Alphamab：grow with small and beauty, explore new R&D model
In the early morning of April 1st, a news was posted on Alphamab website and was quickly spread: Its blockbuster product recombinant humanized PD-L1 single domain antibody Fc fusion protein injection, KN035, was first administered in China for the first patient. So far, China's first PD-L1 monoclonal antibody officially entered the stage of clinical development.
PD-1/L1 antibody as a representative of tumor immunotherapy has become a new favorite in the pharmaceuticals. The latest U. S. ClinicalTrials.gov statistics show that more than 400 registered PD-1/L1 related clinical trials were conducted. More and more pharmaceutical companies are speeding up the layout and research. CEO Xu Ting did not expect such a fiery competition when he founded Alphamab 5 years ago.
KN035：the results of differentiation considerations
In 2011, BMS's CTAL4 antibody, Ipilimumab, achieved good clinical results on melanoma and was approved for listing. This product marks that the concept of tumor immunotherapy into the mainstream and immunological checkpoints is recognized. However, the side effects of Ipilimumab limit its use. Pharmaceutical and biotechnology companies represented by BMS and Merck have developed drug R&D for other immunological checkpoints, of which PD-1 / PD-L1 has become a hotspot.Xu Ting, who aims at the international market, is aware that PD-1/L1 may face strong competition at home and abroad in the future. "Conversely, assuming that our products are still doing clinical research, they already have similar products on the market, if we want to compete, we should consider the advantages and differentiation of the products.". Xu Ting recalled.
In the PD-1/L1 project approval, Alphamab made careful layout: Alphamab is based on single domain antibody , Dingfu biotarget (The oncology immunology company, CO-operated by Suzhou Alphamab and Professor Fu Yangxin )is screened with full human antibody yeast bank, cooperated with academy of Military Medical Sciences and the use of antibody synthesis library phage to display, cooperated with Zhongshan University to develop hybridoma experiments. It can be said that a number of pathways are in place to ensure excellent clinical candidates are obtained.
In 2013, BMS released two articles about PD-1 and PD-L1 large phase I clinical results, due to various reasons, finally, BMS chose PD-1 to develop. Xu Ting believed that BMS's decision will guide more domestic enterprises to follow the subsequent and make the same choice, so he decisively suspended the early PD-1 project, and then concentrate on PD-L1.
"Although there are some signs that PD-L1 is safer, it's not enough to support you to compete. In retrospect, whether it is PD-1 or PD-L1, the targets will be homogeneous, and the difference between the two drugs may not be too great." Xu Ting said. At the time, Xu Ting was very clear the FDA's high standards of IND declaration ,as well as clinical and commercial advantages when he decided to use PD-L1 as the company's first declaration project in the United States.
After comparing several candidates, Alphamab's R & D personnel found that the single domain antibody of camel has the following characteristics not only have small molecular weight, good stability and high activity, but also show low immunogenicity, low toxicity and strong penetrability to tumor tissues. Antibody morphology is only one aspect, and eventually it has to go back to the penetration of the product to the market.
"As we all know, many patients with cancer suffer from venous atrophy after repeated treatment, which suggests that PD-1/L1's intravenous administration requires some changes." Thus, Xu Ting took into account the subcutaneous administration. In addition, several varieties of precedents listed abroad proved that as the convenience of medication and the good compliance of patients, the products given by subcutaneous administration will be more likely to obtain market share after they are listed.
Alphamab CEO PhD. Xu Ting
However, the limitation of subcutaneous preparations can not exceed 2ml means that the drug concentration should be at least 150mg / ml, and high concentrations of subcutaneous preparation will lead to a series of problems like stability, high viscosity as well. Fortunately, these problems were eventually overcome by the Alphamab team, successfully achieved 200mg / ml, and created the highest concentration of biological drugs.
Together with 3DBiopharm
As there is no body data, FDA has a high initial clinical requirement, the declaration of KN035 in the United States is very difficult.
In 2015, Xu Ting learned that Gong Zhaolong, an old friend with 10 years' experience in the review of new FDA drugs in the United States joined 3DBiopharm soon, one concept he wanted to do is to develop drugs that were driven by precision. Integration of the advantages resources of two sides on class 1 new drug R&D. From precision medical to tumor function screening and achieve the desired effect, so as to rapidly promote the clinical application of KN035, which was the vision of cooperation at that time. On the basis of mutual trust and mutual benefit, the two sides will soon reach a joint development agreement on the follow-up study of KN035.
Before cooperation, KN035 had been Alphamab five years of independent research and development results, from project application, target selection, screening of antibodies to CMC. After signing the contract, 3DBiopharm led the global registration, clinical development and commercialization of the new drug, and Alphamab was responsible for the production of clinical samples at the development stage and the production of postmarketing drugs.
