Sky-high experimental monkeys, dangerous?

During the National Day holiday, the news of the US Food and Drug Administration Modernization Act 2.
0 passed by the US Senate was fermented in the pharmaceutical industry, and the problem pointed to the necessity and effectiveness of animal experiments before the clinical development of new drugs, coupled with the fact that the price of primate models has not decreased in recent years, which has triggered many people in the industry
.

01 Will the sky-high monkey brother be cold?

The FDA Modernization Act 2.
0, which is interpreted by some sources in China as "revoking the federal authorization to conduct animal testing on new drugs" (terminating animal testing), could significantly reduce the use
of laboratory animals in the coming years.

Later, after professional translation, the reasonable translation of the original text of the bill actually lifted the animal experiment injunction, but replaced the animal experiment with "non-clinical testing and testing", which can include: cell experiments, biochemical experiments, and animal experiments
.

Therefore, animal experiments can not be "terminated overnight", animal experiments in the development of new drugs are used for safety evaluation (toxicology, safety testing), in the absence of finding a 100% complete alternative, primates as the most suitable & high-quality experimental model is still in short supply resources (eventually to be applied to human clinical trials, no animal experiments need to pay a greater price).

Therefore, this bill is more like the balanced result
of the multi-faceted game of American industry, animal protection organizations, and the government.

From the perspective of the chain of interests, the price of a large number of animals for testing in addition to causing opposition from animal protection organizations, but the rapid rise in monkey prices is also detrimental
to American pharmaceutical companies and research institutions.

The United States is the country with the largest number of experimental monkeys in the world, and the annual use has stabilized at about
70,000 since 2008.
According to the U.
S.
Department of Agriculture's Experimental Monkey Use Report, from 2018 to 2019, the number of experimental monkeys used in the United States was 70,797 and 68,257,
respectively.
About half of the experimental monkeys consumed in the United States are obtained through imports, of which 60% of imports come from China
.

With the outbreak of the new crown epidemic, China has closed the import and export channels
for non-human primate laboratory animals.
According to the statistics of laboratory animals, the number of experimental monkeys imported from Southeast Asia in the United States in 2018 was about 6,000, but in 2021, this number has exceeded 20,000
.
Between 2019 and 2021, the United States imported more than 45,000 crab-eating monkeys
from Southeast Asia.

A while ago, China's policy of importing primates has been relaxed, but considering that although the number of crab-eating monkeys in Southeast Asia is large (the amount of artificial breeding is small, many are mainly wild fishing), the quality is generally poor (carrying tuberculosis, SRV virus, malaria and other viruses), the future is still dominated by imported high-quality female monkeys (monkeys have a long breeding cycle, and imported female monkeys in the short term cannot affect the supply pattern).

In response to the market's mention that "WuXi AppTec, Zhaoyan New Drugs, and Kanglong Chemical Transformation have acquired primate production capacity at a high price and formed a bearish situation", we believe that there is no arguability
in the short and medium term.

02 Biosimilars are no longer mandatory for animal testing?

In addition to the FDA modernization ACT 2.
0, the United States has passed another bill that makes animal testing
no longer mandatory for biosimilars.

Biosimilars exempt animal testing, and the FDA is not without precedent
.

On November 29, 2017, FDA experts highly praised the quality of the product of Tris Pharmaceutical's bevacizumab biosimilars (TRS003), and unanimously agreed that TRS003 was highly similar to the original product, eliminating the preclinical animal experiments FDA allowing it to skip the routine initial expert consultation on biosimilars and directly enter the brief clinical study (that is, after completing the 9-month phase I/III clinical trial, you can apply for marketing).

Do biosimilars necessarily require animal testing? Here we have to mention the difference between chemical generic drugs and biosimilars, comparing from three dimensions of structure, synthesis method, and FDA approval:

● Structure: The structure of chemical generic drugs is equivalent to that of the original drug, and the biosimilar is highly similar to the structure of the original drug, and the main amino acid sequence is the same, but the structure is still slightly different;

● Synthesis method: the chemical production process of generic drugs is the same as that of the original research drug, and the biosimilar drug has been produced by the original research drug, because the production process of the original biological drug is protected by patent;

● FDA approval conditions: The marketing applications of chemical generic drugs and biosimilars are called ANDAs, and the submission of ANDA applications for chemical generic drugs requires proof that the active ingredients must be the same in terms of dose strength, dosage form, and route of administration, and meet production standards
in terms of purity, quality and stability.
The difference is that biosimilars require animal or clinical studies (including: toxicity, pharmacokinetics, pharmacodynamics, and immunogenicity), but less so that they can use data
on the efficacy and safety of the biologics referenced.

Therefore, in the case of the increasingly mature "imitation" technology of biosimilars and the use of less animal experiments, not forcing animal experiments is also a balanced statement (not mandatory does not mean cancellation, but not necessary), not a signal
of "no mandatory animal experiments" for new drug research and development in the future.

03 What are organoids? Can it replace laboratory animals in the future?

The most promising alternative to animal testing in the future may be organoids
.

Organoids refer to a model that uses stem cells, progenitor cells, etc.
to cultivate 3D cell cultures in vitro and has a certain spatial structure and tissue analogues, and has similar organ functions
.

The difference between organoid culture and cell culture is that in 3D, cell culture often appears adherent growth, and organoid culture, matrigel plays an important role, it will form a three-dimensional structure, cells will grow on the matrigel, the formation of a certain three-dimensional structure, such as tube, tumor and so on
.

Organoids can partially reproduce the physiological function of an organ, in the vernacular: you can cultivate a living piece of flesh
.

At present, the mainstream three human body models, primates are the closest to the human environment, but also the highest cost, but there are still differences between animal models and real diseases of the human body, many drugs that have shown effectiveness in animal experiments have failed in clinical trials, which has also made some "doubts about the necessity of animal experiments in the development of new drugs"
.

(Source: NO1 Lab)

The biggest advantage of organoids is that they can build an in vitro culture model
that highly mimics the real situation in the human body in a short period of time.

Between 2013 and 2017, most of the body's glands (such as pancreas, prostate, breast, etc.
) and organoids such as liver, kidneys and lungs were successfully constructed
.

Based on the advances in organoid technology and many advantages, there are many fields that can be applied, including: disease modeling, new drug development, precision medicine, tissue and organ regenerative medicine and so on
.
At the same time, the popularity of organoid technology research has risen sharply in the past two years, and the number of relevant literature published around the world has exploded
.

In August 2022, the FDA approved the world's first new drug (NCT04658472) based entirely on "organoid chip" research to obtain preclinical data
.
This milestone event means that the "organoid chip" experiment replaces traditional animal experiments for the first time and is officially recognized
.

This does not mean that organoids can immediately replace animal testing, there are still many deficiencies and defects, to give two examples:

● Heterogeneity: for example, stem cells may be taken from different individuals, and the cultivated organoids are heterogeneous in size, shape, and cellular composition (some characteristics are different); Not only that, but it is possible that stem cells are taken from the same individual, cultured in the same laboratory, and this heterogeneity exists, which makes it impossible to apply in the field of disease modeling in the short term (because of the need for large-scale, high-consistency models
).

● Organoid function and structure problems: Organoids are still very different from real human organs (too simple), such as the current best multicellular liver organoid model may lack functional bile duct networks, lack of normal liver partition patterns, etc.
, can not summarize the entire functional library
of human organs.

Therefore, there is still a long way to go
for organoids to be truly applied to the field of new drug development, and even to replace animal testing.