Joint research on domestic innovative drugs of Zhongjin Medicinal Packaging Co., Ltd.
Based on China, facing the world, Suzhou Kintor Pharmaceuticals, Inc. is a research and development enterprise of innovative drugs focusing on curing major cancer fields. Pukru amine, as the main product of the company, is aimed at treating prostate cancer and triple negative breast cancer. Currently, Phase I clinical trial has been accomplished in China and Phase II clinical trial on prostate cancer has been launched. Phase I trial on breast cancer has been launched in China and it has gotten approval instructions. Phase I and Phase II trial have been launched coordinately in America. The company is a scarce one which has successfully got double approval instructions for double applications, whose clinical trial is conducted in America and China simultaneously. The management team of the company is led by two experts, Doctor Tong Youzhi and Doctor Guo Chuangxin who are from national “recruitment program of global experts” and have many years’ cooperation experience. Product pipeline is featured by independent research and development, complemented by external introduction. It was listed in New Third Board last year. It is predicted Phase III of indication and monoclonal antibody for prostate cancer, breast cancer will be accomplished or nearly accomplished in 2019, 2012, and it will own 4 products from Phase II and Phase I.
1 Its journey from America to Suzhou
Suzhou Kintor Pharmaceuticals, Inc. was founded in Suzhou Biobay in the year of 2009. The company was not the first batch founded in Biobay and the earliest ones were moved here from Zhangjiang during the year of 2006 and 2007. Our company was directly established after I returned home from America in the year of 2009. In a quite short term, it obtained project subsidy of “major new drug innovation” from national the 12th Five-Year Plan. In the year of 2012, the company confirmed the candidate drug and started all clinical preparation. At the beginning of 2014, it submitted the investigational new drug application to China Food and Drug Administration. In the year of 2015, it obtained the approval instructions and obtained the first round of financing from Bioventure during the period of waiting for the approval instructions. After it got the approval instructions, it received the second round of financing from HighLight Capital with RMB 15,000,000. Phase I was finished in the end of the last year and Phase II was launched. The year before last year, the approval instructions were issued in America. At present, it is at the new stage. It is predicted to have the better products development in the next two years.
2 Abundant and risk-balance product pipeline
4 trials of Pukru amineare conducted simultaneously in America and China. The product for prostate cancer in China is the fastest one and Phase II clinical trial was launched. Besides, AR drug externally used for curing alopecia, whelk has been reported to Jiangsu Food and Drug Administration and the clinical trial will be conducted in America and China soon. There are two mTOR and SMO inhibitors which will be declared clinic trial at the beginning of the next year and the clinical trial will be conducted firstly at home. Also, there is small molecular compound used for immunological therapy. In the next stage, it is predicted to research on 2-3 drugs within 5 years, 4 indications will be conducted Phase III clinical trial, declare NDA. The rest new products could be conducted clinical trial as soon as possible. Some drugs could be drug combination, such as, Pukru amine, mTOR inhibitor and others. We hope by the way of drug combination, it could become the optimal therapeutic method for prostate cancer, breast cancer and others disease fields. The follow-up product research and development will focus on the above two drugs for treating prostate cancer, breast cancer, liver cancer and other diseases and bring solutions to the advanced patients. Oncotherapy is the core of the whole product strategy. Pukru amine is the best in class project and alopecia product is the first in class project. As the innovative drug, it is expected to have 1-2 blockbuster products listed rapidly and then develop them independently and contribute the stable growth of the company.
At present, in the Biobay, except toxicology is outsourced, other molecular design, PK, CMC, safety evaluation and other aspects could be done independently by the company. The company is the fourth one that declares Class I new drug and the second one that obtains clinical trial approval instructions.
Pukru amine, mainly aims at prostate cancerIt mainly aims at prostate. Prevalence rate increase of prostate cancer in China is fairly fast and it is the third cancer with the fastest increase. In the worldwide scale, male morbidity of prostate cancer is the highest and death rate of it ranks the second place. In the year of 2016, the morbidity in Beijing was 22 persons /100,000, which rising to 40/100,000 soon and the average onset age is 70 year-old. It is predicted that the newly-added patients will reach 350,000 in 2020 and the potential market scale of RMB 15,000,000,000. Male morbidity of breast cancer is higher. Liver cancer is the featured cancer type in our country and the morbidity of it overseas is lower than that at home. At present, drugs for hepatitis B, hepatitis C are increasing and the morbidity of liver cancer may reduce in the future.
