Ten big new drugs are coming! Roche gathers "three generals" to welcome the help of medicine o

Like a raging fire in the field of innovation and development in China, adorable drugs have been developed for ten years, especially since the 2015 drug review and approval reform However, in view of the relatively weak basic scientific research in China, the R & D of innovative drugs is still in the state of me too and fast follow To achieve me better or even first in class, we still need to redouble our efforts Although our country has said goodbye to the era of lack of medicine, but the number of new drugs approved for import every year is far more than that of domestic new drugs, and to solve the unmet clinical needs, we still need to rely on imported new drugs Therefore, which new imported drugs are expected to be approved for market in 2020 is very worthy of attention In May 2019 and December 2019, the patients with HER2 positive breast cancer who had been approved by FDA and EMA for new adjuvant therapy and still had residual pathological invasive lesions were treated with enmetrastuzumab (kadcyla, also known as t-dm1) On January 21, 2020, at the coming of the lunar new year, the product was successfully approved by the State Food and Drug Administration for import, basically achieving the simultaneous approval with the international A variety of neoadjuvant therapies can be used in patients with HER2 positive early breast cancer, including neoadjuvant chemotherapy with anthracycline, neoadjuvant therapy with trastuzumab plus other HER2 drugs, or patozumab However, after the new adjuvant therapy, there are still pathological invasive lesions in the breast and / or axillary lymph nodes, which is very dangerous In one clinical trial, patients were assigned to receive kadcyla or trastuzumab on a 1:1 basis, as well as radiation and / or hormone therapy according to local treatment guidelines After a median follow-up of 40 months, the primary end point of the study in the kadcyla group was noninvasive disease survival time (IDFs) The improvement was statistically significant compared with that in the trastuzumab group, and the risk of death or recurrence of invasive disease was reduced by 50% (HR = 0.50, 95% CI 0.39-0.64, P < 0.0001) Three years later, 88.3% of the patients in kadcyla group did not relapse, while 77.0% in trastuzumab group The patient data in China is consistent with the overall population of the Katherine study With kadcyla successfully approved for import, Roche has collected three major HER2 drugs in China, including trastuzumab and patorzumab In addition, kadcyla is the first antibody coupled drug (ADC) approved for marketing in China, which is undoubtedly a great inspiration to the pharmaceutical companies and new drug R & D enterprises that have laid out ADC drug product pipeline in China At the same time, for China's drug regulatory agencies, they have accumulated very critical experience, and have reached a new level in the review and approval of ADC drugs In fact, as early as 2013, FDA approved kadcyla to be used in patients who had previously used trastuzumab, other anti HER2 drugs, and the common first-line chemotherapy drug paclitaxel for breast cancer, which was the first and only one approved as a single preparation for the treatment of HER2 positive metastatic breast cancer that had previously received Herceptin and paclitaxel chemotherapy (alone or in combination) Patient's antibody drug conjugate Kadcyla is the third ADC drug in the world, and it is also the ADC drug with the highest sales volume, approaching 1.4 billion Swiss francs in 2019 Viteximab (adcetris) is an anti-CD30 antibody coupled drug (ADC) developed by Takeda and Seattle genetics It is used to treat recurrent / refractory CD30 positive Hodgkin's lymphoma (HL) or systemic anaplastic large cell lymphoma (salcl) The monoclonal antibody of doxoximab (CD30 monoclonal antibody) can specifically bind to the CD30 antigen of tumor cells, and then deliver the coupled anti tubule chemotherapy drug MMAE to cancer cells accurately and kill them In clinical trials, the overall response rates of patients with Hodgkin's lymphoma and systemic anaplastic large cell lymphoma were 73% and 86%, respectively, while the 5-year survival rates were 41% and 64%, respectively Adcetris was approved by FDA in 2011 and became the second ADC drug in the world In 2019, the global sales volume will exceed US $1 billion Mylotarg (gemtuzumab ozogamicin), the first ADC drug, was ill fated It was approved to be listed in 2000, but was withdrawn in 2010 due to security reasons, and was re approved in 2017 after re study The listing application of vibutoximab was accepted by CDE in April 2019 and included in the priority review procedure in June 2019 Blintomomab (trade name blincyto) is a bispecific antibody drug developed by Amgen One end of the drug is combined with CD19 antigen expressed on the surface of B cells, and the other end is combined with CD3 receptor on the surface of T cells It can collect T cells to the vicinity of cancer cells and promote killing cancer cells Bispecific antibodies (referring to two different epitopes that can target two antigens or one antigen at the same time) have great therapeutic potential due to their double targeting characteristics However, the transformation from theoretical concept to clinical practice has gone through a long process and also faces great challenges As early as 1960, some scientists put forward the concept of bispecific antibody In the next 20 years, with the development of hybridoma and other technologies, scientists were able to prepare different structures of double anti molecules In the next 30 years, a variety of double anti molecules were designed and gradually pushed to clinical trials It was not until 2009 that EU EMA approved the first bispecific antibody drug catumalomab (targeting CD3 and EpCAM) in the world for the treatment of cancerous ascites, which was withdrawn from the market