March 29, 2023

AI teamed up with biotechnology, can microecological pharmaceuticals achieve overtaking in corners?

On September 22 this year, Ferring Pharmaceuticals announced that the efficacy and safety of its drug RBX2660 has been approved by the US FDA Advisory Committee with a high vote, and it is getting closer and closer to being approved for marketing.

The field of microbial pharmaceuticals is about to enter the commercialization stage.

Since the launch of the Human Microbiome Project in the United States in 2007, the development of microecological medicine and microorganism-related technologies has entered an accelerated stage. Driven by the policy, a large number of microbiological pharmaceutical star companies such as Evelo, Finch, Seres, and Rebiotix have emerged. According to incomplete statistics, there are more than 50 micro-ecological pharmaceutical companies in the world, of which more than 30 have accumulated more than 3 billion US dollars. Pfizer, Roche, Johnson & Johnson and other multinational pharmaceutical giants have also deployed micro-ecological pharmaceuticals.

The domestic micro-ecological pharmaceutical industry is in the stage of rapid start. In December last year, Unknown Jun, who just completed a series B financing of 100 million US dollars, is one of the representative companies. Its drug research and development idea is the AI ​​+ BT (biotechnology) model. Unknown Jun focuses on the research and development of AI pharmaceuticals for intestinal microbial treatment. The fecal bacteria transplant drug XBI-302 developed has been approved by the FDA for IND for clinical trials. Currently, four drug pipelines have entered the clinical development stage.

What are the advantages of microbial therapy over traditional therapy? How does AI help micro-ecological drug development? And, in the micro-ecological drug research and development track, where are the advantages of domestic companies?

On September 30, at the Rebuild 2022 of Geek Park, Zhang Peng, founder and president of Geek Park, and Tan Xian, co-founder and CEO of Unknown Jun, talked about the current situation and business development prospects of domestic micro-ecological pharmaceuticals.



Tan Yan is a guest in the “Rebuild” column of Geek Park | Source: Screenshot of the live broadcast



Microbial therapy compared to traditional

Safer and longer-lasting treatment



Zhang Peng: What is the relationship between gut microbes and human health and disease?

Tan test:More than 300 years ago, Leeuwenhoek invented the microscope and discovered microorganisms under the microscope for the first time. Later, humans discovered antibiotics, and for the first time they discovered microorganisms that can kill pathogens. This is a very big progress in human history. After the advent of antibiotics, human lifespan has been greatly extended. Decades ago, after some tumor patients were infected with pathogenic bacteria, the tumor would shrink. At that time, the reason was unknown, but it was later discovered that it was because of the infection of microorganisms and pathogenic bacteria, after the immune system was activated, the tumor cells would be killed. This discovery also led to today’s immunotherapy.

In 2007, scientists in Europe and the United States launched the Human Microbiome Project due to the maturity of sequencing technology, which was compared with the Human Genome Project launched in the 1990s. It has been found that the relationship between health and disease cannot be fully understood through genes alone, and the intestinal flora is also closely related to human health.

Today, in terms of both medicine and science, the scientific community calls the genes of gut microbes the second genome of the human body, which together with the human body’s own genome determine our health and disease, and even some emotions and brains. think. The medical community now refers to the intestinal flora as a forgotten organ. Previously, it was believed that a large number of microorganisms in the intestinal tract had a simple parasitic relationship with humans. However, with the research over the past ten years, we have found that they are not dispensable. It is a very important organic part that is symbiotic with the human body, and its importance is equal to that of other organs.

At present, there is sufficient data to prove that there are more than 50 diseases related to gut microbes. Some microbial therapeutics have entered the clinical stage, and the disease direction is far beyond what was envisaged at the beginning of the research. For example, we initially thought that only some metabolic diseases in the gut may be related to microorganisms. With the discovery that the intestinal flora is a very important immune regulatory organ, many autoimmune diseases are closely related to the intestinal flora. There is also a lot of evidence recently that some neurological diseases, such as autism, depression, etc., are related to gut microbes.

Zhang Peng: Microbial therapy has become a drug that can be treated. What are the technological changes behind it? Or what has facilitated its evolution?

Tan test:There have been many technological advances in recent years, one of which is sequencing technology, which is called metagenomic sequencing in microbial research. The Human Genome Project measured the genes of a single species—human. The gut microbes are a mixture, and metagenomic sequencing is to make a short fragment sequence after obtaining a mixed sample, and then perform a combined test. The development of microbial research, first of all, benefits from the maturity of metagenomic sequencing and the reduction of cost, which can restore simple fragments of metagenomic to the original abundance information at the species or even bacterial level.