The drug of the company mainly aims at castration resistant prostate cancer (CRPC) and triple negative breast cancer (TNBC). Compared with the common cancer, survival time of prostate cancer is longer, among which 40% will become advanced CRPC. Due to the insufficiency of effective treatment, a large number of treatment need is not satisfied. The morbidity of triple negative breast cancer occupies 15% of the whole morbidity of breast cancer, but the insufficiency of the effective treatment, the death rate is higher. Such patients are badly in need of the new therapeutic method. The products of the company are to provide the therapeutic method for patients of such two groups. Pukru amine of the company belongs to the second generation of sex hormone receptor inhibitor. The first generation one has no effect on the advanced cancer and the second generation one exerts effect on the advanced cancer (targeting specificity is more obvious). The current competitive drug, enzalutamide may cause epilepsy and fatigue, Pukru amine has more advantages in drug activity, safety and mechanism. Enzalutamide was researched and developed by Medivation and it was at Phase II when we founded our company in 2009. After it was approved, within 3 years’ time, it ranked the eighth place in global anti-cancer drugs, the sales volume in the last year was approximately 3,000,000,000 US dollars and it is predicted to be ranked at the fourth or fifth place of global cancer drugs in the year of 2020. It is predicted the maximum sales volume of prostate cancer drug would reach 7,600,000,000 US dollars, if the breast cancer drugs are approved, the sales volume will be much greater. It was acquired by Pfizer at cash of 14,000,000,000 US dollars last year and its market prospect in the future is optimistic. Enzalutamide has not accessed to Chinese market at present and it may enter the Chinese market next year.
The indication of the drug has large extended space. Enzalutamide was approved when it was at the stage of chemotherapy, and then, used for chemotherapy, later, it was found to treat prostate at early stage. Now, its treatment on breast cancer takes effect. Average onset age of breast cancer is at the age of 50. After female postmenopause, its androgen expression increases and androgen is the factor for breast cancer worsen. Phase II clinic trial of enzalutamide has been finished in America, it is found that add OS into enzalutamide for treating breast cancer, the survival rate could be prolonged a dozen of months. It is an astounding effect and Phase III clinical trial is conducted. Our progress in prostate cancer may be slower than theirs, but our progress in breast cancer is faster than enzalutamide. They have no layout in breast cancer market in China.
KX826: External used medicines for curing androgen alopecia, whelk and diabetic foot
KX826 has inferior stability of internal use but the external use effect works well. 90% alopecia is caused by excessive androgen and external use could cure alopecia. Wound healing diabetic foot is also related to hormone. The medicine is being researched and developed, is not the same compound with Pukru amine.
Increase of dealing capacity after price fall is not up to expectation.
GT-0486: mTOR selective kinase inhibitor
The first generation of mTOR has been approved and mTOR inhibitor of the company belongs to the second generation which has effect on many solid tumors and could be a drug combination withPukru amine. The project is supported by national major new drug innovation.
GT-1710: Hedgehog/SMO inhibitor
It mainly aims at leukemia and matrix cell tumor and it is planned to declare clinic trial in China the next year.
Spare no effort to push the accomplishment of Pukru aminetrial in America and China. Besides, develop some projects that could be conducted clinical trial and construct the production base simultaneously.
Since the establishment, the company has obtained various kinds of funds from the nation, Jiangsu Province, Suzhou City surpasses RMB ten millions and is supported by major new drug innovation of the 13th Five-Year Plan, which means an endorsement to investors. It is paid much attention by the company.
At last, enzalutamide could bring the company value soaring rapidly. Medivation is a company for single drug. It started in 2004 and its market value was fairly low at 1-200,000,000 US dollars when we were involved in the product in 2009. It was approved in 2012 and acquired by Pfizer at cash with 14,000,000,000 US dollars in 2016. Its value soaring is striking. During the development process, we gave generous return to the previous investors. We hope, with the increase of appraisement, it could bring more sources to the company. However, innovative drug has higher risk and the investor should have professional view when investing.
Q: Could you introduce the detailed data comparison betweenPukru amine and enzalutamide? During the follow-up clinical trial, do you consider to make a head-to-head test to make me better effect, or what is the strategy?
A: In fact, to prove me-better is a process and it is difficult to say me-better will be done well at the beginning. In China, pharmacy is feasible only if it has no gap with others. Its promising prospect was one reason for choosing the project at that time. And the other reason was that it was conducted by university professors. The patent of small molecular compound has higher risk in auxiliary problem. If the patent is infringed, it is risky even be listed. Generally, a large-scale company will protect this field by integrating thousands of compounds and a small-scale company may have loophole in the patent which provides us with the free space.
Besides, enzalutamide has epileptic side-effect at the Phase II in 2009, but it was approved in America (morbidity is 2%, because the patients are mainly old people who drive seldom). Initially, we intended to research out a drug that has its own patent, with equal pharmacological function, but higher safety. We could compound nearly 200 compounds and find higher activity drugs. Polarity of drugs is transformed more higher and it is hard to access blood brain barrier. There is no induced epilepsy found on the dog test, thus, the effect and safety are much higher. Besides, at the aspect of mechanism, our drug could reduce gene expression while the failure reason for the first generation androgen receptor was the increase of gene expression, increase receptor. There is a drug for reducing ER approved in America, and ours is for reducing AR expression. Me-better is achieved on the animal test and whether it is successful on human body is uncertain, but it is promising.
