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Sanofi leads the way, Hengrui, Baekje, Roche, and Merck are deployed, and “organoids” have become a must for global R&D!

Organoids, as the name suggests, are simulations of real human organs and physiological systems. As one of the important achievements of stem cell research, they are of extraordinary value for clinical precision medicine (developing individualized treatment plans for patients) and preclinical drug research and development; therefore, they have also become TOP A stronghold that pharmaceutical companies must win.

In this future field where Pfizer, AbbVie, Johnson & Johnson, Roche, Merck, Novartis, BMS, Sanofi, GSK, AstraZeneca, Takeda and other global TOP20 pharmaceutical companies are competing for layout, there are already companies out Get the top spot.

Recently, the FDA approved the world’s first new drug (NCT04658472) based entirely on “organoid-on-a-chip” research to obtain preclinical data into clinical trials. This milestone event means that the “organoid-on-a-chip” experiment replaced traditional animal experiments for the first time and was officially recognized .
The new drug trial, conducted by Sanofi in collaboration with organoid-on-a -chip company Hesperos , treats two rare autoimmune demyelinating neurological diseases for which the lack of ideal animal models has previously prevented them from being carried out. Research.

So far, Sanofi has come from behind. Although it is not the first layout, it is ahead of the audience in the field of “organoid” practice.

If the project goes well, it may completely overturn the constraints of clinical development and change the rules of the game for global drug development.

1 Why the United States and the European Union will use “organoid-on-a-chip” technology Raised to the height of national strategy?

There are more than 7,000 rare diseases in the world for which there is no cure, of which only about 400 are under research. The main reason is the lack of animal models to simulate these diseases. Major diseases such as tumors and cardiovascular diseases are also facing the same dilemma.

If there is a technology that is expected to bring new drug research and development into the era of “low risk, low investment, high return”, then “organoid chip” may be one of them.

From “Organoids” to “Organoid Chips”

In 1907, Wilson, a 44-year-old professor at the University of Baker Carolina, discovered that mechanically separated sponge cells could reassemble and self-organize into new sponge organisms with normal functions. The results of his research were published in 1910 and became the earliest “organoids”. prototype of the concept .

Since then, the rapid development of stem cell technology has brought key opportunities . In 2009, the team of Dutch scientist Hans Clevers successfully cultured Lgr5+ intestinal stem cells into a three-dimensional structure with crypt-like and villous epithelial regions in vitro, giving birth to the first small intestinal organoid.

Since 2009, 3D organoid culture technology has successfully cultivated most of the tissue organoids with some key physiological structures and functions, including: kidney, liver, lung, intestine, brain, heart, prostate, pancreas, retina, etc. And was named one of the top 10 science and technology of the year by “Science” magazine.

At the same time, another organ-on-a-chip technology based on microfluidic technology began to study complex cell behavior on a chip to build three-dimensional human organs.

organ-on-a-chip

Organoids are highly realistic and have histological features and functions that are highly similar to human organs;
Organ-on-a-Chip has the advantages of controllability and standardization of modeling, and can realize the construction of more complex models.

However, they are all models constructed by a single type of cell, and the degree of system bionics is still not enough for biology .

In 2019, a review published in the journal Science proposed the concept of organoid-on-a-chip for the first time.
Organoids-on-chips integrate the advantages of organoids and organ-on-chip technology; build organ physiological microsystems on chips , reproduce interdependent organ functions, and predict the human body’s response to drugs or different external stimuli. react . The description has almost simulated the complete human body, rather than individual organs.

Organoid-on-a-chip simulates human physiological microsystems

“Low-risk, low-investment” new drug development? U.S. and EU launch support programs

According to statistics, the average cost of developing a new drug in 2021 will drop to the lowest in nearly seven years, still as high as about $2 billion . In addition, the failure rate of new drugs entering the clinical development stage is still nearly 90% .

The above pain points are mainly due to the lack of animal models and the inability of animal models to accurately predict human responses .

Because “organoid chips” are directly constructed from human tissues and can be customized for disease modeling; therefore, titer evaluation can be performed more fully before clinical trials, and inappropriate drugs can be excluded, thereby improving the success rate of drug development. Reduce late-stage drug development costs without harming animals. In addition, the integration of organoid chips and AI technology will also make drug screening more efficient and accurate.

Based on the above reasons, in 2011, the US NIH, FDA and the US Department of Defense took the lead in launching the “Micro Physiological System” program (MPS program), raising the organoid chip technology to the national strategic level for the first time .

At the same time, the EU is also optimistic about the development prospects of organoid chip technology in the fields of new drug research and development, precision medicine, and AI pharmaceuticals. One of the goals of the large-scale research and development alliance (imSAVAR) funded by it is to cooperate with large pharmaceutical companies to develop organ-on-a-chip models.

However, in the following ten years, most of the organoid chips were in the laboratory research stage, and the actual clinical application in drug research and development was relatively small. The reason is that in addition to its high technical barriers and interdisciplinary involvement, the biggest “impediment” is still the lack of regulatory approval; now this “impediment” has been removed .

2 Global market: TOP20 pharmaceutical companies have entered the market directly

At present, the commercialization of the global organoid chip market mainly comes from two aspects: equipment sales and testing services ; the compound annual growth rate is about 29% ; the US market accounts for about 41%, and the European market accounts for about 38%.