"Both Alphamab and 3DBiopharm asked the previous FDA reviewers to be scientific consultants. I am also very confident about the medicine." Xu Ting recalled. The two sides worked together to sort out all the information that were used for the KN035 clinical trial declaration, and it was declared in the United States and China respectively.
At the end of November last year, KN035 was allowed to carry out clinical research in the United states. It was a rare minority of IND that directly to the FDA to declare the first clinical development and was allowed to open clinical trials in the United States. At the end of December, after 8 months, KN035 received CFDA issued clinical trial approval.
At present, phase I clinical trials of KN035 in the United States and China are underway and are basically synchronous development. When asked whether the clinical trial data in China and the United States will influence each other, Xu Ting said, Alphamab and 3DBiopharm are also trying to communicate with the US FDA and the China CDE, trying to explore a new clinical research model. Especially, we hope to find a new way of data sharing in statistics, efficacy and indications.
In addition, the trend of tumor immune combination therapy is becoming more and more obvious. In the future, small molecules, other antibodies and even vaccines may be used in combination with PD-1/L1. Therefore, around the KN035, Xu Ting's next step is to study more advanced technology than the PD-1 / L1 .
"We hope to find a multifunctional molecule that will be made of a product, instead of PD-1/L1 antibody, as the first choice for any combination of drugs." Mentioned the future, Xu Ting began to look forward to.
KN015：Ideas has been sprouted for years
Like KN035, another product - recombinant human follicle stimulating hormone Fc fusion protein injection KN015, also entered the 1 phase of the clinical stage in the product layout of Alphamab bio drug. In fact, the layout of KN015 is far earlier than KN035. It can be said to be a seed buried in Xu Xu's heart for ten years.
The idea of developing long-acting FSH began in 2005. At that time, Xu Ting served as chief scientist of Switzerland Serono company(Later, the company was merged with German Merck to become Merck Serono).The t1/2 in the human body of company's flagship product FSH Gonal F was 35h, and the use cycle was 8~12 days. Once a day, the frequency of the drug gave Xu Ting the idea of improving the t1/2 of the product, but the idea was not approved by the company's leadership.
Two years later, Xu Ting resigned and went to the global biotechnology industry giant Biogen as a senior researcher. The same idea was put forward by him again, but he was still rejected. The reasons were not only technical difficulties, but also similar ideas had been tried, but they all end up with low activity and difficult medicine.
In addition, Elonva, the first long-acting FSH product through C-terminal fusion of CTP to extend the body t1/2 , did not achieve the desired transformation results as well. Later, the drug was bought by MSD and successfully listed. However, as its role time can only be maintained for 7 days, starting from the eighth day, you need to inject rhFSH every day, such as Gonal-F. Its increased complexity of drug use made its listing performance generally,and was refused to be listed by the United States FDA.
Even so, after a scientific analysis, Xu Ting still believed that the idea of a long-term FSH was worth trying, but it had been delayed by manpower and resources. In 2009, Xu Ting returned home to create the Suzhou Alphamab, a year later, the long effect FSH project was officially launched in Alphamab. "This is one of the differences between a big company and a small company. It takes a long time and a lot of difficulty to set up a project in a big company, but it is relatively easy for a small company, the action is unimpeded.”Xu Ting sighed with emotion.
The successful of preclinical challenge
It is not easy to transform FSH from short effect into long effect. How to change the normal FC fusion to the three component protein fusion is the first key point, and is also a patent point for KN015. Secondly, after the fusion, how to produce proteins, how to remove impurities, compared with the original protein, whether the fusion protein is changed in mechanism, pharmacological and pharmacological effects, are the challenges that Alphamab faces.
"The whole process involves a lot of new things. It's a challenging process." Xu Ting said. To this end, Alphamab and Fan Hengyu research team Zhejiang University launched in-depth cooperation. The research direction of the latter is the molecular regulation mechanism of animal ovarian function and the pathogenesis of ovarian related diseases. Later, both sides did a lot of research work at the cellular level and in vivo, and the results gave Xu great confidence.
Alphamab had applied for PCT/ China patent on KN015. In 2014, the Patent Office of China granted the official authorization. At the same time, it also declared clinical trials to the SFDA.
In January 2016, Alphamab and Fan Hengyu research group cooperation article
Was published in "Human Production", disclosed that the t1/2of KN015 in rats and cynomolgus monkeys is 10 times that of Gonal-F, and theoretically, the frequency of administration in the human body can be reached by using a single injection during the use cycle. The data also showed that the results of KN015 were equivalent or superior to Gonal-F in in vitro cAMP induction, in vitro blastocyst rupture, GVBD activity, in vivo biological activity, ovulation enhancement and safety . In September, KN015 acquired CFDA drug clinical trial document, and became Alphamab's first independent intellectual property rights of new drugs.
