Roche HER2-ADC Enmetrastuzumab has been approved for marketing in China

On Jan. 22ed (BJT), Roche's HER2-ADC drug Entrastuzumabimtansine (Trastuzumabemtansine, trade name: Kadcyla, TDM1 for short) has been approved for marketing in China, and it is expected to be approved in the near future. Marketed for HER2-positive breast cancer. As there is no ADC drug officially launched in China, Kadcyla will become the first ADC drug listed in China, and it will also be the first blockbuster imported drug in China in 2020.

The marketing application (acceptance No.: JXSS1900013) of Roche’s HER2-ADC: Trastuzumab Emtansine for Injection (trade name: Kadcyla, T-DM1 for short) in China has recently been changed to "Under approval", which is expected to be approved for marketing soon, with the indication of HER2-positive breast cancer. Trastuzumab emtansine, if marketed successfully in China, will become the first ADC marketed in China and the first imported blockbuster drug marketed in China in 2020, offering a good start this year.

 (Source: NPMA)

The first ADC approved to treat solid tumors

Trastuzumab emtansine is an ADC formed by the HER2-targeting trastuzumab and microtubule inhibitor DM1 (a maytansinoid) conjugated via MCClinker. Wherein, trastuzumab is expressed via CHO cells, MCC and DM1 are produced through chemical synthesis, with every antibody connected with 3.5 pieces of DM1 averagely. The drug has been approved by the FDA for marketing in 2013 to be indicated as a single agent for the treatment of patients with HER2-positive, metastatic breast cancer who previously received Herceptin and a taxane-based chemotherapy, separately or in combination. It was originally developed by Genentech under Roche.

The marketing application for trastuzumab emtansine was filed to the NMPA in Mar. 2019, and the clinical study thereof in China for HER2-positive gastric cancer is in phase II/III. As the world’s first ADC approved to treat solid tumors, trastuzumab emtansine achieved global sales of CHF979 million in the world in 2018, growing by 8% year on year.

Three generations of ADCs

ADCs mean antibody-drug conjugates. ADCs consist of monoclonal antibodies, linkers, and cytotoxic small molecule drugs; small molecule drugs are conjugated with monoclonal antibodies through linkers. ADCs reach tumor cells relying on the specificity and targeting of monoclonal antibodies against the related antigens of tumor cells and enter the cells through endocytosis, where linkers break under the action of the low pH or lysosome protein in the cells and release cytotoxic drugs. ADCs have filled in gaps in antibody drugs and traditional chemotherapy drugs and improved drug specificity and therapeutic window. ADCs have so far experienced three generations.

Representative ADCs of Each Generation

7 ADCs approved in the world, but still none in China

The FDA has so far approved the marketing of 7 ADCs, however, there is still no ADC marketed in China.

ADCs Approved by the FDA for Marketing

 (Source: FDA)

2 HER2-ADCs marketed in the world

HER2-ADCs are definitely an R&D hotspot of global ADCs at present.

AstraZeneca and Daiichi Sankyo have early announced in Mar. 2019 that they signed a global development and commercialization cooperation agreement for the ADC DS-8201, for both parties to jointly develop and commercialize DS-8201 in the world (except Japan) and Daiichi Sankyo to reserve the market exclusivity in Japan and be solely responsible for the manufacturing and supply. Under the terms of the agreement, AstraZeneca would pay Daiichi Sankyo an upfront payment of USD1.35 billion and the subsequent R&D registration and commercial milestones, with a total transaction amount of USD6.9 billion. The transaction attracted intense attention back then. And the drug has been approved by the FDA for marketing in Dec. 2019.

Human epidermal growth factor receptor 2 (HER2) is a receptor tyrosine-protein kinase encoded by the ERBB2 (HER2) gene on chromosome 17 (17q12) and is a member of the epidermal growth factor receptor (EGF) family. HER2 amplification and overexpression are associated with breast cancer, gastric cancer, and lung cancer, etc. HER2 is a hot target in ADC R&D, and currently, two HER2-ADCs: trastuzumab emtansine and fam-trastuzumab deruxtecan-nxki are marketed in the world.

The internationally recognized first-line neoadjuvant therapy/adjuvant therapy for early HER2-positive breast cancer is trastuzumab + pertuzumab + chemotherapy, and trastuzumab emtansine and neratinib can be used as the sequential therapy following first-line therapy. The first-line therapy for metastatic HER2-positive breast cancer is trastuzumab + pertuzumab + chemotherapy, and the second-line therapy therefor includes T-DM1, pyrotinib, and lapatinib, etc. Many HER2-ADCs are currently in different phases of clinical trials in the world; wherein, Daiichi Sankyo/AstraZeneca’s DS-8201, and Synthon’s SYD985 are ahead in the progress, which have entered the phase III clinical trials; among the products in development in China, RemeGen’s RC48 and Bio-Thera’s BAT8001 have entered phase III clinical trials. Please refer to "A Comparison of Chinese-produced ADCs: RemeGen’s RC48 Has the Largest Number of Indications in Development, while Bio-Thera’s BAT8001 Has the Fastest Progress!" for more information.

As the first Chinese HER2-ADC that entered the phase III clinical trial, Bio-Thera’s BAT8001 is formed by trastuzumab conjugated with the cytotoxic linker Batansine via thioether bond.

R&D Progress of Global HER2-ADCs

(Source: Lancet; DS-8201 has been approved by the FDA for marketing)

Many enterprises developing ADCs in the world

ADCs have other targets in addition to HER2. Many international pharmaceutical giants and medical product suppliers have competed to develop ADCs in recent years. AstraZeneca and Daiichi Sankyo reached a global development and commercialization cooperation agreement for DS-8201 in Apr. 2019; under the terms of the agreement, AstraZeneca would pay Daiichi Sankyo an upfront payment of USD1.35 billion, Daiichi Sankyo would receive milestones of up to USD5.55 billion, and AstraZeneca and Daiichi Sankyo would jointly develop and commercialize DS-8201 in the world, with Daiichi Sankyo maintaining exclusive rights in the Japanese market and solely responsible for the manufacturing and supply. In Dec. 2019, MSD and Seattle Genetics/Astellas reached a cooperation agreement, to jointly conduct the clinical trial of the ADC enfortumab vedotin and Keytruda as first-line therapy for locally advanced or metastatic urothelial carcinoma. It is worth mentioning that Hengrui Medicine has taken the lead in developing the ADC that targets c-MET; among the ADCs with this target, only Abbott’s ABBV-399 leads Hengrui’s SHR-A1403.

R&D Progress of Global ADCs

(Source: Lancet)

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