Entering the 21st century, tumor immunotherapy has made great progress, especially the highly anticipated

Entering the 21st century, tumor immunotherapy has made great progress, especially the highly anticipated  ‘epochal’ antibody drugs, which have gradually become the ‘contention point’ for pharmaceutical companies and the ‘hot trend’ for investment in new drug research and development.

In this regard, BioSeedin will prepare a two-day antibody drug research and development workshop for everyone in Zhangjiang, Shanghai from March 20^th to 21^st.  The workshop was fortunate to invite Dr. Zhu Xiangyang, chief executive officer of Shanghai Huaota Biopharmaceutical Co., Ltd., as a guest speaker. Dr. Zhu Xiangyang will focus on the discovery, drug development and project establishment of antibody drug targets for autoimmune diseases, including the road to the market of the monoclonal antibody Skyrizi led and developed by Dr. Zhu when working at Boehringer Ingelheim (the information was never revealed domestically).

Prior to this, Dr. Zhu was invited to an exclusive interview with us, BioSeedin, and brought everyone a rare "pharmaceutical experience" for decades.

Huaota Dr. Zhu Xiangyang

CEO of Shanghai Huaota Biopharmaceutical Co., Ltd, CEO of Huabo Biopharm (Shanghai) Co., Ltd. Dr. Zhu obtained his PhD in microbiology and immunology from the University of Illinois at Chicago (UIC), and has more than 20 years of experience in in antibody drug discovery, process development, and manufacture facility construction. Dr. Zhu has extensive experience especially in the field of monoclonal antibody screening and identification, bispecific antibody engineering transformation, cell line establishment,  technology transfer, pilot plant design and construction, etc. Before join Huahai Biopharmaceuticals, Dr. Zhu worked at Boehringer Ingelheim (BI) for more than 8 years in different function areas at multiple locations, he led and engaged in over 20 global BI biological research projects, including the marketed abroad monoclonal antibody drug Skyrizi (risankizumab) that targets interleukin IL-23 and is used to treat moderate to severe plaque psoriasis in adults, as well as other ongoing projects currently in clinical phase II and phase III.

The Four Secrets of Making Medicine Successful

‘I have participated in the research and development of more than 20 projects in the United States, but very few can reach the end and become medicines. Among them, Skyrizi, which mainly developed and led by BI, is one of the few drugs that can be called can be called best in class. BI later sold the drug to AbbVie and reached $1.5 billion revenue in 2020. After all those years, personally I think that developing medicine is actually a very long process, professionals in pharmaceutical industry must endure loneliness and do things down-to-earth.’ Dr. Zhu said this in an interview. Afterwards, Dr. Zhu shared the four most critical and important success secrets:

1. Clearly Determining the Project

In the process of project selection, you must have your own clear guiding ideology. Once the project is established, the screening of early candidate molecules is a very important process. During this process, in addition to selecting the appropriate target, factors such as the efficacy, safety, and manufacturing of the candidate molecule must also be considered carefully.

In addition, many domestic companies are doing what so called ‘fast follow on’, therefore, we use existing drugs as benchmarks (for example, in the molecular physical and chemical characterization of drugs, biological activity, immunological properties, etc.), only when you find a better candidate than the benchmark, will you decide to move on. Otherwise, once the project is set up and moved forward, it will probably need to be invested ￥50 million to get to the IND declaration stage. If it is to be clinically listed, it may cost more than ￥1 billion, and sponsors may bear great risks in the later periods.

2. Choice Between Advance and Retreat

A product will encounter all aspects of problems from R&D to market, so the choice of advancement or retreat is critical. At this time, as decision-maker, you must clearly know whether these difficulties or problems are the fundamental problems hindering the development of this drug. If it is the case, stop the loss in time, if not, think about how to solve the problems.

3. Find and Solve Problems in Time

If you find a problem, you must solve it as soon as possible. Don't leave the problem that can be solved now until later processing. Because it may only need 10,000 or 100,000 yuan to solve the problem in the early stage, but in the later stages, it may need cost ￥100 million. Secondly, if you procrastinate, it will be a huge waste of time. Time and cost are essential for both companies and individuals.

4. Never Approach Quality Issues with Ambiguous Attitudes

Quality issues run through the entire project development process; therefore we must deal them without any ambiguity. In many cases, some small quality problems may feel negligible at first. If you ignore them, this small problem may lead to new problems, and the accumulation may become a very big problem which is difficult to solve. Eventually the project could not go on in terms of craftsmanship or other aspects, forcing the entire project to end in failure.

Since its establishment, Huaota has mainly focused on the research and development of new drugs in the field of autoimmune diseases (systemic lupus erythematosus, rheumatoid arthritis, ulcerative colitis, psoriasis, etc.) and tumor cancer. In this interview, Dr. Zhu also shared the R&D progress and personal opinions of companies in this field.

· In the field of autoimmune diseases, what new targets are worth studying?

Dr. Zhu: In the area of autoimmune diseases, what everyone is doing now is the interleukin (such as IL-17, IL-23, etc.), TNF, B cell and T cell depletion targets, etc. In terms of selecting new targets, Dr. Zhan Yifan, Vice President of new drug R&D of Huaota, will analyze in detail in this workshop.

· How to treat the role of JAK family in the field of autoimmune diseases?

Dr. Zhu: JAK is a kinase in the cell, mainly involved in the regulation of autoimmune diseases. Like this kind of molecule, it must be a small molecule drug that is chemically synthesized before it can penetrate into the cell and exert its inhibitory effect. The research history of this type of target is relatively long now, and 8 different drug molecules have been marketed. Relatively speaking, this kind of small molecule drugs has its own advantages, for example, it can be made into tablets, which is more convenient for patients to administer; and because its manufacturing process is much simpler than that of macromolecules, the price will be cheaper than that of macromolecular drugs. At the same time, I personally think that if it can be combined with macromolecules, it may have a better therapeutic effect.

