Fang Shuchen Gao Yi丨Written by
Gao Yi丨Edit
A domestic company that makes organ chips. has already ended its financing, but during the just-passed National Day holiday, many investment institutions are eager to come to the door.
The so-called organ chip is an artificial organ physiological microsystem made with the help of multiple disciplines such as biology, electronics, and mechanics, which is used to simulate various physiological reactions of the human body. A large potential application scenario is to change the replacement of experimental animals in drug and toxicological tests.
investment institutions are suddenly so keen on organ chips because of a bill passed by the U.S. Senate on September 29: the FDA Modernization Act (FDA Modernization Act 2.0). The theme of the bill is to promote the reduction of the application of preclinical trials to animals and replace it with more modern scientific methods.
was once interpreted by the media that after the bill was introduced, the US pharmaceutical industry may significantly reduce the use of experimental animals in the next few years, so this change will be a "big earthquake" for the industry.
However, the pharmaceutical circle responded calmly to this - preclinical animal experiments are still very necessary, and there is no good alternative at present, such a "industry earthquake" is obviously still very far away. After all, you ask people from animal protection organizations to participate in clinical trials and take a drug under development that has not been proven preclinical safety, and they may not be willing to do so.
Therefore, although some investors in clearly saw the future of organ chips after the introduction of this bill, everyone still knows that it is not a matter of overnight banning animal experiments during the development of new drugs. The view of the
industry on "the sky-high price of monkeys is about to finish" is more due to the previous "retaliatory psychology" about the surge in monkey prices. But firstly, as the primate closest to humans, it will take some time for monkeys to be replaced in vitro experiments; secondly, the supply shortage caused by slow reproduction and long growth cycle will continue, so for monkeys, it is still difficult to see a big change in the supply and demand pattern within three to five years. What does it mean in the short term behind the bill of
-01 - What does it mean in the short term? The primary reason why the
FDA modernization bill has attracted widespread attention in the industry is that it mentions the termination of animal test mandate, that is, the "animal experiment mandate". The mandatory order
was established in 1938, and the cause of this was a number of serious drug safety accidents.
In the early days, when pharmaceutical companies launched a new drug, they did not need to prove their safety. At that time, the American pharmaceutical industry often used synthetic sulfonamides as antibacterial drugs. Because this type of drug is insoluble in water, a pharmaceutical company used diethylene glycol as a solvent to make it a sweet liquid that children are willing to drink. The drug killed more than 100 people a few months after it was launched.
In order to avoid the recurrence of the tragedy, in 1938, US President Roosevelt signed the Federal Food, Drugs and Cosmetics Act, which stipulates that all drugs need to provide safety evidence before they are launched. Before using it in humans, testing safety on animals has become the only option in the past few decades.
The FDA Modernization Act of 2022 changed "animal tests" to "nonclinical tests and studies" in terms of wording. The latter includes cell-based analysis, organoids, microphysiological systems, computer models, etc., and also includes animal tests.
At the same time, the bill also includes another proposed reform: no longer compulsory biosimilar (i.e., generic biosimilars of biosimilars) for animal testing. An investor analyzed this regulation of
on biosimilars, an investor analyzed: "This is supported by long-term data. When biosimilars started to appear in Europe about more than ten years ago, the science, clinical cognition, and market feedback could not draw conclusions at that time. Therefore, out of caution, the FDA stipulated that even generic drugs should be conducted in animal experiments." He introduced that, after years of accumulation of evidence, it is enough to judge the safety of biosimilars, "I have the confidence to stipulate that such drugs can not be conducted in animal experiments."
But new drugs are different, just like a new car coming out, collision tests are definitely inevitable. In order to ensure the safety of drugs, animal testing is still indispensable - human needs for drug safety are no different from those in 1938. The alternatives to animal testing are still far from mature enough to 2022.
In the view of an investor who has been paying attention to preclinical trials for a long time, this bill has "mainly influenced the concept" of pharmacy in the short term. He pointed out that under the years of push by Animal Protection Organization, the US pharmaceutical industry used to think that it would reduce animal testing, but there were no clear standards. At the same time, since the regulatory authorities mandate to do it, even experiments that everyone feels are unnecessary and a little wasteful are necessary.
After this bill was passed, there will be no longer mandatory requirements for animal testing. "Especially for the requirements for biosimilars, if you make large molecular biosimilars in the future, you can no longer use animal experiments, but alternatives can be used, even if the alternatives are still weak and immature," he said.
He pointed out that this "does break the original regulatory threshold."
Compared with the United States, Europe's awareness of animal protection is more radical. Long before the United States introduced this bill, Europe had similar regulations one after another. Some multinational cosmetic giants no longer conducted animal experiments in Europe, and basically switched to Asia to do it.
