The world's first EZH2 inhibitor, tazemetostat, has been approved by FDA

Wen Liu Liu sir Recently, the FDA approved tazemetostat, the "first in class" EZH2 inhibitor developed by epizyme company, to be put on the market for the treatment of non operative, metastatic or locally advanced epithelioid sarcoma Tazemetostat is a highly active and selective epigenetic drug EZH2 is a kind of histone methyltransferase If it is activated abnormally, it will lead to the disorder of gene controlling cell proliferation, which can cause the unlimited rapid growth of non Hodgkin's lymphoma and many other solid tumor cells The drug has antitumor effect by inhibiting EZH2 enzyme activity Figure 1 Tazemetostat structure In March 2011, Weicai and epizyme signed a global strategic cooperation agreement on epigenetic drug discovery and development On November 5, 2019, Weicai transferred the global copyright of tazometostat to royalty Pharma for us $330 million, including US $110 million down payment and US $220 million mileage Fund approved by FDA based on specific indications Epithelioid sarcoma is a very rare and invasive soft tissue sarcoma, which is often found in young adults aged 20-40 years The prevalence of epithelioid sarcoma in men and women is 2:1 Because there is no effective treatment for this kind of patients at present, once cancer metastasis occurs, most of them have a survival period of less than 1 year Table 1 Global list of drugs for solid sarcoma Sort out the data from Yaodu Data from a single arm, phase II study of 62 patients with epithelioid sarcoma showed that 51% of the patients had shrunk after tazemetostat treatment, and 15% of the patients had shrunk significantly to achieve partial remission In 62 patients, the apparent remission rate (ORR) was 15%, the median duration of remission (DOR) was not reached, the disease control rate (DCR) was 26%, and the median overall survival time (OS) was 82.4 months Among the 62 patients, 24 were initially treated and 38 were relapsed / refractory Among them, the orr was 25%, DOR was 41.1 months, DCR was 42%, median OS was not achieved; the orr of relapsed / refractory patients was 8%, DOR was not achieved, DCR was 16%, median OS was 47.4 months Epithelioid sarcoma is a rare malignant tumor of epithelioid soft tissue In the early stage of this disease, there is no self-conscious symptom, and the onset is slow It is easy to cause misdiagnosis and missed diagnosis More than 70% of the 62 patients had reached the middle and late stage at the time of diagnosis, and 38 patients had received more than one or three kinds of treatment in the past, that is to say, most of the patients have been faced with drug resistance or no drug available This also shows that both patients who have failed in previous treatment and those who have not been treated may benefit from tazemetosat In addition, epizyme is studying other indications of tazemetostat, such as malignant mesothelioma, follicular lymphoma and diffuse large B-cell lymphoma For example, epizyme has submitted a new drug application of tazemetostat to FDA for the treatment of recurrent or refractory follicular lymphoma According to the drug delivery database, there are 123 drugs (on the market and under development) for treating sarcoma in the world Although about 40% of the drugs are on the market, there are still a large number of new drugs entering the clinical stage, which also shows that the research and development of new drugs for treating sarcoma has always been the focus of drug research and development In addition, domestic new drugs include Zhengda Tianqing al-3818 (approved for market in 2018), Zhaoke tumor sti-a1014 (clinical phase III), Jiahe biopharmaceutical cbt-501 (clinical phase II), Beijing jiakesi jab-3312 (clinical phase I) and Guangzhou Xiangxue pharmaceutical taest-16001 (clinical phase I) These five drugs are all class I new drugs in China Figure 2 The number of drugs used to treat solid sarcoma in the world, sorted out from drug delivery database, as of February 2020 Table 2 Global list of EZH2 targeted drugs Sort out the data from Yaodu Tazemetostat is the first EZH2 inhibitor, and its clinical effect is significant, which may bring significant improvement to the symptoms of patients with epithelioid sarcoma According to the existing clinical data, tazemetostat has a significant effect, the main adverse events are level 1 or level 2, and the treatment-related adverse events of level 3 or higher only account for 18%, and the safety is acceptable; however, the research and development based on EZH2 at home and abroad are relatively few, so it is suggested that domestic pharmaceutical companies seize the opportunity to take the lead in the layout and strive to be the first person to eat crabs Reference material 1 Data update of phase 2 trial of tazemetostat in the treatment of epithelial sarcoma reported by epizyme company at ASCO annual meeting in 2019 on June 3, 2019 2 Stacchiotti s et al Published in the Journal of cancer on July 19, 2019, compared and evaluated the antitumor effect of cytotoxin and EZH2 inhibition in xenografts from patients with ini negative epithelioid sarcoma and the mechanism of autophagy induced drug resistance 3 Stacchiotti, S., Zuco, V., Tortoreto, M., et al Comparative Assessment of Antitumor Effects and Autophagy Induction as a Resistance Mechanism by Cytotoxics and EZH2 Inhibition in INI1-Negative Epithelioid Sarcoma Patient-Derived Xenograft[J] 2019, Cancers, 11(7), 1015 4 Drug delivery database