The 2024 JPMorgan Healthcare Conference highly praised the development of ADCs, considering it one of the fastest-growing pharmaceutical areas. According to the latest report from market intelligence company Evaluate, the trend of ADC expansion will continue in the next few years, and the value of the category will be close to $30 billion by 2028 (Fig. 1). ADCs will continue to attract investment from large pharmaceutical companies in the coming years. Evaluate said that in 2023, ADC-focused mergers and acquisitions and collaboration activities will total nearly $100 billion, more than three times the value of similar transactions in 2022 and more than nine times that in 2019. In addition to Pfizer's $43 billion acquisition of Seagen, large transactions centered on ADC assets include AbbVie's $10 billion acquisition of ImmunoGen (involving ADC asset Elahere) and Merck's potential total of $22 billion (with a $4 billion upfront payment) to purchase three ADC assets from Daiichi Sankyo. Bristol-Myers Squibb paid $800 million upfront to purchase SystImmune's bispecific ADC BL-B01D1 for non-small cell lung cancer.

Fig. 1. ADC historical and forecasted market size (Sourcing: Evaluate Pharma).

Antibody-Drug Conjugate

There are currently 11 ADCs on the market in the United States, more than half of which were approved by the FDA in 2019 or later. In 2023, the ADC market size will exceed $10 billion for the first time, with at least five ADC drugs having annual sales exceeding $1 billion. Among them, Enhertu has achieved great success, with a significant sales growth rate. Polivy, Adcetris, Trodelvy, Tivdak and Padcev also have obvious growth rates, while Kadcyla, Bespnsa and Zynlonta have slowed down their growth rates.

Table 1. Sales of ADCs in 2023.

ADC Drug

ADCs are undoubtedly one of the hottest research areas in recent years. So far, there are 15 approved ADC drugs in the world, of which 13 are marketed in the United States, 1 is marketed in China, and 1 is marketed in Japan. Among the 13 FDA-approved ADCs, 6 target hematological indications (Fig. 2 top row), 7 target solid tumor indications (Fig. 2, bottom row), and 3 target HER2 antigens. Among these 13 approved drugs, 11 ADCs belong to the IgG1 subclass and have a crystallizable fragment (Fc) part that can effectively bind to and activate cells expressing Fcγ receptors, while the remaining two belong to the IgG4 subclass, which naturally has a lower affinity for Fcγ receptors (Fig. 2).

Fig. 2. ADC drugs approved by the FDA (Nat Rev Drug Discov. 2023, 22: 641-661).

• Kadcyla

Roche's breast cancer ADC Kadcyla is the standard treatment for HER2-positive early breast cancer with residual invasive disease in 2023. It topped the ADC sales charts in 2022, but was surpassed by Daiichi Sankyo and AstraZeneca's Enhertu in 2023. Kadcyla is the first approved HER2-targeted ADC developed jointly by Roche and ImmunoGen. It combines the microtubule inhibitor DM1 with the HER2 antibody trastuzumab via a non-cleavable linker. Kadcyla was launched in the United States in February 2013. In 2022, its global sales reached 1.89 billion Swiss francs (about 2.136 billion US dollars), and increased by 4% in 2023 to 1.966 billion Swiss francs (about 2.222 billion US dollars). This slowdown is mainly attributed to competition from biosimilars and Enhertu.

• Enhertu

Daiichi Sankyo's flagship product Enhertu and datopotamab deruxtecan, which has submitted a BLA application, are expected to bring more than $9.9 billion in annual sales to Daiichi Sankyo in the future, of which Enhertu's sales can reach $9 billion. Enhertu brought $2.57 billion in revenue to Daiichi Sankyo and its partner AstraZeneca in 2023. Enhertu's approved indications have been expanded from human epidermal growth factor receptor (HER)-2-positive breast cancer to gastric cancer and non-small cell lung cancer, as well as breast cancer with low HER2 expression levels. In 2023, with the breakthrough approval of HER2-low-expressing breast cancer, Enhertu's annual sales doubled from $1.238 billion to $2.556 billion. Earlier this year, AstraZeneca and Daiichi Sankyo again sought FDA approval to expand Enhertu's indications to HER2-positive solid tumors, and further market success is expected in the future.

