Merck & Daiichi Sankyo Submit IND Application in China for CDH6-Targeted ADC DS-6000a

On October 27, the CDE website showed that MSD/Daiichi Sankyo’s CDH6-targeted antibody-drug conjugate (ADC) DS-6000a had applied for clinical trials in China. This product is the second CDH6 ADC to apply for clinical trials in China after AMT-707 developed by Putz Discovery.

DS-6000a (raludotatug deruxtecan, R-DXd) is composed of a humanized anti-CDH6 IgG1 monoclonal antibody, a cleavable tetrapeptide linker, and a topoisomerase I (Top I) inhibitor, with a DAR value of 8 and a bystander killing effect. In October this year, MSD and Daiichi Sankyo reached a collaboration, with a total deal worth $22 billion, granting MSD global development and commercialization rights for three ADCs, including DS-6000a (see: ).

CDH6 (Cadherin-6), a member of the cadherin family, is overexpressed in various tumors, particularly in ovarian cancer (65%-85%) and renal cell carcinoma, but its expression is very low in normal tissues. Studies have shown that CDH6 overexpression is associated with tumor cell growth and proliferation, mainly participating in cell adhesion, organ development, and epithelial-mesenchymal transition processes.

This month, Daiichi Sankyo presented the ovarian cancer subgroup data from the Phase I study of DS-6000a in solid tumors at the ESMO Congress. As of July 14, 2023, the study enrolled a total of 60 patients with advanced or metastatic ovarian cancer who were unsuitable for standard treatment, regardless of CDH6 expression status. These patients were assigned to receive treatment in the 4.8-8.0mg/kg dose group.

The results showed,The confirmed objective response rate (ORR) was 46% (23/50)., including 1 case of complete response (CR) and 22 cases of partial response (PR), with 4 additional patients having unconfirmed disease response; the median duration of response (DOR) was 11.2 months, and the median progression-free survival (PFS) was 7.9 months.

In terms of safety, 15% of patients discontinued treatment due to treatment-emergent adverse events (TEAEs), and the incidence rate of grade 3 or higher TEAEs was 51.7%. The most common grade 3 or higher TEAEs were anemia (18.3%), decreased neutrophil count (11.7%), decreased platelet count (5.0%), fatigue (3.3%), nausea (1.7%), vomiting (1.7%), diarrhea (1.7%), and decreased appetite (1.7%).

In the 4.8-6.4mg/kg dose group, four patients reported Grade 2 interstitial lung disease (ILD) events, two of which were confirmed to be treatment-related. In the 8.0mg/kg dose group, two patients reported treatment-related Grade 5 ILD events. The 8.0mg/kg dose group was discontinued due to a high incidence of Grade 3 or higher TEAEs and minimal treatment benefit.

In 2020, there were approximately 314,000 confirmed cases of ovarian cancer globally and over 207,000 deaths from ovarian cancer. About 70%-80% of ovarian cancer patients experience recurrence after platinum-based chemotherapy, and treatment options for these patients are limited.

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