· In the field of autoimmune diseases, what challenges or opportunities are antibody drugs currently facing?

Dr. Zhu: I personally think that the main challenges and opportunities are as follows:

1. Low complete cure rate. Autoimmune disease is a chronic, long-term disease. Once the patient stops taking the medicine, his symptoms will relapse immediately. It is hard to say that there is a certain medicine that can completely cure the disease.

2. Resistance. Nowadays, after many antibody drugs have been used for a period of time, the body will have anti-drug antibodies. These anti-drug antibodies will offset the efficacy of the drug. Therefore, many patients must change medicine after taking adalimumab for one to two years. Moreover, physicians also need enough choice space to change medicines for patients, which also explains why there are so many varieties of medicines abroad (Adalimumab, Remicade, etc.) that can be sold for more than $5 billion.

3. Long half-life. I personally think that antibody drugs still have obvious advantages over small molecules, because their half-life is relatively long, about 1-3 months. This will greatly improve the psychological and spiritual aspects of patients. If the patient needs to take medicine every day, it seems to remind him that he is a patient all the time. If he takes the medicine only once every 3 months, the patient will think that he is a normal person psychologically.

4. The mechanism of the disease is unclear. In fact, the pathogenesis of many immune diseases is still unclear, such as systemic lupus erythematosus, pulmonary fibrosis, multiple sclerosis (MS), etc. Because the signal transduction system in our body is very complicated, just like a river. After you block one, the adjacent tributaries will be split up instantaneously. Therefore, there is still a long way to go in the mechanism research of chronic diseases. Although in many cases there is no good theoretical basis for the time being, some companies have also made better drugs through reasonable clinical trial designs. As a double-edged sword, the unclear mechanism of action itself also brings new opportunities to everyone. If you have the confidence to challenge these unknown areas, and if you do it well, you may develop a major first in class drug.

5. There is still a lot of room for development in the domestic market. The domestic market for antibody drugs in the field of autoimmune diseases can be said to have not been opened at all. First, because the production process of macromolecular drugs is usually relatively high, the market price will not be too low if launched. Secondly, domestic macromolecular drugs have already started in the field of tumor and cancer diseases. PD-1 drugs have been included in the medical insurance, but it has basically not developed in chronic diseases, and the medical insurance of PD-1 drugs in chronic diseases has not yet been included. For example, Adalimumab has reached $20 billion in sales abroad, while domestic sales are still at the level of ￥2-￥3 billion. Therefore, I believe that with the improvement of people’s quality of life, especially the younger generation’s pursuit of a better life, coupled with the improvement of future medical insurance levels, there is still much room for development in this field.

· It is said that your company has many new drug research and development plans to advance clinical practice this year. Would you mind sharing the company's current drug research and development progress?

Dr. Zhu: I joined Huahai in 2014 and started to formally develop new drugs in 2015. The first project in the field of self-immunization is the monoclonal antibody drug HB0017 targeting interleukin 17 (IL-17R) for the treatment of patients with psoriasis. At present, this project has completed the enrollment of all patients in phase I abroad and is preparing for phase II. The next one is the monoclonal antibody against interleukin 36 (IL-36R), which is used to treat pustular psoriasis. At present, there is no effective drug to treat pustular psoriasis in the world. We are the first in China to study the monoclonal antibody targeting IL-36R, we are in a leading position. Two foreign companies are conducting phase II clinical trials for this target. In addition, we have also deployed a dual anti-IL-36R/IL-17R drug, which is indicated for systemic lupus erythematosus.

· What new plans does your company have in 2021?

Dr. Zhu: Our top priority this year is to complete Series A financing. Huaota is currently a wholly owned subsidiary of Huahai. However, considering that Huaota has seven or eight projects that have reached the clinical trial stage, and the investment in R&D and clinical research has been increasing every year, this is a relatively large burden for the parent company. At the same time, we are a large-molecule innovative drug company. Innovative drugs themselves have many risks. Therefore, the company decided to split the financing, hoping the addition of capital can make our projects move faster to enter clinical trials and enter the markets. In the clinical trials area, our first bispecific drug HB0025 (PD-L1/VEGF) has completed the first patient in in the United States. In addition, the CD137 project is now in the trial phase I, and we may continue to apply 4-5 projects for IND this year.

Shanghai Huaota Biopharmaceutical Co., Ltd.

Shanghai Huaota Biopharmaceutical Co., Ltd. (aka ‘Huaota’) was established in September 2013. Huaota is a subsidiary of Zhejiang Huahai Pharmaceutical Co., Ltd. Huaota is dedicated to developing high quality biological drugs for global market to meet the demand of availability and affordability for high-end biological products for global patients.

Based on innovation and development, Huaota adopts the world's leading biopharmaceutical production technology and manufacturing equipment, strive to build a production line that meets the GMP standards of NMPA, US FDA, EU EMA. The company now possesses 200L and 1000L disposable bioreactors, as well as advanced waterless filling production lines including prefilled needle filling.

The company has established a biological drug development and production team with international advanced level, led by Dr. Zhu Xiangyang, organizing and striving, progressing with passion.

Huaota is a growing biopharmaceutical research and development company dedicated to designing, optimizing and continuously innovating tumor therapies to improve the living standards of patients. The company uses genetic engineering technology and dual-target platform technology with independent intellectual property rights to develop multifunctional antibodies and recombinant protein drugs for tumors and autoimmune diseases. The company strives to create a benign competitive environment of joy, mutual influence and mutual supervision. Make employees understand that what they are doing and working hard to create are new drugs that can change the world.