Donafinil in the first-line treatment of advanced HCC stage III

Original: Xiangdong On the first day of 2020, Suzhou Zejing biopharmaceutical Co., Ltd announced a big news It announced the success of donafenib in the phase III clinical study (trial code zgdh3) of the first-line treatment of advanced liver cancer According to the information on Zejing pharmaceutical's official website, Zejing pharmaceutical will publish detailed data on this research at the international and domestic clinical tumor academic conference in 2020, and there are only the following relatively simple information disclosures at present: ● the phase III registered clinical study of donafinil in the first-line treatment of advanced HCC met the pre-set primary endpoint and statistical requirements; The total survival time (OS) of patients in the donafinil group was significantly longer than that in the sorafenil control group, which had important scientific significance and clinical value; ● donafinil treatment has better safety and patient tolerance Sorafenib is a multi kinase inhibitor targeting Raf-1, VEGFR, PDGFR, etc it is currently mainly used to treat advanced renal cell carcinoma, advanced liver cell carcinoma and local recurrent or metastatic, gradually differentiated thyroid carcinoma which is no longer effective for radioiodine therapy Before that, several drugs, including opdivo (nivolumab), had challenged sorafenib's dominant position in the field of advanced liver cancer treatment in the head-to-head PK, but all ended in failure The success of donafinib had to be surprising According to the information disclosed on Zejing pharmaceutical's official website, donafinil will submit a new drug listing application at the beginning of 2020 As solafinil's Chinese compound patent will expire in 2020, a number of domestic generic pharmaceutical enterprises have completed be and applied for listing The success of donafinil is a big blow to these enterprises After the listing of solafinil, in addition to facing the original research of solafinil It will also face the strong impact of donafini It is worth mentioning that donafini and solafeni have a profound relationship Donafinil is a deuterium derivative of sorafenil, which is a deuterium derivative (- CD3) obtained by substituting deuterium (d) for hydrogen (H) of methyl (- CH3) on sorafenilamide bond The reason why the safety data is improved this time should be that the introduction of deuterium (d) reduces the metabolism rate of drug molecules in the body so that the dosage is relatively reduced (in zgdh3 test, the dosage of donafinil is 400mg / day, while that of sorafenil is 800mg / day) Since the concept of deuterium drug was put forward, around the wonderful conversion between hydrogen (H) and deuterium (d), the improvement of the effectiveness and safety of deuterium drug compared with non deuterium drug has always inspired the exploration of drug scientists in this field The advantages of the first FDA approved deuterium drug, deuterium butylbenzazine, compared with butylbenzazine, and the improvement of the survival benefits and safety of donafinil compared with solafeni in the head-to-head test indicate that deuterium drug may have advantages in effectiveness and safety compared with non deuterium drug The previous article "Teva deuterium butylbenzazine application for China NDA foreign deuterium research and development trends" has introduced the recent foreign deuterium research and development trends So, what is the progress of domestic pharmaceutical enterprises in this field? This paper introduces the development of deuterium drugs in China Compared with foreign countries, domestic research on Deuterium drugs is relatively lagging behind in innovation, but some representative enterprises have made great progress in the field of deuterium drugs, including Zejing pharmaceutical, Haichuang pharmaceutical, taijihongnuo, Zhengda Tianqing, etc Table 1 Danafinil of Zejing pharmaceutical Suzhou Zejing biopharmaceutical Co., Ltd is a domestic company that has made a lot of achievements in the research and development of deuterium drugs It is called the third largest deuterium drug development company in the world besides auspex (which has been purchased by Teva and developed the world's first deuterium drug deuterium butylbenzene) and concert At present, the company's R & D pipeline has three deuterium drugs, donafinil, jaketinib and okatini, which have been put into clinical research At present, in addition to advanced HCC, there are also advanced colorectal cancer and locally advanced / metastatic radioiodine refractory differentiated thyroid cancer, which enter the phase III clinical stage In addition, the indications for advanced esophageal cancer, advanced nasopharyngeal carcinoma, recurrent acute myeloid leukemia and advanced gastric cancer are in phase I clinical stage Table 2 Zejing pharmaceutical Jack TiNi and okatini In addition, two indications of momelotinib of Zejing pharmaceutical are in clinical stage, including myelofibrosis and severe alopecia areata This is the second approved new drug for treatment of alopecia areata in China after pf-06651600 of Pfizer And aucatinib (deuterium derivative of osimertinib) also has indications for advanced NSCLC and alk positive advanced NSCLC at stage I and II, respectively For some reason, the naming rules of the three deuterium drugs of Zejing pharmaceutical are not consistent with the internationally used who international non exclusive name (inn) According to the principle of inn, in order to reduce medication errors caused by confusion of drug names, the naming principle of inn should be followed Deuterium drugs are usually identified by the prefix due - If it is a deuterium derivative of a drug, it is necessary to combine due - with the inn name of deuterium drug For example, deuterium benzozine and tetrabenzozine are named according to this principle Donafenib is named donafenib in English, not deusorafenib according to the principle of inn Since the inn principle has been recognized by many national regulators, donafini may face the awkward situation of changing its name and surname when applying for listing, so it has to admit its