In the past, before sequencing technology came out, research microorganisms had to be isolated, cultured, and then tried various functions. However, after a large number of gut microbes are cultivated, it is impossible to obtain a series of important information such as their abundance in the gut, so the study of gut microbes at that time, whether it is the overall composition or the correlation with diseases, is also good , are very difficult.

With the advent of sequencing technology, instead of cultivating microorganisms, you can first analyze the samples obtained in the gut, what kind of abundance and composition, and what kind of human phenotype or disease, just like autism. This is the most important driver. The Human Microbiome Project is to test as many human fecal samples as possible to restore the structure of the intestinal flora; and to know the phenotype of the corresponding person, whether it is healthy or diseased, and what kind of disease there is, this is the most important .

After knowing this relevant information, we can carry out mechanism research and try to make medicines. At this time, advances in disciplines and technologies such as synthetic biology, culture omics, and germ-free animal models have greatly promoted the development of the field, but the core and earliest driving factor is the improvement of sequencing technology.

Zhang Peng: What is the real challenge of using microorganisms for treatment and production of drugs?

Tan test:For the pharmaceutical industry, there are no more than two things, the first is supervision, and the second is the industrial chain. Of course there is the market, but the market is after the final research is successful.

The first is supervision. Microecology is a new field of medicine, and its complexity is much higher than that of the past, such as small molecule and macromolecular drugs, both of which are non-living drugs. Microecological drugs are called Live Biotherapeutics in the United States, live biological drugs. When a living organism is used as a drug, it is challenging how regulators go about overseeing, such as testing which indicators demonstrate its safety and efficacy. How regulation understands the living drugs themselves and formulates corresponding rules is a big challenge. In 2016, the United States officially issued the specification for the declaration of living biological drugs, South Korea also introduced it this year, and our country will also introduce it one after another.

Followed by the industrial chain, the pharmaceutical industry is an industry with many cross-specialties. According to statistics, innovative drugs require more than 70 professionals, and everyone cooperates with each other. There was no city in China that could gather so many professionals. Microbial pharmaceuticals require even more and newer specialties; it is difficult for a company to gather so many professionals at once, and it is bound to seek external cooperation. There are many problems in the cooperation process, such as: Is the corresponding industry chain mature? Is there a more professional animal model company that can do animal experiments? We didn’t do it before. Later, Unknown Jun hatched a company called Jingtuo Biology, which specializes in sterile animal models and focuses on the field of microecology. In addition, there are some preclinical screening work. To design various screening experiments, it is necessary to explore step by step, which requires the maturity of the industrial chain.

Zhang Peng: What is the mechanism of microbial therapy? Is it to supplement or eliminate some microorganisms? Or what mechanisms are used to generate microorganisms?

Tan test:Microbial drugs themselves, there is a joke called “the mechanism is unknown, the intestinal flora”, what is the mechanism of the intestinal flora, how to regulate human health and disease, and how to analyze and understand this mechanism, is the current scientific research community. reason to clarify.

The gut microbiota works first by interacting with people. How does it play these roles? It is nothing more than some molecules produced by intestinal microbes, whether it is called excreta, or called postbiotics or secondary metabolites in the scientific community, which interact with the human body and cells. We are not unfamiliar with this mechanism. Just like antibiotics, substances produced by some microorganisms can inhibit the growth of other microorganisms, which is also one of the sources of antibiotics.

The second is that the bacteria itself, such as some proteins and polypeptides on the surface of bacteria, interact with human cells, including the bacteria itself passing through the intestinal barrier to enter the human immune system, interacting with immune cells, through a series of mechanisms. Regulates, affects the metabolic and immune systems, and even the nervous system.

In the treatment of diseases under this mechanism, one is addition and the other is subtraction.In addition, if there is a lack of bacteria that play a certain role, add them; in subtraction, if there are too many bacteria of a certain type, or some pathogenic bacteria affect the function of the human body, subtract it. At present, in intestinal flora pharmaceuticals, both “plus” and “minus” are done by some people, and more are still studying the “plus” part, because “minus” may require more extreme means, such as using antibiotics to remove all bacteria kill, which may also cause some other problems.

Zhang Peng: What are the advantages of microbial therapy over traditional therapy?

Tan test:Scientifically speaking, as a regulatory organ, gut microbes are responsible for metabolic diseases, immune-related diseases, and neurological diseases. In terms of mechanism research, a consensus is that gut microbes treat diseases through a multi-target and multi-mechanism approach. In the past, small-molecule drugs were single-target treatments, while gut microbes were living organisms and could produce different products to interact with humans, with more diverse mechanisms. People are complex systems, and it is difficult for every disease to be a key and a lock. For some complex and chronic diseases,In the metabolic, immune and nervous systems, gut microbial drugs are a very important entry point for the future.

