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ADC drug interpretation (4) | ADC market situation and competitive landscape

2022-08-30
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In recent years, the global ADC drug R&D and investment has been escalating. With the advancement of technology, ADC has not only broken through the classic antibody + linker + small molecule toxin model in structure,  but also become a new type of ADC drugs, such as radionuclide conjugated drugs, polypeptide conjugated drugs, bicyclic peptide conjugated drugs, antibody-siRNA conjugates, and multi-target ADCs. It has expanded from cancer treatment to other innovative areas such as autoimmune diseases.

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. .

Three generations of technological change

First generation ADC drugs

As represented by Mylotarg targeting CD33, the use of murine or chimeric humanized antibodies has unstable linkers, low toxicity and random coupling of small-molecule toxins, so the effectiveness is not high and is not enough to kill tumor cells.To kill tumor cells; toxins are released in the plasma in advance and cause serious toxic reactions; so the toxic and side effects are greater.

Second generation ADC drugs

Represented by Adcetris targeting CD30 and Trastuzumab emtansine (T-DM1) targeting HER2, using human-mouse chimeric antibodies and humanized mAbs, With more toxic cytotoxins and more stable linkers, antibodies are more targeted; however, drug-to-antibody ratio (DAR) is not uniform, reducing efficacy; and off-target toxicity from random conjugation persists. In 2013, T-DM1 was approved by the U.S. FDA for marketing, and the indications are: monotherapy or combination therapy for patients with HER2-positive metastatic breast cancer. In January 2020, T-DM1 was approved by the NMPA for listing in China. The indication is for patients with HER2-positive early breast cancer who still have invasive lesions after receiving taxanes combined with trastuzumab-based neoadjuvant therapy. adjuvant therapy. In June 2021, T-DM1 was approved for the second indication in China, for patients with HER2-positive, unresectable locally advanced or metastatic breast cancer treated with taxanes and trastuzumab as monotherapy. Global sales of T-DM1 in 2021 will reach $2.178 billion.

Third generation ADC drugs

Represented by HER2-targeting Trastuzumab (Trastuzumab deruxtecan; DS-8201), using fully humanized antibodies, highly toxic small molecule toxins and site-directed conjugation technology to upgrade non-cleavable linkers to cleavable linkers The drug-to-antibody ratio is as high as 8, which has better curative effect, but the toxic and side effects still exist. In multiple clinical trials, DS-8201 has been found to have the probability of causing interstitial pneumonia, so it was warned by the FDA in a black box. In 2019, DS8201 received FDA approval for later-line treatment of HER2-positive breast cancer. In April 2022, DS8201 was granted priority approval status by NMPA.

ADC blockbuster deal

In 2019, AstraZeneca entered into an agreement with Daiichi Sankyo to collaborate on the development of DS-8201 on a global scale, with a total transaction value of up to $6.9 billion.

In 2020, Gilead Sciences acquired Immunomedics for $21 billion for its first ADC drug, Trodelvy, which was approved to treat triple-negative breast cancer.

In 2021, Remegen sold its overseas interest in Disitamab vedotin (RC48) to Seagen for US$2.6 billion.

In February 2022, Johnson & Johnson and Eli Lilly entered into cooperation with ADC companies Mersana and ImmunoGen respectively for an amount of more than $1 billion.

Recently, the "Wall Street Journal" reported that MSD is in advanced talks to acquire Seagen for more than $200 per share. The deal is valued at about $40 billion or more.

ADC Tournament

In 2020, global ADC drug sales exceeded $3.8 billion. In 2021, global ADC sales will exceed $5 billion. It is predicted that the compound growth rate from 2020 to 2027 will exceed 30%. Under the global ADC drug research and development boom, with the approval of more other ADC drugs and the continuous expansion of indications in the future, sales are expected to grow rapidly. "The oncology market for antibody-drug conjugates" released by Nature Reviews Drug Discovery in 2021 predicts that by 2026, the market size of the global marketed ADC drugs will exceed US$16.4 billion, of which DS-8201 is US$6.2 billion and T-DM1 is US$6.2 billion. $2.3 billion.

A total of 14 ADC drugs have been approved for marketing in the world. Seven are for hematological tumors and seven are for solid tumors. Adcetris and T-DM1 were approved for listing in China by NMPA in 2020, Besponsa was approved for listing in China in December 2021, and RC48 independently developed by Rongchang Biotech was approved for listing in China in June 2021, the first approved New domestic ADC drugs.

