Model small mouse, real big world, Yaokang Bio (688046.SH) hard technology to solve the problem of high failure rate of new drug research and development

Innovative drug research and development has always been a process of "nine deaths".

According to data released by Frost & Sullivan, a global corporate growth consulting firm, the research success rate in the drug discovery stage and 31.8% in the preclinical stage of the global new drug development process is 51%. However, once it entered the clinical stage, the success rate of related studies dropped sharply to 19.3%. Behind this is the inaccuracy of preclinical animal experiments.

Behind each new drug is the "stacking" of hundreds of millions of dollars, of which the investment in research and development at the clinical stage is particularly huge. The market urgently needs a batch of "handy" animal testing models to produce preclinical data that has sufficient guiding significance for clinical trials of new drugs.

At present, Yaokang Bio (stock code: 688046), which will be listed on the Science and Technology Innovation Board, is trying to solve this problem with a mouse model of its own original research.

According to public information, Yaokang Biology was established in December 2017 and was born from the original Institute of Biology of Nanjing University. The founder, Professor Gao Xiang, was the dean of the Institute of Biology of Nanjing University, and now he is also the director of the National Genetic Engineering Mouse Resource Bank, a member of the National Laboratory Animal Expert Committee, and a member of the Steering Committee of the International Mouse Phenotyping Alliance, with more than 20 years of research and management experience in the field of experimental animal mouse models.

Only 4 years after its establishment, Yaokang Bio has established the world's largest mouse strain library, which exceeds the world's first-class mouse strain database such as MMRRC, Jackson Lab, EMMA, etc., and reversed the status quo of this scientific research "smart tool" field imported model card neck. At the same time, based on years of technical practice, Yaokang Bio is also creating a "real world" concept, creating a mouse model that is closer to the real world, and changing the existing preclinical experimental animal model ecology.

Market position of each business segment of Yaokang Biotechnology

Restoring the "Real World" of New Drug Discovery Experiments

"The limitations of existing mouse models have led to a high failure rate for new drug development." Huatai Securities analyzed the crux of new drug research and development in the research report.

In the view of Huatai Securities, the existing mouse models play an important role in drug development, but the current success rate of drug development is still low. Specifically, most of the existing mouse models are inbred lines, and there is a high degree of consistency and genetic stability between individuals within the strain, which helps to reduce interfering variables but faces the problem of lack of genetic diversity.

In addition, existing models have undergone long-term artificial selection and differ from real-world mice. Therefore, preclinically effective drugs are likely to fail at the clinical stage due to the lack of ability to target diverse patients, especially in the "short board" of complex diseases such as neurological and psychiatric diseases, cardiovascular diseases, obesity, diabetes, and NASH.

How to develop a mouse that is both diverse and can be applied to drug discovery? Yaokang Bio believes that the answer to the question may be on a "wild mouse".

In general, wild mice survive in the natural environment, accumulate a large number of genetic mutations, and the genetic diversity is much higher than that of laboratory inbred mice, including single nucleotide polymorphisms, deletion and duplication of sequences, etc., so it has become an important means to enrich the gene pool of existing experimental animals, better carry out disease mechanism research and new drug research.

In this context, Yaokang Bio launched the "Real World Mouse" program, with genetically modified wild-type mice as one of the core, in an effort to create a mouse model that can restore the real world situation, improve the success rate of research and development, and then bring about a leapfrog increase in market demand.

However, the problem remains. Wild mice have problems such as unstable origin, microbial risks and difficulty in breeding, how to standardize the relevant mouse models to meet the standardization requirements of new drug research and development of models, which has become a major obstacle to the research and development of "real-world mice".

In this regard, Yaokang Bio chose to construct chromosome replacement lines (CSSs), and continuously mate and screen wild mice captured in the wild with inbred mice, and cultivated a new inbred line with only one chromosome that is different from the recipient inbred line. The company achieved a single chromosome inversion of 94.1% through a single Cre/loxp reorganization, with a length of 89.7Mb, which is the maximum length of a single inversion that is currently documented.

Taking the newly released 750 fat mound rats (full name of the strain: B6-Chr1YP1) as an example, the mice in this type of mice showed a spontaneous obesity phenotype after 8 weeks of age (non-high-fat diet induction), and the cholesterol level was significantly increased, and leptin and insulin were also significantly increased, showing a certain degree of leptin and insulin resistance. Compared with existing disease models (DIO, BKS-db, B6-ob), it is closer to the development of human obesity and can be applied to the study of metabolic diseases such as obesity, hyperlipidemia, and fatty liver.

Traditional obesity model mice often use genetic mutations or dietary induction, which are actually very rare in the population, and dietary induction also has the problem of large variability and long induction time. The 750 chubby rats in the "Real World Mice" program do not need dietary induction, introduce natural mutations, provide new resources for the analysis of new signaling pathways and disease mechanisms, and provide new model options for preclinical related drug evaluation, bringing new opportunities to reduce the difference between preclinical and clinical drug testing.

Creating a new industry standard for mouse models

In the process of the IPO of the Science and Technology Innovation Board, Yaokang Bio has also raised the plan to create a "real-world mouse" to a new strategic height. A portion of the proceeds from the listing will be used for the "Real-World Animal Model R&D and Transformation Platform Construction Project", with a total investment of more than RMB230 million.

"Animal models are the 'test tubes' of life science research and new drug development, and building appropriate animal models according to clinical and experimental needs can help people efficiently carry out basic research and various disease mechanism analysis." In the view of Yaokang Biology, in recent years, the research on complex diseases and symbiotic microorganisms has become a hot scientific research direction, which requires animal models to have higher simulation capabilities for the real world.

According to the plan, the "Real-world Animal Model R&D and Transformation Platform Construction Project" of Yaokang Bio will not only include wild-type mice, but also the research and development, preparation and supply of germ-free mice, and will prepare and supply a variety of sterile-grade genetically engineered mouse models, and the bacteria-induced bacteria group of naturalized mice, mycobacterial disease models and wild-type mouse disease models induced by specific microbiota will establish a real-world animal model resource library. At the same time, the corresponding symbiotic microbial research, and mouse custom breeding, functional pharmacodynamic analysis technology are also included in the company's grand strategy.

The ability to quickly open the "real-world mouse" program also stems from the accumulation of Yaokang Biology for many years.

According to the prospectus data, as of the first half of 2021, the company has accumulated about 20,000 kinds of commercialized mouse models with independent intellectual property rights, and the number of strain resources ranks at the forefront of the industry, with dual barriers of core technology and resource endowments.

Among them, in the field of basic scientific research and drug research and development, the most common gene knockout mouse, Yaokang Bio has established the world's largest gene knockout mouse strain library, and in 2019, a large-scale mouse coding gene total knockout program was carried out, aiming to pre-construct all more than 20,000 protein coding genes KO and CKO mouse strain libraries in mice.

In addition, in view of the problem that the target genes of humans and mice are often not homologous, genetically humanized mice are often used in the process of new drug development. Yaokang Has also developed a large and complete arsenal of humanized mouse strains at immune checkpoints over the past few years.

"Existing mouse models limit the efficiency of innovative drug development due to their single genetic background and large gap with real-world mice, while primates are not suitable for preclinical research due to ethical issues." The real-world mouse model of Yaokang Biology is expected to solve these two defects at the same time, solve the problem of inefficient development of existing drugs, and then occupy an absolute advantage in the whole industry chain of drug research and development. Huatai Securities predicted that "the company (Yaokang Biology) is expected to become a new industry standard setter in the future." ”

This article originated from Grand Gateway