At present, the product is being prepared for the phase I clinical research at the First Affiliated Hospital of Jilin University. New mechanisms seem to have been discovered based on the study of fusion proteins. Xu Ting said the drug also participated in a basic research of “major R&D project “,further studies will be performed, and generalized to male indications.
In China, in the case of FSH market with Gonal-F and urine FSH of LiIVZON as the main source , the long acting FSH after transformation will have great clinical advantages in the market. IMS data showed that total sales of FSH related drugs in the domestic market in 2015 was 22 billion Yuan. However, in China, at present, the use of FSH was only about 1% in at least 20 million infertile women of childbearing age. With the release of the two child policy and the increasing incidence of infertility, the potential demand for long-term FSH will continue to expand.
Two new drugs, two experiences
The difference in clinical development speed between KN015 and KN035 reflects not only the enhancement of domestic capital, technology and R & D capability in the past 5 years, but also the change of new drugs understanding in drug reviews.
From the project application to the present, KN015 is almost accompanied by the growth of Alphamab. In the company, more than ten older employees,including "PhD Guo Kangping and Yun Lihong who do molecular purification, Yang Dong, Wu Jie who do the cell line earliest , Dong Yanrong who does the upstream process, Huang Yan who does the quality control analysis , PhD. Wang Pilin who does pharmacological are involved in the development process." Xu Ting counted the events of the past 8 years. The experience of KN035 and KN015 clinical declaration in china makes Xu Ting feel the bonus of drug trial system reform.
They are class 1 new drugs, with good safety and effectiveness .However, because of the great changes before and after the reform of CDE drug trials, the review rhythm is quite different. KN015 was set up in 2010 , declared in 2014 , approved in 2016 and it took two and a half years. KN035 was set up in 2012 , declared in April, 2016 , and was approved after 8 months. "This is also CDE changes in perceptions and reviews of new drugs before and after the reform," Xu Ting said.
Xu Ting's biggest feeling is that the transparency and openness of the two projects in the review phase are entirely different. During the KN035 declaration process, the CDE reviewers maintain good communication with the bidders. The review procedure, progress, and other information are open, and Xu Ting just met the new communication meeting in the CDE review work.
“In macromolecules, KN035 may be the first project to perform face-to-face meeting with the CDE clinical pharmacological department. Each have 7 or 8 people to participate in, in advance, the CDE reviewers have read our submitted information, at the meeting ,we also communicated fully about the KN035 declaration on the clinical trials. The two sides discussed the key issues in the clinical trial program, including the shortcomings put forward by the reviewer, business considerations , and ultimately formed a meeting summarize.”Xu Ting said. After the communication meeting, the problems associated with KN035 clinical trials were quickly resolved, which accelerated the approval document to obtain.
Exploring the appropriate development model
Among more than 460 high-tech R & D enterprises in Suzhou BioBAY. In 2009, Suzhou Alphamab founded by Xu Ting is one of the enterprises settled in the park earlier. In BioBAY, the growth methods of Suzhou Alphamab is different from CINDA ,which is committed to expanding the company's size ,Alphamab completes its industrial layout in the form of subsidiaries and branches.
“Generally speaking, for company, there are two growth models , one is to expand the company, and the other is to disperse and maintain the entrepreneurial status of small enterprises. we're also exploring which model is better for Alphamab.” Xu Ting said. The establishment of new companies such as DingFu Biotarget , SmartNuclide, Suzhou Alphamab, and Jilin Alphamab have their specific goals.
DingFu Biotarget set up in 2011is focus on tumor immunity ,R&D of the class1 new drugs, Xu Ting hopes the company will be able to focus on immunotherapy and make the best in the next 3 years.
In 2014, Jilin Alphamab was set up in Changchun, its orientation is to support the domestic market, at the same time, to realize the industrialization of Suzhou Alphamab, and some foreign varieties suitable for the Chinese market will also be introduced from abroad.
SmartNuclide found at the end of 2015 is engaging in accurate diagnosis and prognosis of tumor based on single domain antibodies molecular imaging techniques and metabolomics platform techniques.
Jiangsu Alphamab set up in 2016 is engaging in production, clinical development and industrialization, it complies with the highest international standards and is ready to participate in international competition.
Suzhou Alphamab is an open R&D institution, it also has a certain incubation effect. In the future, it may involve areas other than protein antibodies, such as cells and gene therapy, it also considers research and development for rare diseases.
These small companies have their own characteristics and independence, and the next step of growth is more dependent on spontaneity. In Xu Ting's view, they will be a good financing platform and listing platform in the future. Among them, Jiangsu Alphamab and Jilin Alphamab will be a very important link in the future, as well as provide an industrialization platform for other R & D companies(not only Suzhou Alphamab).