Target layout: The more popular targets include CD22, HER2, EGFR, Trop-2, BCMA, Nectin-4, etc. Indication layout: mainly tumors, followed by autoimmune diseases, bacterial infections, wet age-related macular degeneration, etc. Tumors are mainly breast cancer, lung cancer, gastric cancer and so on. R&D progress: At present, the vast majority of R&D projects are in the early stage. Mainly focus on preclinical and clinical phase I.

Domestic ADC drug track

In recent years, many domestic pharmaceutical companies have competed to deploy ADC drug technology platforms, which has become a hot segment in the innovative drug industry.

Remegen

RC48 is China's first self-developed ADC drug, and it is currently the only domestic ADC product that has received FDA breakthrough therapy designation. In June 2021, the State Food and Drug Administration passed the priority review and approval process and conditionally approved the marketing of RC48 for HER2-overexpressing locally advanced or metastatic gastric cancer (including gastroesophageal junction adenocarcinoma) who have received at least 2 kinds of systemic chemotherapy. treatment of patients. In December 2021, RC48 was officially approved by the NMPA for the second indication for the treatment of HER2-expressing locally advanced or metastatic urothelial carcinoma (UC), becoming the world's first ADC drug targeting HER2 for the treatment of UC. RC48 has demonstrated excellent efficacy in advanced or metastatic urothelial carcinoma, gastric cancer, breast cancer and other indications.

lanova medicines

In May 2022, lanovamedicines reached a licensing agreement with Turning Point in the United States. Turning Point will pay lanovamedicines an upfront payment of US$25 million and a milestone payment of up to US$1 billion to acquire lanova's ADC drug LM-302 in Exclusive development and commercialization rights in licensed territories. lanovamedicines has a screening platform for monoclonal antibodies targeting GPCRs and multiple transmembrane proteins, and a development platform for ADC drugs and dual-antibody drugs for solid (especially digestive tract) and hematological tumors, and implements a differentiated drug development route.

Kelun

In May 2022, Kelun and Merck reached a licensing agreement to license one of its ADC drugs to Merck. Colombo will receive a total of US$47 million down payment in two installments and milestone payments of up to US$1.363 billion. . Kelun Biotech is a subsidiary of Kelun Pharmaceutical, which mainly focuses on ADC drug research and development. Currently, there are 3 ADC products disclosed on the official website: A166 and SKB264 target HER2 and TROP2, respectively, and are in phase II clinical trials; SKB315 targets CLDN -18.2, IND filing accepted by NMPA on August 30, 2021.

Dacbiotech

Dacbiotech is the company with the largest ADC drug distribution in China. It has established a complete ADC technology platform and has 20 ADC drugs in different stages.

Profoundbio

Based on Profoundbio's innovative technology platform, aiming at the pain points of current ADC drug development, Profoundbio can design and synthesize highly active drugs with better mechanism of action and physicochemical properties, and develop more optimized conjugates for next-generation ADCs The creation of drugs has achieved a greater breakthrough in the treatment of cancer by ADCs.

Conclusion

In recent years, the field of ADC drugs has developed rapidly, and more and more ADC drugs have been approved, which has stimulated the enthusiasm of medical professionals for the research and development of ADC. No matter the thriving Biotech or the deeply developed Biopharma, they all need to find their best position in the track, focus on their own advantages, differentiate and develop their core competitiveness, and promote the approval and marketing of more ADC drugs with higher efficiency and lower side effects.
Reference

[1] Ibrahim Azar, et al. Spotlight on Trastuzumab Deruxtecan (DS-8201,T-DXd) for HER2 Mutation Positive Non-Small Cell Lung Cancer. Lung Cancer (Auckl). 2021 Oct 7;12:103-114. doi: 10.2147/LCTT.S307324.

[2] Carolina do Pazo, et al. The oncology market for antibody-drug conjugates. Nat Rev Drug Discov. 2021 Aug;20(8):583-584. doi: 10.1038/d41573-021-00054-2.

[3] Zhiwen Fu, et al. Antibody drug conjugate: the "biological missile" for targeted cancer therapy. Signal Transduct Target Ther. 2022 Mar 22;7(1):93. doi: 10.1038/s41392-022-00947-7.

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