Another advantage of gut microbes is that they are safe. These microbes have co-evolved with humans for millions of years, not artificially created. There is no need to worry about the safety effects of long-term use.

There is also the long-term effect. Gut microbes are living drug factories. Once colonization is successful, they can continue to produce drugs in the human body like small drug factories and exert their mechanisms. We believe that in the future, gut microbes will play a very important role in complex and chronic syndromes.




Selecting the gut microbiome track is

Because it has the greatest impact on the human body



Zhang Peng: Is there any special reason behind your choice of gut microbiome?

Tan test:From a business point of view, it must be to find a larger field to cut in.

In the past ten years, we have found that in addition to the gut, there are microorganisms in the mouth, skin, and vagina. Recently, it has been found that there are microorganisms in many organs. However, the gut is the most complex and has the largest number of microorganisms. The gut microbes affect far more disease areas than the oral cavity and other parts. The gut microbes may have the greatest impact on the human body in the future. That’s one reason we cut in from the gut microbiome.

It can also be seen now that oral and vaginal microorganisms have good application scenarios. A series of methodologies, technical platforms, product development ideas, and post-microorganism preparation processes that we have accumulated in intestinal microorganisms can be replicated in the future. used in other fields. Our logic is to first find the biggest, most challenging, and most influential aspects to cut in.

Zhang Peng: The current progress and status of gut microbiome research?

Tan test:At the U.S. Food and Drug Administration (FDA) drug approval meeting on September 22, Ferring Pharma’s RBX2660 received an overwhelming vote of approval from the advisory committee. This drug is an FMT Enterobacterial Transplant, which is used to treat Clostridium difficile infections.

This affirmative vote is a very landmark event in the emerging field of microbial drugs, which means that intestinal microbial drugs are likely to be approved for marketing in the United States as soon as this year, or at the latest in the first quarter of next year. It means that the entire field will enter the commercialization stage. This is on a global scale. Our progress in China will be a little slower, and it is still in the process of Phase I or Phase II.

Zhang Peng: What are the main concerns or concerns of regulators?

Tan Xun: Safety and efficacy are the two most important indicators, In the process of supervision, it is mainly to look at the balance between safety and effectiveness. The more benefits, the less risk, the better. For microbial therapy and cell therapy, because they are faced with living organisms, they will change and grow. What method is used to detect it and what kind of indicators are used to define it, this is the bottom one. logic. Why do regulators need time to adapt when new drugs come? Because regulators also need to learn the relationship between new testing methods and drugs, and how to use these methods, formulate rules and reference standards to regulate, which will take time.

Zhang Peng: What is a drug pipeline? What are the technical difficulties of R&D?

Tan test:Pipelines can be simply understood as product lines. For example, when we say that there are three pipelines, they are actually three products. Why is it called a pipeline? As a pharmaceutical company, the research and development cycle of medicine is very long. Before it is approved for marketing, or it may even fail clinically, we cannot call it a product, but only a semi-developed product. Because it has a process of advancing linearly like a pipeline, clinical phase I, clinical phase II, and clinical phase III, so it is called a pipeline.

In the pipeline advancement process, every step has the risk of failure. In the field of biomedicine, according to historical statistics, the probability that a drug that starts the first phase of the clinical trial will be successfully approved in the third clinical phase is about 20%. No matter what drug it is or what direction it is, in the past 100 years, innovative drugs have only had a 20% success rate. Therefore, biomedicine is a challenging industry, but it is also an industry that can bring hope to mankind.

For new fields, the design methods and detection indicators of clinical trials need to be explored, such as what dose is more appropriate, and which markers to detect to measure the relationship between drugs and diseases. So, inevitably, for a new drug field, the success rate at the beginning must be lower than that in the mature stage.

An emerging field is a process of constant exploration. Failed clinical trials are not necessarily completely worthless, and we can draw some conclusions from them, which may be successful after making changes. For us, human data research over the past so many years has given us more and more guidance, such as how to use drugs, what doses, and which biomarkers to monitor can help clinical design, etc. In this way, the field moves forward in a gradual iterative process.




Microbial R&D in China

The advantage lies in the data



Zhang Peng: How do human body data come from, and will it become data that can be shared by the industry?

