**: Briana***
Strictly speaking, the concept of ADC "magic bullet" has been proposed as early as more than 100 years ago, and it was not until 2000 that the first ADC was approved for marketing, and so far 15 new ADC drugs have been listed in the world, and ADC technology has been praised by many international journals such as Nature as a "breakthrough trend" in new drug research and development.
A list of new ADC approved drugs worldwide.
In terms of data, the period from 2019 to 2021 is the period with the highest number of approvals in the ADC field, during which not only the most breakthrough drugs in the field of breast cancer such as Enhertu were born, but also the rare situation of "three generations of ADC drugs coming together", that is, the first-generation ADC drug Mylotarg, The second-generation ADC drug Adcetris and the third-generation ADC drugs Besponsa and Enhertu are on sale at the same time, which is also in line with the subsequent three phases according to the approval time of the ADC drug.
3 stages
Reveal the path to the rise of ADC
Looking at the history of ADC development, looking back at the approval time of the above 15 new ADC drugs, in terms of marketed drugs, according to the number and concentration of new ADC drugs approved for marketing each year, with the vigorous promotion of the capital market, the approval of ADCs can be divided into three stages, namely the emerging stage, the accumulation period and the outbreak stage.
Emerging period: From 2000 to 2016, it was the stage of starting from scratch in the ADC field, and Pfizer, Takeda, and Roche, three multinational pharmaceutical companies, brought Mylotarg, Adcetris, and Kadcyla to the world respectively, providing an important template for follow-up research in the ADC field.
Accumulation period: During 2017 and 2018, Pfizer's Besponsa and AstraZeneca's Lumoxiti were approved successively, and a large number of ADC pipelines around the world entered the clinical stage, paving the way for the subsequent outbreak of the ADC field.
Outbreak period: From 2019 to 2021, the ADC field officially ushered in an explosion, and 9 new ADC drugs were approved in three years, which is unprecedented. More importantly, the original research companies are no longer limited to traditional MNC companies, but are gradually dominated by innovative biotech companies such as Seagen, Gilead, and LMMUNOMETRICS (5 of the 9 new drugs are biotech companies).
In terms of research pipelines, according to Informa Database, as of December 21, 2023, a total of 1,166 ADC pipelines have been developed worldwide, and 524 pipelines are under development
3 new drugs
It is expected to be approved in 2024
According to PharmaIntelligence, there are currently 23 phase III clinical projects in the global ADC field, spanning from 2016 to 2023 and spanning 8 years. And with the increasing attention of the capital market to the ADC field, the number of ADC projects that have entered phase III clinical trials continues to increase.
According to the "Clinical Development Success Rates and Contributing Factors 2011-2020" jointly released by BIO and QLS Advisors, the average time taken by the FDA to approve new drugs for marketing is 33 years, with an average of 13 years. According to this rule, in the existing phase III ADC clinical projects, some pipelines obviously have the premise of being launched in 2024, that is, they will enter phase III clinical trials around 2021 or the current phase III clinical data has reached the clinical endpoint.
Under the preliminary screening, among the 23 phase III projects, 3 new drugs are the most promising to be launched in 2024, 7 new ADC drugs are terminated from clinical trials, 2 new ADC drugs are inactive (no research progress within 3 years), 11 new ADC drugs have entered phase III clinical trials for a short time (2022 and 2023), and the three new ADC drugs that are expected to be launched in 2024 are AstraZeneca's Daiichi Sankyo's DS-1062, AbbVie's ABBV-399, Miyak Biotech MRG002.
Data**: Pharmaceutical intelligence data.
AstraZeneca Daiichi Sankyo (DS-1062): The successor to the new ADC drug king?
Following DS8201, DS1062, another humanized monoclonal antibody targeting Trop2 jointly developed by AstraZeneca and Daiichi Sankyo Co., Ltd., may be expected to become its new "king of medicines".
First of all, at the technical level, as one of Daiichi Sankyo's three ADC carriages, DS8201 and DS1062 both belong to the DXD-ADC technology platform, and the former is a HER2-targeted drug, mainly targeting breast cancer. However, in order to effectively avoid competition with Gilead's TROP2-ADC (breast cancer + urothelial carcinoma), Daiichi Sankyo chose to focus on lung cancer indications (4 of the 7 phase clinical trials for lung cancer), which may currently be the fastest pipeline on lung cancer indications, which is also one of the biggest features of DS-1062.
Global clinical phase III "non-small cell lung cancer" ADC research and development progress.
In terms of research progress, on September 23, 2023, the primary clinical endpoint has been met in the latest phase 3 clinical trial of DS1062 breast cancer, and AstraZeneca and Daiichi Sankyo Co., Ltd. said that they are planning to submit a new drug application globally, and according to the previous FDA approval efficiency, it is very likely to be successfully launched in 2024.
