"Unlike the previous use of drugs to directly kill tumors, what Hui He wants to do is to regulate the immune cells well and let the immune cells help us treat the tumor." Dr. Huaxing Zhu, founder of Huihe Biologics, said.
In 2015, when biopharmaceutical companies were flocking towards generic drugs, the newly founded Huihe Biologics carried out proof-of-concept work with an obscure and modest attitude, trying to change the fundamental logic of tumor treatment and carry out biological innovation.
Now, 7 years later, Huihe Biotech has grown from a team of only 4 R&D personnel to a technology-based small and medium-sized enterprise. The idea of "conditioning cells" was also replaced by a more focused new concept of "creating an antibody drug version of cell therapy products".
At present, the first class 1 innovative drug CC312 (targeting CD19/CD3/CD28) for B-cell-associated tumors developed by Huihe Biopharma has been approved by FDA and NMPA, and is undergoing clinical phase I studies. CC312 is the world's first "dual signal activation" T cell adaptor triantibody drug targeting CD19, and it is also the third innovative drug in the world and the first in China to enter clinical research after the multinational pharmaceutical company Sanofi and Regeneron based on this mechanism.
After recently completing the A+ round of financing of nearly 100 million yuan, the company focusing on the development of new tumor immunotherapy macromolecular drugs is ready and is planning to move towards the next phased goal.
Image from left to right: COO Zeng Li, CTO Chen Li, founder Zhu Huaxing
01
Innovate at the biological level in a different way
Lang Jiaming, a well-known innovation expert in the mainland, once pointed out in "The Mystery of Innovation" that for innovation, methods are new worlds, and the most important thing is not knowledge, but ideas.
The innovation of Huihe Biotech is an innovation in ideas.
"Around 2015, the emergence of two drugs made people see the hope of tumor treatment, one is PD-1 and the other is CAR-T." The founder of Huihe Biotech told Zhang Tongshe that before these two immunotherapies were developed, most drugs to treat tumors could only prolong the survival of patients to a limited extent.
Different from previous therapies that focus on killing tumors, PD-1 and CAR-T themselves will not kill cancer cells, but activate the body's own immune cells through certain methods, and then use immune cells to destroy cancer cells.
The advent of these two new drugs has given Huihe Biotech the confidence to develop effective cancer treatment drugs, prompting the R&D team to continue to explore along the idea of "treating tumors with immune cells".
At that point in time, Huihe Biotech was officially incorporated and introduced the concept of "dual signal activation of immune cells". The company's English name is "CytoCares", which means "conditioning and taking care of cells", "I don't need to do anything to the tumor, I just need to take care of the 'police' in the human body and let them remove the tumor." ”
From 2015 to 2019, the R&D team of Huihe Biotech verified the correctness of its ideas and initially built the immune cell drug development platform, the T cell TriTETM platform, on which the PCC molecule of the drug CC312 was developed.
"The situation in 2019 is that any new drug you see has dozens of companies fast following, and the generic drug track basically has no chance, and it is too late not to make some innovative products at this time."
02
Take an unusual path and build a management team with complementary advantages
In 2019, at the critical moment when CC312 was about to enter preclinical research, Dr. Zhu, the founder of the company, invited Dr. Chen Li to join Huihe Biologics as CTO.
Dr. Chen Li has 20 years of experience in new drug research and development, and has worked in many new drug companies such as Changjiang Life Science (HK), Kangda Pharmaceutical (HK), and Xingmeng Biotech (TW).
"Dr. Zhu has a very active mind and does not like to take the usual path, and I appreciate what he does, and everyone hit it off." Dr. Chen Li bluntly said that she has previously participated in all aspects of drug research and development in many companies, involving drug discovery, CMC, early clinical research and clinical trials. "This cross-disciplinary experience is very helpful for R&D, I don't develop for R&D's sake, I often consider the drug under development through the user side."
