Domestic HER2-ADC heavy debut fixed-point coupled technology is more secure and effective

ADC drugs have grown rapidly in recent years, and in 2013, the FDA approved Testuzumab Emtansine Kadcyla (T-DM1, Hessele) for the treatment of HER2-positive metastasis breast cancer patients, becoming the world's first approved antibody drug association for single-drug treatment of solid tumors.
2020, the State Administration of Drug Administration officially approved the launch of the innovative target drug Hessele.
is the first and only HER2-targeted ADC product to be linked to chemotherapy in China.
December 21, 2019, based on the TESTINY-Breast01 study, the FDA officially approved DS-8201, developed by AstraZeneta and The First Third Party, for the backline treatment of HER2-positive breast cancer.
recent days, ADC drugs have made new advances, such as the ARX788 to be described below.
ARX788 is a HER2 fixed-point coupled ADC drug jointly developed by Ambrx/Zhejiang Pharmaceuticals, arx788 fixed-point coupled process using the proprietary technology of Ambrx Corporation of the United States, the first use of non-natural amino acid insertion protein, p-acetyl phenylalanine (pAF), through -bonded coupled toxin AS269, to achieve accurate toxin-toxin on the single molecule.
with TDM1, ARX788 has good advantages in process control and drug stability, in vivo metabolism, etc.
T-DM1 has multiple coupled bits, with a coupled rate of 0-8 and an average DAR of 3.5.
ARX788 is fixed-point coupled and DAR is 2.
more importantly, the -key of the pAF-AS269 is extremely stable, with only pAF-AS269 metabolites in the body and no free toxin AS-269, which makes the ARC788 stable and safe.
December 2019, Zhejiang Pharmaceuticals announced the results of phase 1 clinical studies of ARX788 as follows: Studies have shown that ARX788 has good tolerance in patients with HER2-positive advanced breast cancer who have been treated many times in the past.
of the 51 subjects, only 2 were drug-related ≥ level 3 toxicity.
dose-limiting toxicity (DLT) was not observed in dose climbing and expansion trials from 0.33 mg/kg to 1.5 mg/kg and the maximum toned dose (MTD) has not been achieved.
as of November 20, 2019, a total of 51 Chinese female subjects had received at least one ARX788 treatment, and 17 subjects were still being treated, including one in the 0.88 mg/kg Q3W group who had been treated for nearly two years.
all subjects experienced clospaedia monotherapy and 47 percent experienced lapatiniid failure.
a total of 48 assessable subjects were assessed, and 3 subjects did not reach the time of the first assessment.
response was partial remission (PR) 19 cases, stability (SD) was 25 cases, disease control rate was 91.7% (44/48), efficacy increased with dose increase, of which 1.3 mg/kg dose group total The mitigation rate (ORR) reached 56% (9/16) and the ORR in the 1.5mg/kg Q3W group reached 63% (5/8), and the expansion study of this group is still in progress, and the total mitigation rate is expected to be further improved.
dose climb is still in the process, taking into account the benefit/risk ratio, it is proposed to use 1.5 mg/kg as the recommended dose for the later development of HER2-positive breast cancer in the late STAGE of ARX788.
follow-up results of the ARC788 were presented at the CSCO conference.
study was conducted using the standard 3-3 model (up to 1.5mg/kg Q3W) and then 2-4 doses were selected for expansion.
dose-related toxicity (DLT) for 21 days and special DLT for 63 days.
with the increase in dose, ORR is better, 1.5 mg/kg group ORR reached 68.4%, DCR 100%, no DLT occurred.
patients who had previously been treated with TKI also had ORR of 44.7%.
as of 11 August 2020, 17 of the patients were still being treated, of whom one subject in the 0.88 mg/kg Q3W group had received 937 days of treatment.
patients continue to have long-term, sustained efficacy after they stop taking the drug.
studies have shown that ARX788 has good tolerance in patients with HER2-positive advanced breast cancer who have been treated many times in the past.
safe at doses up to 1.5 mg/kg Q3W.
unique design of the ARX788 ensures that the toxin couple is very stable, that pAF-AS269 is released very little in circulation, and that the internal swallowing release of HER2-positive cells is efficient.
result is a significant increase in safety while enhancing anti-tumor activity.
from the research data, arX788 shows great potential.
, although different from DS-8201 for patients who failed treatments such as T-DM1, ARX788 showed a high response rate to patients who failed treatments such as Herceptin and Rapatini.
more importantly, the unique design of the ARX788 determines its very good security and therefore its potential.
we look forward to the continued good results of the follow-up Phase II/III study.
also hope that more innovative HER2-ADC drugs will emerge.
source: 1. Nonclinical Development of Next Generation Site-Specific HER2 Targeting Antibody Drug Conjugate (ARX788) for Breast Cancer Treatment (2020); Zhejiang Medicine and Ambrx Present Positive Top Line Data from from a Phase 1a/1b Clinical Trial of ARX788 in Metastatic HER2 Positive Breast Cancer, Retrieved December 12, 2019, from;3. Ambrx Official Website, Retrieved December 12, 2019, from