-02 -
alternatives? How mature is currently?
At present, it seems that the technology that is most likely to partially replace animal testing is organoids and organ chips. However, compared with real animal systems, this type of technology is still very immature.
"Compare animal experiments to adults, and the alternatives are all children ." An investor in compared it, "but organ chips or organoid-related solutions are at least a child in elementary school; AI maturity is second, which may be equivalent to kindergarten." He said that other technologies are still "baby in swaddling clothes", which is far from maturity.
"When you have not been an adult or have obtained a higher education or degree certificate, no rigorous and realistic pharmaceutical company dares to completely give up on for animal experiments." He concluded that new alternatives still have a long way to go.
What is an organoid or organ chip?
Simply put, organoids are small in vitro organ models that develop from cells and highly simulate real organ characteristics. Organ chips go further, and build a three-dimensional physiological microsystem of human organs on the chip based on organoids.
The above-mentioned investor took pulmonary fibrosis as an example. "This is an organ-based disease. If a single cell undergoes preclinical trials, how can it be used to verify whether this drug has any effect on the cells during the pulmonary fibrosis process? It is impossible."
"develops the cell into an organoid and makes it into a chip format, allowing it to simulate the functions of some human or animal lungs. Then simulate the drug for treating pulmonary fibrosis on it to see if it can have some effects." He explained, "Of course, it can only be partially verified, because it is completely different from the real lung situation." The current relevant technology of
is still at this stage of research.
However, organ chips will replace animal testing in the future, and this is far from enough.
He still uses lung fibrosis as an example to explain: This disease is not a problem with a single lung, but also involves complex pathological diseases such as fibroblasts and in the human metabolism and digestive system. Therefore, if there is only one artificial lung chip and the test results on it are good, it does not mean that this drug can succeed. The next step in the development of organ chips is to "make a synthesis of organs."
. In the real human body, the medicine will circulate in the body after entering, and it also involves the blood-brain barrier, etc., and there are more aspects that need to be considered. The existing model is far from convincing scientific researchers, let alone the regulatory agencies with stricter standards. Therefore, in order to truly play a better simulation role, it needs to go further.
"Combining multiple artificial organ chips and connecting them together to form the operation of the system, and it may further add physiological, exercise and other related functions. Simulate it on such a model to see how this medicine metabolizes in the human body and how effective it is to treat this specific disease." He imagined the future of organ chips.
At present, another branch of preclinical testing is developing in full swing, that is, gene editing animals. In conventional experimental animals, adding or knocking out genes makes the disease model more targeted and the data produced are more convincing. In this way, experimental animals can be used more accurately and effectively, which in a sense is consistent with the original intention of the Animal Protection Organization to reduce animal experiments. Liu Dan, senior partner of
, invested in an organoid company and a company that gene editing mice. In his opinion, this is a two-way direction in the way of thinking, and it is also a hedging in value investment in time dimension.
For the direction of organ chips, he said that the development of this field will take many years. In five years, there may be a development process that promotes pattern animals, but at least it has not yet reached the point of subtraction. "It must be given time to grow, but it will definitely grow."
-03 -
influence when will it be passed to China? The bill
is only a regulatory standard for companies in the United States and has no binding force on other regions. However, China's drug regulatory authorities have also shown strong interest in related technologies.
China Food and Drug Authentication Research Institute , a subsidiary of China Medical Products Administration, has begun to discuss with industry companies to formulate industry standards for organ chips. If the normal progress is followed, the next rhythm should be issued by the standard, and then the Central Procuratorate will take the report and submit CDE, and finally form formal regulations. "This bill may play a role in accelerating role," said the above-mentioned investor.
Since joining ICH, China's drug regulatory authorities have been in line with the world's front line in terms of regulatory technology and new rules. Whether it is the macro-indication of clinical guidance such as clinical value-centered clinical guidance proposed by the Drug Administration last year, or the clinical guidance of various subdivided therapeutic areas that CDE updates every Monday, as long as new things are useful and can play a positive role in the industry, CDE is willing to participate in the promotion.
However, back to the new regulations on animal experiments issued by the FDA, the most important impact on the changes in preclinical trial standards in recent years is on early clinical model animals, such as mice. Monkeys are the last and most important level before new drugs are used in people. No one or some technology can bear such a great responsibility faster.
" So, the introduction of this bill has caused more sensation in the investment circle. Everyone has seen a new explosion point and can chase it, and also see the potential of the organ chips ." An investor mentioned, "But at the same time, for some companies that do ordinary mice, such as Charles River, it may have a certain impact, and may force them to go to higher-end directions, such as gene editing mice."
"But the organ chip industry has the threshold for supervision, compliance and technology, which is no lower than other tracks in the pharmaceutical field." The above-mentioned investor added.
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