Joint research on domestic innovative drugs of Zhongjin Medicinal Packaging Co., Ltd.
The company was founded in April, 2009 after I returned home after abroad. “Ning” was written as “coagulation” of blood coagulation, because we focused on the recombinant blood coagulation factor at that time. At first, we researched on recombinant VIII factor and VII factor, due to unsuccessful financing, VIII factor was transferred to Chia Tai Tianqing which was the first major breakthrough in its true sense in China. After transferred, we formed a new drug biosimilar system. There was no blood coagulation factor any longer and its name was changed correspondingly. At present, Alphamab is a system. There are approximate 120 staff doing research and development in Suzhou; some dozens of staff are doing research and development on internal secretion, related reproductive system, external fertilization, ovulation induction and other aspects in Jilin, the industrialization base has been basically built; here, I’m emphatically introducing Alphamab to you, of which the main body used for financing and being listed reaches 80 mu. Also the video company is subordinated to it. Due to the insufficient accuracy and time for immunohistochemical detection used for expression of PD-1/PD-L1, the company was founded in 2015. The first project shall be declared clinic trial this year.
Our featured product for infertility is follicle-stimulating hormone. Male infertility and implantation rate shall be involved in the follow-up research. Our research on such aspect is related to our background. Besides, morbidity of infertility in China is 17%, which is higher than that of diabetes and hepatitis B. Under the background of an aging population, reproductive health problem will be a big issue in the future if it is not solved. National Health and Family Planning Commission of the People’s Republic of China referred to the maximum priority. Moreover, the field basically has no rivals in world-wide scale.
The following one is coagulation and anti-coagulation. It was my initial intention after return home from abroad. It was interrupted for insufficient capital. At the period of 2009, there was no investor to invest the new drug. The field is in the process of deep research now. Recently, Roche has made the ground-breaking SE910, that is, antibody is used to substitute blood coagulation factor. We have researched in this aspect from 2012, it is predicted to conduct clinic trial recently. It is a bran-new mechanism. After the research on coagulation is accomplished, research on anti-coagulation shall be conducted. Warfarin and others are still being applied, but hemorrhage may be caused. Among coagulation pathway, there is partial inhibitor which could reduce thrombus without hermorrhage.
Metabolites are mainly diabetes. In consideration of the centenary changes of insulin, the development prospect of GLP-1 is promising. We will cooperate with some small-scale companies of America in the aspect of hyperlipidemia, also, including damp, dry macula lutea of ophthalmology.
Research and development ability of Alphamab mainly focuses on early screening and engineering. Simple research on antibody may look bleak with limited target points, in return, if antibody is regarded as a kind of albumen with better drug properties, many poor druggability shall be improved through engineering approaches, thus, the space will enlarge. It is no doubt that our quality evaluation system is world-class. So far, about one third of the domestic biosimilars approved by instructions are originally researched by us. We have our own pilot-plant production and cooperation. Phase II could be achieved entirely. As a whole, a great deal of pipelines, 90% biosimilars under research are transferred.
It is a thorny problem for us to achieve first-in class, but best- in class could be accomplished. Take an example of PD-1, it is done by a large number of enterprises, however, such target point would have no sense, if there were no difference in early technology design. We will avoid it to the greatest extent.
As for Best- in class, the listed one and PD-1 under research in China are special in its own way. Whereas, it is difficult to do the best and to possess the own technology platform is indispensable. Technology platform patent is totally different from the drug patent. It took us enormous energy to do antibody engineering and protein engineering platform in previous years. To possess the technology platform patent means to monopolize a block of space. In a short term, our double-antibody platform obtained the patent licensing in Europe and America, as was expected and the patent protection is formed in several years.
Our representative product pipeline will be mentioned later on, 1-2 ones will be transferred annually and 2-3 INDs will be declared and all INDs will be global in the future. In my opinion, European and American market is 10 times larger than that of China within 10 years. If the new drug doesn’t be marketed in European and American market, its value will be less.
It is predicted to be listed in September and October. The planned volume is annual value of production of RMB 15,000,000,000. In 2015, we obtained a plot of land in Biobay and it will be used for industrialization. It is predicted to commence in September and come into use in 2019. Based on the research and development pipeline of Alphamab, the modernized pharmaceutical enterprise with the integration of development, manufacturer and sales will be formed. It is planned to input 5 innovative drugs and the company scale will reach 200 staff in 2019, in theory.
There are several industrialization projects, including research on tumour or internal secretion field at early stage. KN035 is PD-L1, and it is a global clinic of China, Japan and America; CTLA-4 is biosimilar, declare a new indication as RA; HER2 double-antibody has promising prospect which obtains major special project support with and PD-L1; in my opinion, KN046 is most likely to be the massive variety, difunctional antibody, block two check points. The details will be described later.
