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HER2 ADC Terminator?

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If there were pharmaceutical companies involved in making PD-1 antibodies before 2012, they might have become companies with a valuation of tens of billions by now. But if you only do PD-1 drugs now, you may lose money. After the great success of the PD-1 track, ADC has become the next hot track, and the field of HER2-targeted ADC drugs is even more popular. The success of new drug research and development often belongs to those companies that do the world's first-in-class or best-in-class. In the past few years, domestic pharmaceutical companies are rushing to be "fast follower", and they can also rely on the "rain and dew" of star products to obtain huge economic returns. However, doing "fast follow" will lead to serious product homogeneity, and have to compete fiercely in the stock market, which eventually turns into a "price war". There is also a tendency to start a "price war" in the HER2 ADC field. In March 2022, the first HER2 ADC drug T-DM1 announced a 52% price reduction in the domestic market, and the 100mg/bottle dosage form was reduced from 19,282 yuan to 9,200 yuan, all of which were affected by the strong development of DS-8201. Since the approval of DS-8201, it not only has advantages over T-DM1 in traditional indications, but also opens up the indication for the subtype of breast cancer with low expression of HER2. DS-8201 seems to be both the leader of the HER2 ADC craze and the potential terminator of the same kind of target?

01  The battle for HER2-targeted ADCs

According to the forecast of Evaluate Pharma and BCG, the global ADC market is expected to reach US$12.9 billion in 2024, with a compound annual growth rate of about 35% from 2018 to 2024, and is expected to reach more than US$16 billion in 2026. Whether it is a large overseas pharmaceutical company or a domestic company, they have all deployed the ADC field.

At present, 14 ADC drugs have been approved for marketing in the world, namely Mylotarg and Besponsa from Pfizer, Kadcyla and Polivy from Roche, Lumoxiti and Enhertu from AstraZeneca, Adcetris and Padcev from Seagen/Takeda Pharmaceutical, and Tivdak from Seagen/Genmab. GlaxoSmithKline's Blenrep, Gilead's Trodelvy, Rakuten Pharma's Akalux, ADC Therapeutics' Zynlonta, Rongchang Bio's Vidicitumab.

Up to now, Medicilon has undertaken more than 100 IND application biopharmaceutical projects, including monoclonal antibodies, double antibodies, polyclonal antibodies, ADCs, viral vaccines and fusion proteins. As of May 2022, Medicilon has successfully helped 10 ADC drugs to be approved for clinical trails, and has multiple ADC projects under development. Medicilon has in-depth exchanges with customers in the formulation of the preclinical integrated research plan of ADC. The backbone of scientific research combines the characteristics of each case with years of practical experience and technical accumulation, and carefully submits high-quality experimental plans and results to customers.

So far, 3 ADCs targeting HER2 have been approved for marketing in the world:

T-DM1 (Kadcyla): The first ADC drug approved in the field of solid tumors, the first ADC drug used in the anti-HER2 treatment of breast cancer.

DS-8201 (T-DXd; ENHERTU): Approved by the FDA in December 2019, it is the second approved new HER2 ADC drug. In addition to breast cancer, it has also shown good efficacy in the treatment of other cancer types such as HER2-low expressing breast cancer, HER2-expressing gastric cancer, and unresectable advanced or metastatic non-small cell lung cancer.

Domestic pharmaceutical company Rongchang Bio's RC48 (Vidicilumab): Approved in China in 2021 for the treatment of HER2-overexpressing locally advanced or metastatic gastric and gastroesophageal junction adenocarcinoma who have received at least 2 systemic chemotherapy , and patients with urothelial carcinoma. The drug will be included in the National Medical Insurance List in 2021.

In addition, about 30 HER2-targeting ADC drugs have entered the clinical stage or are applying for marketing. One of them, SYD-985, is under application for marketing, 4 drugs have entered clinical phase 3, 7 drugs have entered clinical phase 2, and 2 drugs have entered clinical stage. Entered clinical phase 1/2, and the rest were clinical phase 1.

Many products are still in the stage of simple imitation and slight improvement, and those that can enter the late clinical stage are also mainly introduced or jointly developed. There are even many drugs that have not updated their clinical progress for a long time. Although there is no news of the termination of the trial, they must have fallen into a state of "stagnation" of drug development. Before DS-8201 was approved for marketing, most domestic pharmaceutical companies were targeting the second-generation ADC drug T-DM1, making me too or me better products. It is difficult for domestic competitors to gain a first-mover advantage, and they fail to produce stronger effects, which puts many pharmaceutical companies in a dilemma.

02  Which new drugs are affected by DS-8201?

Almost every well-known domestic pharmaceutical company has an ADC drug in the pipeline, and HER2 is the hottest target on the ADC track. As early as 2010, the first HER2 ADC drug, T-DM1, was approved by the FDA, but at that time, although T-DM1 was effective, it did not achieve stunning results and did not attract much attention. It's the DS-8201 that really makes the HER2 ADC hot. The advent of DS-8201 has made the market truly see the potential of HER2 ADC drugs, and many pharmaceutical companies have begun to bet on this field. The dimensionality reduction attack of DS-8201 not only made T-DM1 tremble, but also made a group of Me too companies that follow HER2 ADC a big head. How many domestic biotech can play? Cost considerations have become another shackle. Whether it is the old pharmaceutical company Hengrui Medicine, Fosun Pharma, CSPC, or Biotech BeiGene, Duoxi Bio, Jiahe Bio, etc., all have layouts. In particular, the big brother Hengrui Medicine has both SHR-A1201 benchmarking against the second-generation ADC drug T-DM1 and SHR-A1811 benchmarking the third-generation ADC drug DS-8201 in the pipeline.

As a result of the expansion of the DS-8201 clinical development program, nearly 50 clinical trials are currently underway, covering a broad range of cancer types and cancer stages. The clinical trial and development of Ambrx's HER2 ADC drug ARX788 was negatively affected by the strong development of DS-8201, which competed with DS-8201 in terms of patient resources, clinical trial speed, and application speed. Under pressure, Ambrx also replaced the company's CEO. In addition, according to Hengrui's disclosure at the recent performance exchange meeting, due to the good data of DS-8201, Hengrui stopped some overseas clinical trials of pyrotinib, which is also a HER2 target.

03  Conclusion

The DS-8201 payload, DXd, has been reported to have excellent efficacy while exhibiting the gastrointestinal toxicity profile of camptothecins in clinical trials. In addition, a recent study published in ESMO Open once again warned that although DS-8201 brought a considerable survival benefit, it caused major adverse events of interstitial lung disease (ILD) or pneumonia. DS-8201 may not be impeccable. It is possible to improve safety as much as possible while ensuring efficacy. It is possible to surpass DS-8201.

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