Trop-2 ADC is surging: Fudan Zhangjiang joins the battlefield Daiichi Sankyo/AZ joins hands again

Recently, Fudan Zhangjiang’s Trop2-ADC drug FDA018 clinical application was accepted by NMPA and will soon enter the Trop-2 ADC battlefield
.

Looking at the world, Immunomedics’ Trop2 ADC drug Trodelvy has been successfully demonstrated.
After the launch of DS-8201, Daiichi Sankyo/AstraZeneca will soon launch a flagship product targeting Trop-2 ADC——DS-1062; focus on domestic , Genting Xinyao License in Trodelvy, may be a blockbuster with this explosive product, and Kelun Pharmaceutical and Junshi Biology are not far behind, and they have started clinical efforts
.
However, the development of drugs is by no means easy, and Biotech’s Trop-2 ADC has already failed

The curtain of ADC in the country is slowly being opened, and it is worth tracking who will die in the future
.

1.
Analysis of Trop-2

Trop-2 is a cell surface glycoprotein encoded and expressed by the TACSTD 2 gene
.
Studies have found that in different tissues of the human body, the expression level of Trop-2 is different.

2.
Trodelvy bears the brunt

Sacituzumab Govitecan is the first Trop-2 ADC drug approved for marketing under the trade name Trodelvy
.
In April 2020, the FDA approved the marketing authorization of Trodelvy, which is indicated for adult patients with metastatic triple-negative breast cancer (TNBC) who have previously received at least two treatments for metastatic disease

The approval of Trodelvy's TNBC indication is based on the ASCENT study.
Experimental results show that among 108 patients with metastatic TNBC who have received second-line treatment, Trodelvy’s ORR reached 33%, with CR of 2.
8% and PR of 30.
6%.
It is much higher than the efficacy of TPC (eribulin, capecitabine, gemcitabine or vinorelbine) in the chemotherapy group
.
Among the 39 patients who responded to treatment, the median duration of response (mDOR) was 7.

Trodelvy’s excellent experimental data stems from the ingenious design of ADC drugs.
Trodelvy’s design has three significant advantages:

(1) Trodelvy’s payload uses the DNA topoisomerase inhibitor SN-38, which is the active metabolite of irinotecan.
Compared with tubulin inhibitors, the toxicity is significantly reduced
.
Through the design of medium toxin payload and high DAR (DAR=7.

       (2) The shorter polyethylene glycol unit linker structure overcomes the hydrophobicity of the drug, improves the solubility of the drug in water, and may help fight drug resistance;

       (3) The use of cleavable Linker has a bystander effect
.

       3.
DS-1062-Daiichi Sankyo/AstraZeneca join hands again

       DS-1062 is a Trop-2 ADC drug jointly developed by Daiichi Sankyo and AstraZeneca
.
The Phase III clinical trial of NSCLC has been initiated .

       From its structural analysis, the selection of DXd is consistent with DS-8201.
This DNA topoisomerase inhibitor is ten times more toxic than SN-38, and can more effectively interfere with the replication and recombination of tumor cell DNA
.
But unlike DS-8201, DS-1062 only uses the design of DAR=4, and the overall toxicity of the drug is lower than that of DS-8201

       Since they all target solid tumors, lower drug toxicity may require higher doses.
This can be seen from the disclosed phase I clinical data.
WCLC19 announced the first human trial data of DS-1062, the MTD of DS-1062 and The RDE is 8mg/kg, which is significantly higher than the 5.
4mg/kg of DS-8201
.
However, in WCLC20, considering the adverse effects of 8mg/kg of interstitial pneumonia, the final MTD was determined to be 6mg/kg

       From the analysis of phase I clinical data, DS-1062 is expected to become a new treatment for advanced NSCLC.
At present, the phase III clinical trial of DS-1062 versus docetaxel for advanced or metastatic NSCLC has been carried out
.

       4.
Genting Xinyao, Junshi Biology, and Kelun Pharmaceutical make efforts

       Domestic drug R&D for Trop-2 ADC is also surging.
Three drugs have entered the clinical stage, including IMMU-132 from Genting Xinyao, SKB-264 from Kelun Pharmaceutical, and JS108 from Junshi Bio/Duxi Bio
.
In terms of clinical progress, Genting Xinyao currently ranks among the top in research and development

       IMMU-132 stands for Trodelvy.
In April 2019, Genting Shinya won the exclusive rights of Trodelvy in Greater China, South Korea and some Southeast Asian countries for US$835 million
.
In May 2020, Trodelvy was approved by the NMPA to carry out phase I clinical trials for mTNBC, and has now advanced to phase II clinical trials
.

       SKB-264 is a Trop-2 ADC drug independently developed by Kelun Botai.
On April 9th, 2020, it obtained the clinical trial notification from the State Food and Drug Administration.
It is currently in Phase I/II clinical phase.
Phase I is mainly to determine MTD, II The purpose of the phase is to evaluate the ORR of SKB264 monotherapy
.

       JS108 is a Trop-2ADC drug developed by Junshi Bio/Duxi Biosciences.
On July 21, 2020, JS108 was approved and issued by the NMPA in the "Drug Clinical Trial Approval Notice" for clinical trials of advanced solid malignant tumors
.
On November 25, 2020, Shanghai Junshi Biologics Phase 1 clinical study of JS108 has completed the first patient administration
.

       In addition to the above three Trop-2 ADCs in the clinical stage, Fudan Zhangjiang’s Trop-2 ADC is currently applying for clinical application.
Trop-2 ADC drugs such as CSPC and Hausen Pharmaceutical are in the preclinical stage.
The future Trop-2 ADC field Who will rise and fall, let us wait and see
.