Enormous input is invested on PD-L1 monoclonal antibody which got project approval in 2011. It took a long time to make differentiation. A great deal of molecules was tested. We were overwhelmed by the leading place of Merck and BMS in PD-1, thus, we started to research PD-L. We did experiment on mice, human and camels and molecule KN035 was found in the experiment on camel at last. It was an exciting moment for us and the result was published in Cell Discovery. The molecule has many intellectual property protections and a dozen of patents will be constituted.
Which is the better one, PD-1 or PD-L1? Is it better to have Fc function? It is a controversy. PD-L1 not only has tumour cell expression, but also has immune cell expression. It is unclear biologically. Immune of tumour is at the initial stage and there may be different development strategies and different results. Our obvious differentiation lies in the convenience of use and it is the first and the unique subcutaneous injection preparation in the world. At present, intravenous injection is oriented. The impatient beds of large-scale hospitals in Europe and America are in tight demand. If subcutaneous injection is available, it will be much more convenient. Take an example of IL-6, subcutaneous is listed three years after intravenous injection listed, but it takes up half of the market share in a short period. Roche has developed subcutaneous injection preparation of trastuzumab and others, and it got approved instructions of Europe and America. But there is difference, because it needs a pump to push injection. Such strategy and biosimilar be produced in the market will form different advantages.
We selected this molecule after verified the target point and its safety and other aspects. Other molecule weight is only half of the common molecule weight, and subcutaneous injection is adopted, thus, the speed entering solid tumor is fairly fast. It takes effect in no time. In general, it could take effect within 2-3 weeks. It is important to the patients with advanced tumor. Moreover, it has high safety. The critical factor is that subcutaneous injection is much safer than intravenous injection. Subcutaneous injection has higher tolerance to impurities and the concentration peak is lower, stable state is quickly to achieve. In the process of intravenous injection of PD-1/PD-L1, the moment when dropping liquid entering, high concentration is reached which has great impact on immune system.
The reason for cooperation with 3DBiopharm was that our clinic hadn’t built up and we were intended to make the above mentioned levels more accurate. It is necessary for our cooperation. In January, 2016, it was launched and the contract was signed. In March, IND was declared in China and was declared in America in August. Later, we intended to get approval instructions of Japan, it was difficult for us, but we got it successfully and the current progress goes smoothly.
It is done by using double-antibody platform and reconstructing light chain. The structure was published in Oncotarget in 2017, with a series of patent protections.
HER2 locus is a breakthrough in breast cancer expression. Response rate of trastuzumab is higher, but relapse may occur. Genetech made two molecules at that time, one was Herceptin, a dozen of enterprises are declaring biosimilars at present, and the other was Perjeta which combined the different positions on HER2. The combination effect of the drugs is good. After Perjeta came into the market, its sales volume broke through 2,000,000,000 US dollars in a short time. Compared with antibody cross-linking drug, TDM1, it was approved one year earlier, but the sale volume was not up to 1,000,000,000 US dollars till now. HER2 has potential market and it is predicted that the two drugs will break through 14,000,000,000 US dollars in the future.
Our 026 has two locus expressions by one antibody. It gets patent and has good effect, as was expected. By in vitro screening, it is easy to turn into clinical effect. The effect of equal 026 is better than the combination of the both. If only trastuzumab biosimilar and Perjeta as well as Roche subcutaneous preparation are in the market in future, it is predicted that the drug will occupy 1/4 market share, because its effect is better. It is planned that in July, IND will be declared in China; declared in America in October and Phase II will be finished in 2020.
It is few in number that is kept by us, but it hasn’t be approved in China. Due to the production capacity, the drug of BMS will not be under expanded production and its production difficulty is greater. Sales of BMS have exceeded 2,000,000,000 US dollars.
The drug is featured by the complex posttranslational modification and it is closely related to half-life period in the human body. There are nearly 900 patents of Squibb, and to solve posttranslational modification is to solve pharmacodynamic relational degree. The molecule is kept by us. One reason is that the technology is difficult and it takes much time. So to speak, it epitomizes all biosimilars we researched. The other reason is that follicle-stimulating hormone. Original drug has many peaks and it needs to adjust technology to be in full accord. I think there is no one willing to compete with us within 3 threes, because the difficulty is unparallel.
It is our leading project and it is the only one likely to reach 1,000,000,000 US dollars in European and American market, because it is the First- in class. Its targeted two immune check points are PD1/PDL1 and CTLA4. As is known to us, the combination aimed at PD1/PDL1 and CTLA4 from large-scale enterprises is no less than hundreds. And its effect on lung cancer and other adaptation diseases is good. But the issue is that the tolerance of CTLA4 antibody is fairly poor, most of them are at 4-5 class AE, thus, BMS may be made by intermittent administration. We place the side effect in the first place and we conduct in-depth engineering. Firstly, it is easy to manufacture the antibody, with good druggability. Secondly, there is no side-effect under the condition of 100 mg/kg on the experiment on the monkey. By comparison, the side effects of BMS Ipilimumab appear under the condition of 50 mg/kg. How about pharmacological function? We made double humanized mouse model by CRISPER and the dosage for taking effect is 0.3 mg/kg which could help tumor regression. It is predicted to declare clinic in China in January the next year. At present, its effect is good and it may be effective to lung cancer and other solid tumors.