As an important boost for new drug research and development, the downstream customers of organoid chip companies mainly include CROs and pharmaceutical companies .

Main business models of organoid chip companies

HubrechtOrganoid Technology (HUB) established by the team of Hans Clevers, the originator of organoids, is the world’s first organoid research and development center, and HUB has also helped Epistem, Cellesce, Crown Biosciences, STEMCELL Technologies and other first batch of organoid companies to emerge through technology authorization.

In addition, technology companies established by university research institutes are also the main force of this type of organ-on-chip companies, such as Emulate, a biotechnology company established in 2013 by the Wyss School of Bioengineering at Harvard University.

Previously, most organoid chip companies indirectly provided services to pharmaceutical companies by selling products to CROs. After 2015, more and more pharmaceutical companies entered the market directly through the purchase of products, cooperation authorization and investment , becoming another force in this field .

In 2015, Johnson & Johnson purchased Emulate’s thrombus chip to test its procoagulant properties in marketed drugs or drugs under development.
In 2016, Merck , Seres Therapeutics and others purchased Emulate’s organoid chips for new drug development and testing.
In 2018, AstraZeneca reached an agreement with Emulate to integrate its organoid chip technology into AstraZeneca’s IMED drug safety laboratory; AstraZeneca is also the first TOP drug to integrate organoid chip technology into its internal laboratory. Enterprise .
In May 2018, Pfizer partnered with HUB to develop a human intestinal organoid platform to study diseases such as Crohn’s disease and ulcerative colitis.
In September 2018, System1 Biosciences, a neurotherapy startup led by Pfizer , received US$25 million in Series A financing. It developed its own brain organoids for the development of new neurotherapy methods.
In 2021, Sanofi will collaborate with Hesperos on the preclinical study of NCT04658472.
In January 2022, Bristol-Myers Squibb partnered with Prellis to create high-affinity human antibodies against human proteins based on its human lymph node organoid platform.
In March 2022, Sanofi entered into a collaboration with Prellis to use its platform to reconstitute immune responses in vitro to provide antibodies with significant genetic diversity.

In addition, more than 20 TOP pharmaceutical companies including AbbVie, Merck and Novartis jointly established the non-profit organization IQ Consortium (Innovation and Quality Consortium), which is committed to promoting the standardized application of organoid chips to accelerate the process of drug research and development. A series of industry standards have been published for liver, kidney, lung and other models.

IQ alliance member pharmaceutical companies

3 Chinese market: Hengrui, BeiGene; Roche and Merck have taken the lead

From 2021, China will officially promote the development of organoid chip technology systematically from the scientific research and regulatory levels.

On January 28, 2021, the Ministry of Science and Technology issued the “Notice on Solicitation of Comments on the 2021 Project Application Guidelines for the Six Key Special Projects of the “14th Five-Year Plan” National Key Research and Development Plan”, which listed the “organoid-based malignant tumor disease model” as a In the “14th Five-Year” national key research and development plan, the first batch of key special tasks will be launched.
In November 2021, China CDE for the first time included organoids in the non-clinical pharmacology research of gene therapy products in the Validation Guidelines for Gene Therapy and Cell Therapy.
In July 2022, China’s first expert consensus on organoid-guided precision drug therapy for tumors was published.

Although the development of organoid chips in China has been about ten years ahead of that in the United States, the pace of progress is rapid.

The improvement of China’s scientific research accumulation has accelerated the relevant industrialization process.

From 2009 to 2019, in the field of organoid technology, the published literature from China accounted for 8%, ranking sixth in the world; by 2020, the published literature from China had reached 14%, second only to the United States, ranking second in the world.

The Chinese capital market has begun to pay attention to organoid companies.

Since 2019, Chinese organoid companies have begun to win capital attention, and have completed angel rounds of financing. In 2021, they will complete the A round of financing.
Chuangxin International completed a round of financing of nearly 100 million yuan, led by Qudao Assets;
Danwang Medical completed 120 million yuan in Series A financing, led by Guofang Capital, followed by Delian Capital and Kunlun Capital, and Hans Clevers, the “originator” of organoids, joined as co-founder and chief consultant scientist;
Great Oak Technology completed tens of millions of yuan in Series A financing, led by CDH VGC (CDH Innovation and Growth Fund), followed by Qiji Innovation, and the old shareholders WuXi PharmaTech , Furong Investment and Jiuyou Capital continued to follow. cast;

From the perspective of pharmaceutical companies, China’s R&D “First Brother” and the former R&D “First Brother” have already deployed in the field of organoids.
BeiGene is the only Chinese pharmaceutical company in the IQ Alliance. In December 2021, it signed a strategic cooperation agreement with Chuangxin International to jointly establish a technology platform for new organoid drug research and development.
The translational medicine department of Hengrui Medicine has established in vitro organoid culture, which can conduct drug research in simulated human organs and tumor microenvironment;

Multinational pharmaceutical companies have also expanded the China Innovation Center project to related fields of “organoids”.
In 2020, the Merck China Innovation Center began to explore innovative “organoid” platforms.
One of the key projects of Roche China Pharmaceutical Sciences is the application of human model systems (organoids and microphysiological systems) into the drug discovery product pipeline.

With the FDA’s landmark approval, China’s NMPA may also be approved for clinical trials of new drugs based on “organoid-on-a-chip” data in the future. Who will be the first to be approved?

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