It is clear that AstraZeneca's cooperation with Daiichi Sankyo in the ADC field is just the beginning, and after the success of DS8201, the $6 billion introduction of non-Japanese rights to DS-1062 is just an appetizer for AstraZeneca, and in February this year, it again introduced Lepu Biotech for $1.1 billion Claudin182-ADC drug CMG901;In May, it entered into a $600 million deal with LaNova for LPRC5D-ADC LM-305It can be seen that AstraZeneca is bound to win in the ADC field, and DS1062 may be just one of the many "king bombs" in the hands of AstraZeneca.
On the other hand, for domestic pharmaceutical companies, there are more than 10 ADCs in the same TROP2 field as DS1062, which are expected to compete on the same stage.
AbbVie (ABBV-399): A key turning point in regaining ADC.
AbbVie tried to break through with ADC technology, but many assets such as ABBV-414, ABBV-221 and ABBV-321 unfortunately became a stepping stone to trial and error, and ABBV-399 has become a key turning point for AbbVie to regain ADC.
At the technical level, ABBV-399, as a C-Met ADC independently developed by AbbVie, is not only the fastest progressing project in its current ADC pipeline, but also the only C-Met ADC in the world that has entered the phase III clinical stage, one position ahead of competitors such as AstraZeneca and Regeneron, and was awarded breakthrough ** status by the FDA in January 2022.
On November 29, 2023, the latest clinical results based on the topline data of clinical Luminosity showed that the overall response rate (ORR), median duration of response (MDOR) and median overall survival (MOS) were all good, and the phase III clinical study of **NSCLC patients was also advancing.
In line with the positive results of ABBV-399, AbbVie's $10.1 billion acquisition of Immunogen not only brings Elahere under its command and has a blockbuster product in the field of solid tumors, but more importantly, it is highly complementary to its own ADC pipeline in terms of research pipelines, which is expected to bring breakthroughs to AbbVie in the field of ADC, which has been difficult to conquer. At present, AbbVie's ADC pipeline includes a number of cutting-edge targets such as CMET, SEZ6, PSMA Steap1 and CD123.
Now, AbbVie is on the agenda for the launch of its first ADC drug, ABV-399, but the specific timing depends on the results of specific clinical trials and corporate strategic planning, which is likely to be between 2024 and 2025.
MRG002: The glory of autonomous ADC.
MRG002 is a new HER2-targeting ADC drug developed by Meyak Biotech. It is the only ADC drug independently developed in China among the three new ADC drugs that are expected to be marketed.
Institutionally, the structure of MRG002 is composed of sugar-modified trastuzumab conjugated to the small molecule toxin MMAE through enzymatically digestible VC linkers, and trastuzumab is improved through unique design and innovation to improve patient safety and tolerability while ensuring enhanced anti-tumor efficacy.
From the perspective of the indications of its layout, it is mainly focused on breast cancer, urothelial carcinoma and gastric cancer, and its overseas competitors are mainly AstraZeneca and Daiichi Sankyo's DS-8201, while in China, MRG002's main competitor is Remegen's RC48, which has a more stable linker in drug design, which can ensure a more stable systemic circulation effect and reduce off-target effects.
In terms of progress, MRG002 is currently in phase III clinical trial of urothelial carcinoma, and is advancing the comparative study of MRG002 with the chemotherapy regimen selected by the investigator in patients with **HER2-positive, unresectable locally advanced or metastatic UC. Previous clinical data have shown that it is reliable. In addition, the single-arm registrational clinical trial of MRG002 in HER2-overexpressing advanced breast cancer complicated with liver metastases has also met the clinical endpoint, and it is currently preparing for NDA application and is expected to be marketed in 2024.
ADC battle at home and abroad
What is the future breakthrough of China's ADC industry?
If the DS-8201 in 2019 has opened a new door for the global ADC industry, it has made the position of ADC drugs clearer, and also provided a direction for more follow-up ADC pipeline research. So, after the rapid development of ADCs from 2019 to the present, with the overall number of ADC pipelines currently under development and the difference in the technical routes of the four new ADC drugs that are expected to be launched in 2024, what aspects can Chinese innovative pharmaceutical companies compete with?
In Feng Zhenqing's article "Innovation and Future of Antibody-Drug Conjugates", he said that the integrated innovation in the molecular design and mechanism of action of ADCs will continue to drive the R&D and upgrading of ADCs, and the research and development of ADCs in the future can promote the innovation and development of ADCs from the study of non-internalized antigen targets, new antibody forms, new delivery systems, new cytotoxic drugs, site-specific bioconjugation methods, immunostimulatory ADCs, and expanded non-cancer indications of ADCs.