Q: Foreign companies have strict PD-L1 patent protection, and we conduct global clinic trial, how to avoid the patent disputes in the future? Except for administration dosage form, is there any distinction from Roche products?
A: Our product is single-domain antibody, and Roche product is Fc fusion protein. In fact, the patent disputes between Merck and BMS are not as what we think. The both cooperated and formed the market share, after Merck made concession. The discovery of PD-L1 is earlier than that of PD-1, but the patent of PD-1 is clear. As for the patent of antibody epitope, there is no dispute at all, Roche knows nothing about the locus, but we clearly know the high resolution structure. PD-L1 of other enterprises may infringe our patent.
Q: Double antibody is conducted abroad a few years ago, and it seems there is no solid tumor breakthrough. Many enterprises at home are intended to reseach on it. What is the difficulty?
A: Double antibody is a platform technology at present. The most difficult thing lies in amplified manufacturer and quality control of CMC. The project we declared this year has been researched for 5 years by CMC, thus, a great many of double antibodies stay on platform technology layer. The listed ones are simply combined antibody fragments, short half-life period. T-cell engaged, is useful to blood tumor. HER2 under research by us is breakthrough aimed at the same target point. However, we should understand, double antibody made into one molecule will have advantage only when two combinations producing 1+1＞2. The situation is scarce. It is an obvious phenomenon to simultaneously conduct the recognition of tumor cell and the recognition of T cell. Other aspects are unavailable at present.
Q: How about production status?
A: Two bases will produce and the current scale is 3,500 L. After the accomplishment of Phase I project, 12,000 L shall be excessive, and it is the same as Phase II. It is depended on the development situation of the product.
Q: What kind of strategy of GLP-1, injection or oral administration?
A: The project has been conducted for nearly 5 years and its target is higher. Injection is preference, as for diabetes, oral medication may bring much uncertain factors. Our initial goal was to make the in-depth reconstruction and it is promising from the current situation, but the project is in progress. If the final achievement fails to realize, we will do twice week a time which has been realized at present, it is the best one in the world.
Q: How to reconstruct the long-acting effect of GLP-1?
A: We haven’t applied for the patent for this, not only fusion protein, it is an all-around transformation.
Q: How to judge the proper proportion of double antibody in PD1 and CTLA-4?
A: Firstly, trial and error is necessary. There is plenty of possible proportion, affinity is one aspect to be taken into consideration for the choice, besides, antibody is not the same as small molecule that has accurate dosage range, thus, it has a wider range of tolerance and there is much space for the adjustable range. The molecule is ready and its pharmacological function will be tested on the mouse.
Q: How to build technology platform patent?
A: For example, if an antibody mixture is intended to apply for, cell strain must be transformed. How to transform it from 1 stable cell strain to 2 antibodies? The concept is just like that in our patent. Two antibodies could be produced from one stable cell strain and the manufacturability and other aspects of two antibodies have reached the level of single antibody. The patent includes the top-bottom concept to the specific implementation scheme. If antibody A and antibody B is produced separately and then mixed, it has nothing to do with us. However, if two antibodies are produced from one cell strain, it will infringe our patent protection range, that is combo, the proportion could be adjusted in the technology.
Q: What is the advantage between this technology and that of separate production, then mix?
A: Yeah, its advantage is production efficiency, big difference. Separate production means different production process, from the aspect of GMP, the mixture of the both is another set of technology. In the declaration, if C is produced by the mixture of A and B, the supervisor will demand to conduct A, B and C separately. In simple integral process, if stable mixture is declared, there is no deviation risk of mixture.
Q: There are many combination of PD-L1 double antibody or Combo target point, what is the selection strategy?
A: It is difficult, because there is no stable model to measure it. At present, we use heterozygote of antibody protein to change microenvironment. At present, although there are more than 800 clinical combination of PD-1/PD-L, there are basically random.
Q: Currently, the dosage of PD-1 is much higher than that of PD-L1, is there any difference between PD-L1 subcutaneous injection and intravenous injection?
A: It is about 150 mg, at most 300 mg which is almost the same with PD-1, because the functionality of antibody is fairly strong, with high availability, longer staying time in tumor and small molecule. Concentration distribution of subcutaneous injection is different, with longer half-life period.
Q: Cell line of PD-L1 uses the developed ones, whether the subcutaneous injection could be realized?
A: In theory, it is feasible. The earlier one than ours is in Europe which could be approved soon. It is at the Phase II, a kind of orphan drug. Firstly, an orphan drug indication will be declared for approval in America. By subcutaneous injection, it will push to the lung cancer and other second line pharmacy. At home, if it is directly used for first line liver cancer, it is inevitable to conduct head-to-head comparison with Sorafenib, except our safety is higher than theirs.