kidney organ transplantation has increased year by year, from 21411 to 47382 for kidney transplantation, and from 2209 to 4763 for liver transplantation. The heart and lung distribution system was launched on October 22, 2018, and in the first year (2019), 338 people were waiting for heart transplantation, and 89 people expected to be able to transplant their lungs as soon as possible.
However, as of 2019, only 1583 heart transplants have been completed since the full implementation of brain-dead heart donation in 35 heart transplantation centers across the country.
According to the data of the Chinese Organ Donation Management Center, as of January 20, 2022, 38,047 cases of organ donation had been realized in China.
Although there are many waiting people, the proportion of people who can enter the surgical state or receive a donor donation is not high. Kidney transplantation, as the most skilled transplant and can be donated by relatives, the proportion of surgeries has increased repeatedly from 2015 to 2019 (from 6950 to 12124), but this number is far from enough compared with the waiting people.
Heart transplantation is even worse. First, the skills should be profound, and second, the donor should be "exquisite". Under this requirement, there were still only 279 cases of heart transplantation in the country in 2015, although the technological breakthrough after 2019 (donor preservation from short-term preservation of ice cubes to ischemic heart transplantation technology shifted), but due to conditions, only 679 cases were able to enter the surgical stage in 2019, in addition, there are not a few waiting people.
For the huge number of sick people, the huge difference between supply and demand is destined to make many people have to wait all the time. Some experts have said that because of the lack of donors, some qualified hospitals have not even completed a transplant for several years.
The emergence of the "pig heart transplantation" technology gives another idea - xenotransplantation.
After the technological breakthrough, the industrial outbreak period is bound to be the harvest period of upstream and downstream. Once the bottleneck of organ donation is broken, the immunosuppressive market will show explosive growth.
The question worth paying attention to is, how far is the "pig heart transplantation" technology from the world's first case to the maturity stage?
Li Qiang is optimistic about this, and he prefers to see this as a long-term investment. According to his observation, the domestic organ transplant market has been accumulating potential energy. For him, the current industry silence period is the time to reserve bullets, the current domestic immunization preparation industry growth rate is slower, a large number of patient needs have not been met. With the advancement of technology and the increase in cases, immune agent products may have a new era of "small and beautiful".
03 Epilogue: Many questions to be solved
A kidney transplant takes at least 2 hours, while a liver transplant can take up to 4 hours, the slowest can take 12 hours, and may even be divided into the first half of the operation and the second half of the "final". For heart transplant surgery, the operation time can be higher than that of liver transplantation. As the nurse in the operating room of a third-class hospital said, only senior nurses (more than 5 years of service) are eligible to follow a heart transplant.
The 180 hospitals are the specific numbers that are qualified to practice human organ transplants. In the latest statistics in 2021, only about 1/3 (66) of the hospitals are eligible for heart transplant surgery, while only 4 hospitals can serve as training bases for heart transplant doctors (Fuwai Cardiovascular Disease Hospital of The Chinese Academy of Medical Sciences, Union Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology, Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology, and Guangdong Provincial People's Hospital).
"License" means professionalism and technology, and behind it represents the odds of survival. Taking the survival rate of domestic statistics of heart transplant patients in 2019 as an example, in general, the total survival rate in the hospital is 93.2%, but nosocomial infection, cardiac arrest, secondary chest opening, tracheostomy, etc. are always a molecule that increases the risk, and the molecule may not be able to stir the overall situation, but a slight wind and grass is likely to change the patient's survival chances.
However, for every patient who has surgery, this is only one of the problems of the intraoperative or postoperative buffer period, which has been accompanied by decreasing survival rates for many years thereafter. From 2015 to 2019, the average survival rate in the postoperative year was 85.2% overall, and the average survival rate decreased to 80% in the third year. Compared to children, or because of age and disease. The 1-year/3-year survival rate for adults is slightly lower than that for children overall.
Medicine itself is a discipline of long-term benefits, and it is more demanding in the field of organ transplantation, and neither technology nor talent can be bad.
However, in addition to technology and talent, it is not easy to obtain a "legitimate" heart. Since January 1, 2015, voluntary organ donation by Chinese citizens has become the only legal source of organ transplantation. Prior to this, organ trading and so on can jump back and forth in the gray area, although after the blessing of measures, the "gray channel" is only relatively reduced, but the relevant blow to the organ trading industry is even worse.
On the one hand, the regulations are becoming stricter, and on the other hand, the human organ donation system that has just been established. From 2015 to 2019. The number of donations from inter-kinship activities was basically flat. However, donations after the death of citizens have basically experienced peaks and troughs (2766 cases in 2015 to 5818 cases in 2019). Huang Jiefu, former vice minister of health, used "scraping bones to cure poison" and "brave men with broken wrists" to describe the history of organ donation and transplant reform, although 2015 was not the beginning, but it was one of the nodes.
Maybe a pig heart is the beginning of a possible change of heart, but there are still insurmountable problems behind a fist-sized heart, such as gene editing, rejection processing, and so on.
In the existing domestic rules, human gene editing experiments are limited to medical or research purposes, and reproductive cell genetic modification is carried out, and it is not allowed to cultivate chimeric embryos of humans and other organisms, let alone clone human beings. The He Jiankui incident at southern university of science and technology is one of them, but not necessarily the only one (on November 26, 2018, the He Jiankui "gene editing baby" incident caused an uproar), and even this time the heart patient was imprisoned for murder, which has become one of the requirements for whether the world's population can pass the medical ethics review, not to mention other requirements of medical ethics.
There is a market behind a heart, and then there is still the blessing of technology and talents outside the market. In addition, every policy, and the medical ethics behind it, is still a long way to go.
Although a pig heart makes people see "gold", there is still a dark pit behind gold, which has caused a lot of changes in the industry after the promulgation of the "Human Organ Transplant Regulations" on March 21, 2007. What will happen to the market after technological innovation? Only practice can give the answer.