At the beginning of Dr. Chen Li's joining, Huihe Biotech only had 4 R&D personnel, and later in the process of promoting the CC312 project, some recent graduates joined in, "There was a lot of pressure at that time, because it was necessary to quickly push CC312 to the clinical stage. ”
At that time, the fundraising environment in the biomedical industry was good, and companies that had just started and raised a small amount of financing were generally in a very unfavorable competitive position. In addition, Hui He Biotech does not pursue popular targets like most companies in the market, but tries to do biological innovation, and many links in the research and development process do not have established routines to follow.
However, Dr. Chen Li is still optimistic, "Most of the members of the R&D team are inexperienced, but they are smart, passionate and driven. It was not easy to grab talents at that time, and the existing members were selected and recruited little by little. ”
Under her leadership, Huihe Biologics completed preclinical research on CC312. In various animal model tests, CC312 has demonstrated a powerful effect of inhibiting tumor activity; In tumor model tests, the drug can completely clear the tumor. In addition to continuing to improve the T cell TriTETM platform and develop pipeline products for solid tumors, the R&D team also built the NK cell CCNKTM platform and the macrophage CCMφTM platform.
Due to the different characteristics of the three immune cells – T cells, NK cells and macrophages – the three platforms target different indications. The first pipeline of the TriTETM platform, CC312, is used to treat B-cell-associated tumors, and the follow-up R&D pipeline focuses on various solid tumors; The CCNKTM platform platform and CCMφTM platform are respectively for hematological tumors and solid tumors, and multiple pipelines of the two platforms have locked PCC molecules and established a complete intellectual property layout.
In 2021, Dr. Zeng Li joined Huihe Biologics as COO, and one of the management team members with rich investment and operation experience has worked for professional investment institutions and biopharmaceutical companies such as Fosun, Purun and GK Genomics. He is now responsible for the company's brand, operating system and team building, external business cooperation, and financial and financing management.
This year, another veteran of the biopharmaceutical industry, Mr. Huang Yingfeng, also joined Huihe Biopharma to take over the position of CEO. "The company has come to this day, and it needs a manager with a wide network of contacts to push it to the capital market and let Huihe move forward." The company's board of directors said.
Huang Yingfeng, CEO of Huihe Biotechnology
Before joining the company, Huang Yingfeng worked in Fudan Zhangjiang and Baochuan Biotechnology for many years, but now he has jumped from a team of more than 200 people to a team of more than 20 people. He told Zhang, "My most important starting point is the opportunity to succeed. ”
For Huang Yingfeng, the underlying logic of his career is to hope to put an innovative drug on the market through personal struggle and teamwork, and eventually put the company on the market. "Huihe's novel idea of developing drugs and the high technical content of the platform created are a disruptive innovation with great potential for success."
03
Disruptive innovation to create an antibody drug version of cell therapy products
In recent years, tumor immunotherapy has continued to be popular, and various drugs have emerged one after another. In the fierce competition, how can Huihe Biotech gain its foothold?
Huang Yingfeng said that through verification, Huihe Biotech's three major technology innovation platforms and existing pipelines have proved that it can be similar to, or even better than, cell therapy in efficacy and safety, and the side works of drugs can also be effectively controlled. On this basis, the price, accessibility, and delivery mode of the product CC312 will also be disruptively improved.
At the level of mechanism of action, Dr. Chen Li introduced that CC312 belongs to the T cell adaptor class of antibodies. Unlike many pharmaceutical companies, CC312 uses dual signals to activate T cells. "In addition to giving immune cells a major activation signal through target CD3, we also give a coactivation signal through target CD28, so that CC312 has a stronger ability to activate T cells and a stronger ability to induce its proliferation."
After the T cells are activated, CC312 grabs the tumor cells with "one hand" and the T cells with the "other hand", pulling the two within a certain range, so that the T cells release perforin-granzyme and cytokines to kill tumor cells. In addition, after drug treatment, a large proportion of T cells will differentiate into memory T cells, which has great potential in preventing tumor recurrence and prolonging survival without disease progression.