relationship with solafeni Table 3 Deuterium substitute of Haichuang pharmaceutical Chengdu Haichuang Pharmaceutical Co., Ltd is another domestic enterprise that has gone far in the development of deuterium drugs According to the official website of Haichuang pharmaceutical, there are two deuterium drugs in its R & D pipeline, hc-1119 and hp505 In order to enhance the R & D strength in the field of deuterium substitute drugs, Haichuang Pharmaceutical Co., Ltd introduced Dr Zhang Chengzhi, a famous chemist, to join Haichuang in 2018 as the executive vice president of Haichuang, who is responsible for the overall management of the pharmaceutical and CMC of the company's innovative drug platform According to the website of Haichuang pharmaceutical, Dr Zhang Chengzhi was the senior director of Teva, senior director of auspex, chief scientist of Bayer, Novartis and other companies He has dozens of authorized new drug patents, and has successfully promoted a number of drugs including DBB to enter phase I / II / III clinical trials He is also the inventor of DBB and one of the main promoters of its successful listing Hc-1119 is a deuterium derivative (- CD3) independently developed by Haichuang Pharmaceutical Co., Ltd based on enzalutamide It is a deuterium derivative (- CD3) obtained by substituting hydrogen (H) of methyl (- CH3) on the amide bond of enzalutamide with deuterium (d) In 2016, Haichuang Pharmaceutical Co., Ltd obtained the equity investment of 33.454 million yuan from Sichuan hisic Pharmaceutical Co., Ltd., while hisic Pharmaceutical Co., Ltd obtained the exclusive patent license of hc-1119 and various pharmaceutical preparations with its active ingredients in China Nzalutamide is the second generation of androgen receptor inhibitors, which was approved by the US FDA in 2012 for the treatment of metastatic castrated resistant prostate cancer (mcrpc) Nzalutamide can significantly improve the overall survival of patients with mcrpc, but it has the risk of epilepsy Because of its dose-dependent side effects, deuterization may improve the PK and toxicological characteristics of nzalutamide In vivo, n-azalumide is mainly metabolized by cyp2c8 and CYP3A4 / 5 to N-demethylation, while n-cd3 can weaken the process of N-demethylation by replacing n-ch3 The design of hc-1119 is based on this concept, and preclinical studies have also proved the advantages of deuterization At present, hc-1119 has completed the phase I clinical study of mcrpc in China, and there are two phase III clinical studies One is a placebo-controlled study (ctr20190199), which is being conducted in China and is currently in the enrollment stage; the other is a non inferiority study (nct03850795), which also shows Haichuang pharmaceutical's confidence in hc-1119 The study is planned to be carried out globally and has not yet started to be recruited (as of January 1, 2020, it has not yet been in the clinical medicine) This study was inquired on the platform of experiment registration and information publicity) It should be noted that in the nct03850795 test, the dosage of hc-1119 is 80mg / day, while that of nzalutamide is 160mg / day It can be predicted that the safety data of hc-1119 in this test should be better than that of nzalutamide Nzalumin was approved to be listed in China in November 2019, which is not good news for Haichuang pharmaceutical industry Unless the clinical data of hc-1119 can be significantly improved compared with deuterium based prototype drugs like donafinil, hc-1119 may need to face the triple attack of the original research of nzalutamide, the imitation of nzalutamide and the Hengrui medicine shr3680 (the me too drug of nzalutamide is in phase III clinical stage), even if it can complete the clinical trial and successfully go on the market According to the official website of Haichuang pharmaceutical, hp505 is another deuterium drug of Haichuang At present, there is no more disclosure about the structure of this compound It is only known that this compound, like hc-1119, is an androgen receptor inhibitor and the indication is advanced prostate cancer In addition, Haichuang pharmaceutical also has more layout in the field of deuterium substitute drugs According to the patent information inquiry of the State Intellectual Property Office, at present, Haichuang pharmaceutical has applied for deuterium substitute lucitanib (public No.: cn110551065a), deuterium substitute capmatinib (public No.: cn110526916a), deuterium substitute deficinib (public No.: cn110452229a), deuterium substitute vistusertib (public No.: cn110407833a) Patents Table 4 Deuterium substitute drugs of taijihongnuo and Zhengda Tianqing Zhengzhou taijihongnuo Pharmaceutical Co., Ltd is also deeply involved in the research and development of deuterium drugs Its subsidiary Zhejiang Yuankang Pharmaceutical Co., Ltd has developed two deuterium drugs, ty-9591 and ty-302 Ty-9591, a deuterium derivative of crizotinib, is currently in phase I clinical stage, and its indication is locally advanced or metastatic non-small cell lung cancer Ty-302 is a deuterium derivative of palbociclib, which has been implicitly approved by CDE clinical trials The indication is HR + / HER2 - locally advanced or metastatic breast cancer and other advanced solid tumors or hematological tumors In addition, Zhengda Tianqing also has a layout in the field of deuterium drugs Its anti hepatitis C drug tqa-3326 (dacatavir deuterium derivatives) has already entered the phase I clinical state, but there is no further clinical trend According to the patent inquiry of the State Intellectual Property Office, Zhengda Tianqing has also applied for a patent for a piperacillin deuterium derivative (public No.: cn106432223a), which is different from ty-302 of taijihongnuo in its deuterium position This time, donafinil's improvement in survival benefit and safety compared with solafeni in head-to-head test shows that deuterium drugs may indeed have some advantages over non deuterium drugs in effectiveness and safety At present, the only approved deuterium drug in the world is deuterium butylbenzazine, and this time donafinil is likely to become the second deuterium drug in the world with excellent clinical data