Not to mention new antibody forms, new delivery systems, and new cytotoxic drugs, perhaps the transition from monoclonal antibodies to bispecific antibodies, the upgrade from "off-target toxicity" to "targeted toxicity", and the drug combination of ADCs will be several key directions for domestic ADC companies.
Bispecific antibodies: On December 11, Baili Tianheng reached a cooperation with BMS, and BMS obtained the BL-B01D1, its bispecific antibody ADC product BL-B01D1, with a down payment of 800 million US dollars and an additional conditional recent payment of 500 million US dollars, with a total price of up to 8.4 billion US dollars, creating the highest amount of domestic innovative drugs authorized to go overseas.
After all, in the face of today's hundreds of ADC R&D pipelines, bispecific antibodies can target tumor cells more specifically, overcome drug resistance while increasing drug safety, and theoretically can achieve better results, which can be described as the next outlet of ADC.
For different targets, bispecific antibodies can be divided into dual-target ADCs and dual-epitope ADCs, the former is currently mostly combined with EGFR and other targets to achieve stronger specificity and safety, and is expected to cover a wider range of peopleThe latter is dominated by HER2 biepitope, MET biepitope and FR biepitope, in order to improve the overall internalization efficiency and overcome the problem of drug resistance caused by the decline of receptor expression.
Compared with the gap in the R&D progress at home and abroad in the field of single-target ADC, the most attractive point of bispecific antibody ADC to domestic pharmaceutical companies is that most of the relevant research in the global field is in the preclinical stage, which is also one of the biggest reasons for the cooperation between Baili Tianheng and BMS, and it is an excellent opportunity for domestic pharmaceutical companies to compete with overseas pharmaceutical companies on the same stage.
Target toxicity: According to the content description of data 11, the main reason for the adverse reactions of most existing ADC drugs at this stage is the off-target toxicity of ADC drugs, and the instability of ADC conjugates and the drug toxicity of the drug loading itself are the two most important points.
However, with the advancement of related technologies in the future, the study of off-target toxicity to on-target toxicity will surely become the main research direction of ADC in the future, for example, to solve the cardiotoxicity of HER2 drugs, then DS-8201 will definitely show excellent advantages in indication expansion to some extent, which will also become the main research direction of ADC drugs in the future.
Combination: Although theoretically speaking, ADC claims to be suitable for all tumors, but in fact, there are differences in the efficacy of the same ADC in different indications with the same target, and the "drug combination" of ADC may become one of the main lines of research and development in the future.
On December 15, Merck announced that the FDA had approved drug K (pembrolizumab) in combination with NECTION-4 ADC (PADCEV) in the first line** for locally advanced or metastatic urothelial carcinoma, which is the world's first approved "PD-1+ADC" combination**. Its key three clinical data are exceptionally good, with OS and PFS nearly doubling, and the risk of patient death reduced by 53%.
Behind this approval, although Merck is trying to use ADC technology to extend the life cycle of its mature product K drug, it has almost ended the era of PD-1 monotherapy, and on the other hand, it has also confirmed that IO (tumor immunity**) ADC is expected to become the main line of tumor immunity in the next 5-10 years
Summary
In fact, with the deepening of the exploration of new targets, new mechanisms of action and new ADC forms in the field of ADC, its future development path will definitely become wider and longer, don't look at the fact that no ADC will be approved in 2023, and only 3 new drugs are expected to be launched in 2024, but for 2025 and 2035, perhaps this number will expand tenfold or hundredfold.
At that time, it may be the era of ADC.
Reference: What does the future hold for ADCs?Xiaoyao Says Medicine, 2023-09-18;
After the number of transfers ranks first in the world, what is the future of domestic ADCs, Amino Observation, 2023-10-26;
Abandoned bulky drug conjugates, Biopharma, 2023-07-26;
Understanding Clinical Staging: The Differences in Phase 0, Phase I, Stage, Stage IV, Drug Time and Space, 2023-09-11;
Report!Is 2023 the end of the year or the new year of ADC?The future breakthrough is in**?BIG Bio Innovation Club, 2023-09-10;
The pipeline will explode: the next big card of the leading ADC pharmaceutical company is IO+ADC, same as Freehand, 2023-08-29;
Daiichi Sankyo AstraZeneca TROP2 ADC first phase III clinical success in breast cancer!Global listing plan in progress, Insight Database, 2023-09-22;
Feng Zhenqing. Innovation and future of antibody-drug conjugates[J].Journal of Graduate Medical Sciences,2021,34(12):1233-1237 doi:10.16571/j.cnki.1008-8199.2021.12.001.
ADC is the future?Huang Zhongping, 2023-12-22
drago jz, modi s, chandarlapaty s. unlocking the potential of antibody-drug conjugates for cancer therapy. nat rev clin oncol. 2021 jun;18(6):327-344.
Challenges and responses, how much do you know about ADC drug toxicity?
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