Writer: Danni Yin
Editor: Justin Fischer
Antibody-drug conjugates (ADCs) have made considerable progress since 2019 in China. On June 9,2021, Remegen’s HER2-targeted disitamab vedotin (RC48) became the first ADC product to gain approval for use in China. Currently, three ADCs have been approved by China’s National Medical Products Administration (NMPA).
Several ADCs are in late clinical stages
As of July 20, 2021, 54 ADCs are in active clinical studies, including two in NDA, 15 in Phase III or Pivotal Phase II, while 35 are in pre-clinical stages.
Among the advanced stage ADCs, ARX788 by NovoCodex, TAA013 by TOT Biopharm, VB4-845 by Qilu and IMGN853 by Huadong Medicine have all entered clinical Phase III studies.
Everest Medicines's sacituzumab govitecan, licensed from Immunomedics, has submitted a marketing application to the NMPA and appears set to be the first Trop-2 ADC drug to be marketed in China.
Developed independently by Chinese company TOT Biopharm, TAA013 is the second ADC in late phase follows RC48, which was developed to be an affordable alternative to Kadcyla, a widely used treatment for HER2-positive breast cancer.
Most ADCs from multinational pharmaceutical companies are in late clinical stages. One prominent example is DS-8201a by Daiichi Sankyo. This ADC consists of an HER2-directed mAb trastuzumab and was approved by the FDA in late December 2019 after a successful test against T-DM1 in a Phase III clinical study. In China, DS-8201a is currently in Phase III trials and was recognized as a breakthrough therapy for treating gastric cancer.
Trop-2, Claudin 18.2 are becoming hot targets
The successful launch of trastuzumab emtansine (T-DM1) has led to anti-HER2 targets saturating the market in China. Anti-HER2 ADCs have progressed at a remarkable pace with 23 published ADCs focusing on HER2 targets as of July 20, 2021.
Nevertheless, Trop-2 and Claudin 18.2 are expected to become the hot targets after HER2.
The Trop-2 glycoprotein is overexpressed in a variety of solid tumors related to breast, urothelial, lung and pancreatic cancers. Seven anti-Trop-2-target ADCs are under development in China, and five projects are in active clinical stages. Of these, Everest Medicines's sacituzumab govitecan are making the fastest progress. Close behind are SKB264 of Kelun, DAC-002 of DAC Biotech / Junshi Biosciences and FDA018 of Fudan-Zhangjiang. Another competitor, ESG-401, a novel Anti-Trop-2 antibody-SN38 conjugate, co-developed by Escugen (诗健生物) and Levena(联宁生物), got its first Investigational New Drug (IND) application approval from the Center for Drug Evaluation (CDE). Only one ADC candidate, BAT8003 was given up by Bio-Thera in March 2021.
Claudin 18.2 is highly expressed in patients with gastric cancer. In China, we've seen five companies develop Claudin 18.2 targets, but no ADCs have made breakthrough progress yet. Among them, two are in Phase I clinical trials: Hengrui's SHR-A1904 and Miracogen's CMG901.
Some new entrants have begun developing novel and differentiated targets, such as CD38, which is highly expressed in multiple myeloma cells, BCMA, TNFα, Nectin-4, TF, ROR1, MUC1 et al.
Daiichi Sankyo announced its patritumab deruxtecan (U3-1402), an HER3 directed DXd ADC, got IND approval from the CDE to treat metastatic or unresectable non-small cell lung cancer (NSCLC). A similar Phase I study is ongoing outside of China.
ZW49, licensed to BeiGene from Zymeworks, is the only targeted biparatopic ADC in China combining a novel auristatin payload with the unique mechanisms of action of ZW25, the anti-HER2 biparatopic antibody which binds to the same domains as trastuzumab and pertuzumab.
ADCs are primarily directed against solid tumors
Currently, ADC drugs are mainly used in the field of oncology. Because of the different targets and mechanisms of action, the corresponding indications for development are also different.
They are primarily directed against solid tumors in the breast, lung, stomach, pancreas and ovaries. Some are directed against hematologic tumors such as lymphoma and multiple myeloma as well.
Not limited to oncology, AbbVie has also coupled the TNF-alpha antibody adalimumab with a glucocorticoid receptor modulator (GRM) to form ABBV-3373, a treatment for moderate-to-severe rheumatoid arthritis. DSTA4637S, developed by Genentech for patients with staphylococcus aureus infections, has entered Phase I trials as well.