Tan test:Human fecal samples are most commonly used to study gut microbes. After sequencing the samples, information such as abundance can be obtained; other omics-level measurements will also be performed, including metabolome measurement of metabolites, proteome, etc. However, the existing technology will be more expensive. This is the process from sample to data. But this is only from the gut microbiome; we also want to understand the relationship between gut microbes and people, so we also collect information on people. For patients, it is to collect various clinical information, such as disease, blood markers and tissue conditions, and then convert it into data. If we want to obtain patient data, we must cooperate with hospitals or qualified third parties to initiate different clinical studies and collect them in compliance with national regulatory requirements.

Data must be a very important barrier and an asset of the company.With certain aspects of data, there is an opportunity to mine more information, and it is possible to do drug development. On the other hand, it is not enough to only have data. It is like having a bigger gold mine without a better excavator. Only with matching algorithms and computing resources can data be valuable. Therefore, combining data with algorithms and computing power is an important advantage in the research and development of microbial drugs, a barrier to the company’s future, or a new technological foundation.

Zhang Peng: How does AI play a role in the pharmaceutical field? What is the challenge?

Tan test:The number and types of human intestinal microbes are very large. There are about 10 trillion to 100 trillion microbial cells in the intestine of each person, which is 10 times the number of human cells. The number of genes reaches millions. method one by one. The role of artificial intelligence here is to reduce the search range. For example, through the comparison of patients with normal people, through artificial intelligence modeling, narrowing the area, and then doing experiments, the efficiency can be improved.

Secondly, because of the accurate data of microorganisms, we can use a large number of machine learning methods to more quickly predict which functions of a certain microbial gene sequence, or whether the functions are strong or weak, further reduce the number of experiments and increase the success rate of experiments. This is the big help of artificial intelligence for both of us.

In the unknown gentleman, we call these two aspects Top-down and Bottom-up. Top-down is to analyze the relationship between intestinal flora and diseases from the perspective of people, and analyze which microorganisms are related to which diseases. Bottom-up means that the strain predicts its function on the basis of existing data such as gene sequencing, spends as little time as possible, and achieves more accurate prediction through data methods.

Zhang Peng:AI What are the challenges in the pharmaceutical field?

Tan test:Our generation of artificial intelligence is essentially a statistical probability model, and we already have many successful cases in the field of images and natural language learning.

For the life sciences, the first challenge is how to translate the problem into a known framework, and the second is to find the right algorithm to perform the computation. This requires biologists, mathematicians and computer scientists to cooperate.

The second challenge, the fusion of biology and computer science presents some challenges. The data in the biological field has some particularities, that is, the data dimension is very large, but the amount of data is relatively small. This requires us to adjust the algorithm of artificial intelligence to adapt to the characteristics of biological data.

Zhang Peng: What is the current situation of Chinese microbial pharmaceuticals? What are the long board and short board compared with foreign countries?

Tan test:From the perspective of talents, I think it has an advantage, because the basic research in this field started in 2007, and China has already attached great importance to the research of life sciences. We have made a statistic that the field of microbiology is developing rapidly, and the basic research articles related to microbes published in academic journals have grown exponentially in recent years, and in terms of quantity, the trend of progress in China, the United States, and Europe is comparable. This is due to the advantages of equipment, data, and also the corresponding scientific researchers. I think we have a very good talent advantage,Compared with many other fields, we have produced a group of world-class researchers.

But in terms of industry, because this industry started a little later in China, we have fewer talents; but many talents came from the scientific community, and I believe they will catch up very quickly. In terms of policy, national regulatory agencies, such as the Ministry of Science and Technology and other relevant government departments, are all paying attention to this field. I think some policies will make progress in the past two years.

Compared with foreign countries, China’s biggest advantage is data,We began to collect data on tumor patients receiving treatment in 2018, and now there are four or five thousand sample data, which is currently one of the largest tumor databases in the world, which is our great advantage. The data advantage is not only due to the large population, but also due to my country’s medical system, cooperation environment and the process system of the entire system.

I think we have room to catch up quickly in terms of micro-ecological drug regulation. China’s innovative drug system has not been established for a long time. With so many pharmaceutical companies, there are constantly a variety of drugs. How to supervise the emerging new technologies? What kind of framework is in place to regulate new technologies faster and faster? This is a very challenging thing. At this stage, the speed of policy introduction will definitely be relatively slow. However, this is not a problem that the micro-ecology field alone has to face. The entire bio-innovation field requires better interaction between regulatory agencies, industry, and scientific research. This is something our generation has to explore together no matter what role we are in.

Ewen Eagle

I am the founder of Urbantechstory, a Technology based blog. where you find all kinds of trending technology, gaming news, and much more.

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