At present, globally, Sanofi and Regeneron are also using the same concept to make multi-specific antibodies, "but in China, the first to do this piece is us, this idea is very innovative." Dr. Chen Li explained that CD28 was once a high-risk target, and CD28 monoclonal antibody also faced a bleak development failure. After carefully studying the reasons for its failure, the R&D team of Huihe Biotech conducted various explorations on integrating the CD28 antibody domain in the design of the tertiary antibody before developing a product with technical content. ”
The R&D process was not all smooth sailing, and the team had encountered great difficulties in quality research and production process. "The dosage of CC312 is very low, so the concentration of the formulation product is also very low, and it does not achieve detection sensitivity for many quality analyses." In order to produce drugs, Dr. Chen Li led the team to make a large number of breakthroughs, which have now become the moat of the entire technology platform of Huihe Biologics.
In terms of administration method, unlike CAR-T, which needs to extract immune cells from the patient for in vitro culture, CAR transduction, cell expansion and a series of processes to be infused back to the patient, CC312 adopts a similar administration method to general antibody drugs, directly injecting a certain dose of the drug into the human body by intravenous infusion.
It is worth noting that the price of CC312, the "antibody drug version of the cell therapy product", is much lower than the price of the cell therapy drug CAR-T. "CAR-T therapy costs nearly one million a year, and the price of our products should be around several thousand yuan after they are launched, compared with the high cost of cell therapy, our products will not be a problem at the payment end of the market in the future," Huang Yingfeng pointed out, CAR-T needs customized treatment, and each patient has his own exclusive treatment plan; Antibody drugs can achieve mass production, and the commercialization potential is greater.
According to the plan, CC312 will take three years to complete clinical trials and enter the approval stage.
Regarding the future direction of the three major technology platforms of Huihe Biotechnology, Dr. Chen Li told Zhang Tongshe that the platforms can cooperate with each other to use the advantages of different types of immune cells to create some combination products, "Now everyone has a consensus, the treatment of tumors is definitely not a single drug can solve, combination products will be the main strategy for the treatment of tumors in the future."
04
And giant PK, do asset-light, small and beautiful enterprises
As an entrepreneurial team of less than 30 people, Huihe Biotech faces competitors from two pharmaceutical giants, Sanofi and Regenerative. How to PK with the giant and promote the product launch as soon as possible is a major problem faced by the company.
"Compared with the giants, Hui He started relatively early on the one hand, and the speed of the entire pipeline is comparable to theirs; On the other hand, the maturity of platform construction is relatively high, and IP protection is more perfect. "Why some breakthrough technologies are always produced in small biotech companies, because we only do this, because we are focused, so professional." ”
In terms of company construction, Huang Yingfeng has his own ideas, "For biotech companies, it does not make much sense to focus on developing new targets. We need to clarify our own boundaries, and companies are engaged in transformation, not mechanism research."
Only by understanding where the boundaries lie can the deliverability of the enterprise be guaranteed. "A company must have a concept of time, and all innovative product development must focus on innovation and differentiated value, as well as development cycle and timeline, otherwise when the project is delayed, internal employees and external investors will lose interest in you."
In addition, "do something, do something" is also one of the principles of Hui He Biologics' development. "The industrial ecology of Zhangjiang Biomedicine is very perfect, and many CRO and CDMO companies can help companies provide research and production services. Huihe only needs to achieve the ultimate in R&D innovation. ”
In the next three years, in addition to the completion of the key clinical trial of CC312, Huihe Bioplan's T cell TriTETM platform and NK cell CCNKTM platform each achieved a project to enter clinical phase II. In the next five years, all three platforms will have pipelines to clinical trials.
Before the listing node, Huang Yingfeng hopes that the company can maintain a team size of 50-60 people. "Biotech company should do the most cost-effective thing, and Huihe must be an asset-light, small and beautiful enterprise in the future."
Looking at the entire industry, the investment of biomedical related enterprises has been cold in the past two years, and Huihe Biotech will also face the challenge of "how to survive". In this regard, Huang Yingfeng said frankly, "'surviving' is only a result, and the deep logic is 'what do you rely on to survive'."
With years of experience in the industry, he believes that truly competitive biotech companies cannot be abandoned by the market, "We cannot influence industry policies, we cannot change the capital environment, what Hui He can do is to make a truly useful innovative drug on the basis of independent judgment, and if we can achieve this, we have no reason to be pessimistic." ”