• Adcetris

Adcetris is an anti-CD30 antibody conjugated to the potent anti-microtubule agent monomethyl auristatin E (MMAE) via a protease-cleavable linker and was originally developed by Seagen. In 2009, Takeda Pharmaceutical and Seagen reached an agreement granting Takeda the commercialization rights for Adcetris in countries outside the United States and Canada. Adcetris was approved by the FDA in August 2011 for the treatment of Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL). In 2021, Adcetris was approved by the European Union as a first-line treatment for sALCL expressing CD30, becoming the world's first ADC approved for first-line treatment.

• Padcev

Padcev is the first approved ADC targeting Nectin-4, co-developed by Seagen and Astellas. It was initially granted accelerated approval by the FDA in December 2019, followed by full FDA approval in July 2021 for the treatment of urothelial carcinoma. In addition to monotherapy, Padcev has also been studied in combination with Keytruda in clinical trials. In October 2023, positive results were reported from the Phase 3 EV-302 trial evaluating Padcev in combination with Keytruda in patients with previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC). The EV-302 study met both primary endpoints of overall survival and progression-free survival compared with platinum-based chemotherapy.

• Polivy

Polivy is the world's first approved ADC targeting CD79b, developed by Roche. It combines the cytotoxic agent MMAE with the CD79 antibody polatuzumab through a cleavable linker. It was approved for marketing in the United States in June 2019 for the treatment of diffuse large B-cell lymphoma (DLBCL). In April 2023, the FDA approved Polivy in combination with rituximab products, cyclophosphamide, doxorubicin and prednisone (R-CHP) for the treatment of previously untreated adult patients with DLBCL with an International Prognostic Index (IPI) score of 2 or higher. This combination is the first FDA-approved therapy for the first-line treatment of DLBCL in nearly 20 years. Thanks to the approval of this first-line combination therapy, Polivy's sales increased by 108% in 2023 to 837 million Swiss francs (946 million US dollars).

• Trodelvy

Originally developed by Immunomedics, Trodelvy is an ADC targeting Trop-2. It combines the Trop-2 antibody sacituzumab with the active metabolite SN-38 of the DNA topoisomerase I inhibitor irinotecan via a cleavable linker. In September 2020, Gilead acquired Trodelvy through its $21 billion acquisition of Immunomedics. Trodelvy received FDA accelerated approval in April 2020 and was fully approved by the FDA a year later for second-line or later treatment of patients with metastatic triple-negative breast cancer (mTNBC), making it the first FDA-approved ADC drug for the treatment of TNBC. Subsequently, Trodelvy was also approved for the treatment of urothelial carcinoma and HR+/HER2- locally advanced or metastatic breast cancer indications. With the approval of new indications, Trodelvy's sales have increased year by year. Its first full-year sales after listing were $380 million, and global sales reached $681 million in 2022. In 2023, Trodelvy sales exceeded $1 billion ($1.063 billion) for the first time, a year-on-year increase of 56%, making it a blockbuster drug.

• Elahere

ImmunoGen's Elahere (mirvetuximab soravtansine) is the latest ADC to be approved, having received accelerated approval in late 2022 for the treatment of folate receptor alpha (FRα)-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer. Elahere filed for full approval in early December 2023, a week after the AbbVie acquisition was announced.

* Representative ADC products:

According to statistics, in the first half of 2024, the total publicly disclosed transaction volume of ADC bioconjugates worldwide has exceeded US$16 billion, up 65% from the transaction volume of approximately US$9.7 billion in the same period last year. At the recently concluded American Society of Clinical Oncology (ASCO), nearly 30 ADC studies from around the world were selected for oral presentations. These drugs under development have successively disclosed positive and excellent clinical data. The innovation enthusiasm of the ASCO conference is also reflected in the ADC transactions disclosed in the first half of this year. From the perspective of targets and varieties, transactions of ADC varieties with more differentiated targets continue to heat up rapidly. ADC licensing transactions in the first half of 2024 are not limited to popular targets, but ADC transactions targeting c-MET, ROR1, FRα, and PTK7 have emerged, indicating that the industry has high hopes for the future development potential of these low-key targets.