Most often, medicine failure means the high threshold of the pre-existing medicine rather than it is not a patent medicine. If the pre-existing drug occupies the market, only the drug with better or equal pharmacological function could access market overseas. We may conduct head-to-head test in the future, but the cost we pay may greater. At present, the drug has not been approved in China, thus, it is exactly to say we conduct Phase III clinic trial rather than head-to-head test. If it is approved in America and it is likely to require conducting head-to-head test. However, enzalutamide is fairly expensive, 320 US dollars/day, 90,000 US dollars per year. If head-to-head test is conducted, the price for buying drug reaches RMB hundreds of millions. The cost is so high that we avoid it sometimes. Second-line drug may be adopted on the patient with chemotherapy failure. For 12 years, enzalutamide is conducted on the patient with chemotherapy failure and head-to-head test on chemotherapy has not been conducted, either. As for us, the current situation is different from that in 2012. The new drug could be approved only being tested for taking effect. However, American doctor will assess the drug strictly as per the indication.
Q: The main adverse drug reaction is epilepsy, what about ours?
A: Incidence rate of safety problem at Phase I is lower and the main side-effects are epilepsy and fatigue. However, in consideration of the shorter life of the advanced patients, it is hard to say the side-effect is caused by drug or progressive disease. As a whole, the overall adverse reaction of enzalutamide is less than that of abiraterone, which is depended on the effect at the Phase II, III. In China, at Phase I, a dozen of patients are tested and a dozen of patients in America. The main mode is 3+3 model, if the accident is happen to 3 patients, another 3 patients will be tested. The highest amount is tested without serious side-effect. At Phase II, our dosage is 100-300 mg.
Q：MTOR is conducted by many people, why select this target point?
A: mTOR/PI3K target point was selected in 2009. We selected two target points at that time, mainly the drugs of Phase II/III in America. Due to the limited fund, we reserved one project to test, that was mTOR. The drug was selected from more than 200 synthetic drugs and it has better safety. It is difficult for single drug to cure certain disease, and drug combination may be used for increasing pharmacological function. Frequent use of PI3K、PARP in enzalutamide may activate channels. Thus, mTOR may be not oriented on single drug, and it may be combined with Pukru amine. Also, IDO molecule may maximize activation by the way of drug combination.
Q: Do you have any strategy for the selecting drug variety in the future?
A: At present, the more advantages for innovative drug company are oriented by the existing products. It is to find a better way within the existing field. It may be not complex as the past. Druggability is the key factor before, because the druggability is related to its possibility of entering the market. With the development of the company, it has profound understanding on druggability and has more arrangement of druggability on disease fields, including license-in on some things.
Q: Pharmacological function of Pukru amine is better than that of the previous products, why?
A: The different binding rate of target points leads to the better pharmacological function.
Q: As for CRPC, what is the difference between the direct use of enzalutamide and use of docetaxel first, then, use of enzalutamide?
A: Enzalutamide has not been conducted head-to-head comparison with chemotherapy. Overseas drug enterprises are unwilling to make head-to-head comparison. Often, doctors may conduct head-to-head comparison within the small range and then publish articles to express attitudes. Chemotherapeutic drug has less threat on enzalutamide. The number of patients who are willing to receive chemotherapy is 20% of CRPC, exceeding 10% in China. The market share of targeted drugs is enormous. The doctor thinks, if the patient is young with poor economy income-it is suggested to receive chemotherapy; if the patient is old person with rich economy income- it is suggested to use abiraterone (it was approved last year in China and the sales volume was RMB 190,000,000 in the first year of China)
Q: Enzalutamide has more flexibility in clinical use, is there explicit range in clinic use overseas?
A: There is no uniform stipulation in oversea treatment. The patient has its own judgment on acceptance level and treatment effect.
Q: Could you introduce the data of Phase I? When does drug take effect?
A: Drug takes effect at the second group of Phase I and takes effect at the first group in America. At Phase I, it is prohibited to use drug for a long term in China; as for the patient at clinical stage, it is allowed to use drug until extinction of clinical benefit in America.
Q: How about the market prospect of triple negative breast cancer, compared with PD-1 product?
A: Triple negative breast cancer AR+ occupies 50%-70%, enzalutamide is used for 13-14 months at breast cancer OS. Patient may have more choices on drug use in the future. Our threshold on triple negative is lower than that of prostate cancer. The corresponding rate of triple negative chemotherapy is 10% which is fairly lower than 30% of CRPC, thus, the threshold of triple negative is much lower.
Q: At home, if one buys three pieces of abiraterone, another four pieces are for free, it costs RMB 17-180,000 annually. How about price fall and patient’s progressive measurement in the future?
A: The drug has much development space in China. Pharmaceutical chemical has low fabricating cost. Acceptance level of patients must be taken into consideration, even though, one buys three pieces of abiraterone, another four pieces are for free. Patients cannot afford it. The approval of abiraterone takes shorter time, but 509 is another situation and several enterprises at home are conducting it.
Q: Is there any change to the clinical speed under the big environment?
A: According to our experience, the approval of clinic trial in China takes longer time than that overseas, however, patients in China are extensive and the speed of entering the group is rapid. There are many problems in Chinese clinic. Many doctors make generic drug and have insufficient understanding and observation on new drugs. Chinese doctors are unwilling to take much time and energy on it. Overseas doctors have much higher enthusiasm for it. At present, the additional review in China exerts plenty of pressure on doctors virtually.