in 2017 due to commercial reasons Blincyto was approved by FDA in December 2014 and became the second bispecific antibody in the world, which was used to treat acute B-lymphoblastic leukemia In 2019, the global sales volume was about 310 million US dollars In October 2019, the listing application of bilintomolobib was accepted by CDE and included in the priority review procedure in December 2019 However, the title of the first bispecific antibody drug in China has been gained by emicizumab The product is the third bispecific antibody drug in the world It was approved by FDA in November 2017 and imported in China only one year ago It is used to treat hemophilia A patients with clotting factor Ⅷ inhibitor The research and development of PD-1 / PD-L1 antibody drugs has occupied the hottest field of immunosuppressive drugs Seven immunosuppressive drugs (including four domestic PD-1, two imported PD-1 and one imported PD-L1) have been approved for marketing in China However, the world's first approved immunosuppressive drug, antibody to CTLA-4, epilimumab (yevoy), has not been approved for listing in China This situation may become history in 2020 The listing application of the drug was accepted by CDE in December 2019 In April 2011, epimumumab was approved by FDA as the first immunosuppressant Since then, new immunotherapies for immunocheckpoint molecules have swept the world, with global sales of nearly $1.5 billion in 2019 At present, it has been approved to treat melanoma with single drug, and to treat renal cell carcinoma and metastatic colorectal cancer with high microsatellite instability (MSI-H) or mismatch repair defect (dmmr) in combination with drug o (nafulizumab) Although the market time of epimumumab is early, its clinical application has been overtaken by PD-1 / PD-L1 The main reasons include the limited efficacy of single drug, large side effects and the use plan to be optimized Although the value of epimumumab in single drug therapy is limited, it plays an important role in combination therapy At present, it is mainly used in combination therapy with PD-1 antibody (I-O combination scheme for short) to improve the anti-tumor effect of the latter In clinical trials, the objective response rate of epimumumab combined with drug o in patients with renal cell carcinoma was 41.6%, while that of sunitinib was only 26.5% The overall response rate of epimumumab combined with O in patients with MSI-H or dmmr was 49%, while that of O alone was only 32% If epimumumab is approved to go on the market successfully, it will greatly enhance the advantage of BMS drug o in the competition of many PD-1 / PD-L1 antibodies in China The importance of rituximab (target CD20) to Roche need not be discussed, but with the expiration of the patent, many biological analogues have been listed one after another, and now they are facing great competitive pressure For this reason, Roche took precautions to develop the next generation of product, antinutuzumab (gazyva), which was approved by FDA in November 2013 and used in combination with nitrogen mustard benzoate to treat untreated chronic lymphoblastic leukemia (CLL) In 2019, global sales reached US $550 million Atozumab also targets CD20 antigen on the surface of precursor B cells and mature B lymphocytes After binding to CD20, B cell lysis is mediated by immune effector cells participating in and directly activating intracellular death signaling pathway or activating complement cascade reaction The mechanisms of immune effector cells include antibody dependent cytotoxicity (ADCC) and antibody dependent cell phagocytosis As an antibody to reduce the amount of algal sugar, the use of atozumab in vitro has a greater ADCC activity on the induction of pretoximab in human cancer cell lines Compared with rituximab, atozumab also showed an increased ability to induce direct cell death Atozumab has a higher affinity with FC γ RIII binding to rituximab through purified protein Atozumab and rituximab have similar affinity binding with overlapping epitopes on CD20 In clinical trials, in the first phase, the median progression free survival time and the overall response rate were 27.2 months and 78.2% respectively, while in the second phase, the median progression free survival time and the overall response rate were only 11.2 months and 33.1% respectively 6% of the patients were treated with rituximab and NBR for 14.9 months and 66.3% respectively It is proved that the therapeutic effect of atrozumab is better than that of rituximab The listing application of atozumab was accepted by CDE in September 2019 and included in the priority review catalogue in December 2019 Venetoclax is jointly developed by abwi and Roche, where Roche is responsible for the U.S market and abwi is responsible for markets outside the U.S This product was approved by FDA for marketing in April 2016, and was used to treat leukemia It has been awarded many breakthrough therapies by FDA Venecla is the first oral B-cell lymphoma factor-2 (Bcl-2) drug in the world Bcl-2 plays an important role in cell apoptosis and is the leading oncogene of most blood tumors Venacla can be used alone or in combination with rituximab or atrozumab in the treatment of CLL / SLL In one clinical trial, patients in both the trial group and the control group were fixed for one year The proportion of patients who achieved progression free survival after treatment with vinecla and atrozumab was 87%, while that of patients in the treatment group with atrozumab and nitrogen mustard benzoate was 63% In addition, 69% and 87% of the patients in the treatment group were negative for the minimal residual lesions in bone marrow and peripheral blood, while 45% and 62% in the treatment group were negative for the minimal residual lesions The listing application of venecla was accepted by CDE in January 2020 and included in the priority review catalogue in February 2020 If venacla and atozumab can be approved simultaneously, then for chronic lymphocytes