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    Home > Medical News > Medical World News > Chemotherapy drug ds-8201 or ADC in the blue ocean market?

    Chemotherapy drug ds-8201 or ADC in the blue ocean market?

    • Last Update: 2019-12-20
    • Source: Internet
    • Author: User
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    Wen Xiang eastward Since the use of nitrogen mustard in the treatment of lymphoma in 1943, the exploration of using chemotherapy drugs to treat tumors has never stopped At present, more than 50 kinds of chemotherapy drugs have been used to treat various malignant tumors However, the anti-tumor process of chemotherapy drugs is often the process of "killing a thousand enemies, self damage 800" With the death of tumor cells, normal cells are also attacked by drugs In clinical use, side effects such as myelosuppression, gastrointestinal toxicity, immunosuppression, cardiopulmonary, hepatorenal injury and neurotoxicity often occur, leading to doctors and patients' hesitation in the use of chemotherapy drugs In today's era of targeted therapy and immunotherapy, chemotherapy drugs seem to be on the wane and will be eliminated by the times However, its strong killing ability to tumor cells makes drug scientists unable to stop, so it has produced anti drug conjugate (ADC) aimed at improving the precise killing ability of chemotherapy drugs Ds-8201 (trastuzumab deruxtecan) to be introduced below is an ADC drug On December 11, 2019, the New England Journal of Medicine (NEJM), a top medical journal, published a phase II clinical study (destiny-breast01) of ds-8201 in the treatment of HER2 + breast cancer [2] Before introducing the results of the study, it should be noted that among 184 patients who were included in the study of destiny-breast01 and received the recommended dose (5.4mg / kg), the median of the previous breast cancer treatment was 6, and 100% of these 184 patients had used trastuzumab, and 100% of them had used trastuzumab Emtansine (kadcyla, a FDA approved ADC drug), 65.8% of patients used pertuzumab, 54.3% of patients used other anti-HER2 therapy, 48.9% of patients used hormone therapy, 99.5% of patients used other systematic therapy In other words, these patients are almost incurable However, in such a group of patients, the objective response rate (ORR) of the primary end point of destiny-breast01 reached 60.9%, of which 6% (11 patients) achieved complete response (CR), i.e complete tumor disappearance; 54.9% achieved partial response (PR); and the disease control rate (DCR) of one of the secondary end points was 97.3% In other words, after using ds-8201, which is an ADC drug, these patients with almost no drug to treat have a great clinical benefit Let's talk about the ADC drugs that rejuvenate the traditional chemotherapy drugs Since the birth of traditional chemotherapy drugs, due to its strong side effects, scientists have been trying to tame it, so that it can kill tumor cells at the same time, not damage normal cells by mistake With this idea, drug scientists finally developed Antibody Drug Conjugate (ADC) ADC drugs are generally composed of three modules: monoclonal antibody, cytotoxic drugs and linker The main mechanism of action is to make ADC drug molecules highly targeted by monoclonal antibodies, which can target tumor cells; then when ADC drug molecules are targeted to tumor cells to be swallowed, release small molecules of cytotoxic drugs connected by linkers and monoclonal antibodies, destroy DNA or prevent tumor cells from dividing, so as to achieve accurate killing of tumor cells [4] 。 In this mechanism, cytotoxic drugs are mainly aimed at DNA and tubulin of tumor cells The cytotoxic drugs used in the early development of ADC include alkaloids, methotrexate, anthracycline antibiotics and taxanes However, in the follow-up study, these cytotoxic drugs are found to be unable to reach the payload and lack of targeted specific toxicity, so their use is limited After a long-term exploration, the cytotoxic drugs commonly used in the current ADC drug development include: (1) anti DNA classes: caliceamicins, duocamycins and pyrrolobenzoidizepins; (2) anti tubulin classes: auristatins (monomethylauristatin e, MMAE; monomethylauristatin F, MMAF) and maytanines (DM1, DM4), etc At present, there are five ADC drugs approved by FDA for marketing, namely gemtuzumab ozogamicin (Mylotarg, developed by Pfizer), brentuximab vedotin (adcetris, developed by Takeda and Seattle Genetics), inotuzumab ozogamicin (besponsa, developed by Pfizer), polatuzumab vedotin piiq (poly, developed by Roche) and trastuzumab emerging (kadcyla, developed by Roche) Among them, gemtuzumab ozogamicin was approved as a single therapy as early as 2000 by the U.S FDA However, due to the poor efficacy and safety concerns in later clinical trials, Pfizer voluntarily withdrew the drug from the market in 2010 After years of optimization of use method and dosage, and further verification and assurance of safety, the drug was re approved for marketing in 2017 to treat adult patients with newly diagnosed acute myeloid leukemia (AML) expressing CD33 antigen, and at the same time, it was approved to treat patients with CD33 positive AML aged 2 years and over Previously, in March 2019, ds-8201 and AstraZeneca announced a global cooperation on ds-8201, reached a global development and commercialization agreement on ds-8201, with ds-8201 in full charge of the manufacturing and supply of the product, while AstraZeneca is in charge of the global commercial development except Japan The combination of the two pharmaceutical companies shows that they attach great importance to ADC drug field According to adreview statistics, as of March 27, 2019, 192 clinical trials of ADC drugs have been registered in clinicaltrials.gov, which also shows that global pharmaceutical companies attach great importance to ADC drug development [5] At present, the representative ADC drugs entering the late clinical stage in foreign countries include trastuzumab deluxtean (ds-8201, developed by the first three parties and AstraZeneca), sacituzumab govitecan (immu-132, developed by immunomedics), enfortumab vedotin (asg-22me, developed by Seattle genetics and astralas), mirvetuximab soravtansine (imgn-853, developed by immunogen) [Vic -] trastuzumab duocamazine (syd985, developed by synthon biopharmaceuticals BV) [6], its corresponding target, loaded cytotoxic drugs, indications, clinical stages and registration number are shown in Figure 6 There are also many domestic enterprises in this field [7] It includes bat8001 and bat8003 of biota bio, rc48 of Rongchang bio, arx788 jointly developed by Zhejiang Pharmaceutical and ambrx company, shr-a1201 and shr-a1403 of Hengrui pharmaceutical, dp303c of Shiyao group, a166 of Kelun pharmaceutical, b1452 of Tianshili, gb251 of Jiahe bio, etc Table 1 Biota bat8001 and bat8003 Among them, BioTek's bat8001 has made the fastest progress The indications for HER2 positive advanced breast cancer have entered the phase III clinical stage Another product, bat8003, has also carried out phase I clinical research for advanced epithelial cancer However, Rongchang biological rc48 has the most indications It has targeted at cholangiocarcinoma, non-small cell lung cancer, urothelial cancer, gastric cancer, breast cancer, and large-scale solid tumors, and its progress is mostly in phase II Table 2 Rongchang biological rc48 Other products, including arx788 jointly developed by Zhejiang Pharmaceutical and ambrx company, shr-a1201 and shr-a1403 of Hengrui pharmaceutical, dp303c of Shiyao group, a166 of Kelun pharmaceutical, are all in phase I, and their progress is behind that of biota and Rongchang Table 3 Other ADC clinical information It is worth noting that most of the clinical indications of ADC drugs declared in China are HER2 positive tumors, which indicates that most of the monoclonal antibodies selected for ADC molecules are anti HER2 antibodies, plus the tradtuzumab emerging (kadcyla) and tradtuzumab dextecan (ds-8201), [Vic -] tradtuzumab which are in the late clinical stage Duocamazine (syd985), which means that the homogeneity competition of such products is inevitable Of course, unlike the fierce competition between tumor targeting and immunotherapy drugs, ADC is still a blue ocean in the field of drugs This kind of drugs upgraded to traditional chemotherapy drugs known as anti-cancer missiles have a broad market waiting for many enterprises to open up, and we hope that this process will bring new gospel for the majority of tumor patients.
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