The U.S. Food and Drug Administration (FDA) earlier today confirmed that it has granted Breakthrough Therapy designation to DS-8201, an investigational HER2-targeting antibody-drug conjugate or ADC being developed by Daiichi Sankyo. The agent is designed for the treatment of patients with HER2-positive, locally advanced or metastatic breast cancer who have been treated with trastuzumab and pertuzumab and have disease progression after ado-trastuzumab emtansine (T-DM1 | Kadcyla®; Genentech/Roche).
Using Daiichi Sankyo’s proprietary ADC technology, DS-8201 is a smart chemotherapy comprised of a humanized HER2 antibody attached to a novel topoisomerase I inhibitor payload, a derivative of the camptothecin analog exatecan (DXd; DX-8951 derivative), by a tetrapeptide linker. 
We’re committed to rapidly progressing the development of DS-8201 and look forward to working closely with the FDA to potentially bring this new treatment option to patients with metastatic breast cancer as quickly as possible…
A topoisomerase I inhibitor works by binding to the topoisomerase enzyme molecule. This blocks the ability of the topoisomerase to bind the DNA back together after it has been cut, thereby making the enzyme nonfunctional.
Overall, the novel investigational agent is designed to deliver enhanced cell destruction upon release inside the cell and reduce systemic exposure to the cytotoxic payload (or chemotherapy) compared to the way chemotherapy is commonly delivered.
Mode of Action
Upon antibody/antigen binding and internalization, the DX-8951 derivative moiety which is the cytotoxic payload attached to DS-8201, detaches and inhibits Top1-DNA complexes. In turn, this results in an inhibition of DNA replication, cell cycle arrest and tumor cell apoptosis. HER2, a tyrosine kinase receptor, is overexpressed by many cancer cell types. In addition, DS-8201 induces antibody-dependent cell-mediated cytotoxicity (ADCC) and causes a bystander killing effect, thereby killing neighboring HER2-expressing tumor cells.
Breakthrough Therapy designation is designed to expedite the development and review of medicines that may demonstrate substantial benefit over currently available treatments in order to ensure that patients with serious diseases have access to new treatments as soon as possible. And currently, there is no FDA-approved therapy for patients with HER2-positive metastatic breast cancer with disease progression following treatment with other HER2-targeting agents trastuzumab (Herceptin®; Genentech/Roche), pertuzumab (Perjeta®; Genentech/Roche) and ado-trastuzumab emtansine.
“The Breakthrough Therapy designation for DS-8201 in HER2-positive metastatic breast cancer acknowledges the unmet medical need these patients face when currently approved treatments no longer control their disease,” said Antoine Yver, MD, MSc, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo.
“We remain committed to rapidly progressing the development of DS-8201 and look forward to working closely with the FDA to potentially bring this new treatment option to patients with metastatic breast cancer as quickly as possible,” Yver added.
The Breakthrough Therapy designation was granted based on the results of the ongoing phase 1 study assessing the safety, tolerability and preliminary efficacy of DS-8201. In the phase 1 study, no dose limiting toxicities were observed, and the maximum tolerated dose was not reached. Preliminary results of DS-8201 from a subgroup analysis of HER2-expressing metastatic breast cancer pre-treated with trastuzumab, pertuzumab and T-DM1 were recently presented at the 2017 annual meeting of the American Society of Clinical Oncology (ASCO).
About one in five patients with breast cancer overexpress HER2, a tyrosine kinase receptor growth-promoting protein found on the surface of some cancer cells, which is associated with aggressive disease. Many tumors advance to the point where no currently approved HER2-targeting treatment continues to control the disease. Furthermore, there is no standard of care for HER2-positive tumors following treatment with trastuzumab, pertuzumab and T-DM1.
As a result, the Breakthrough Designation, based on preliminary clinical evidence, highlights the potential of the novel investigational agent in offering substantial clinical benefit to patients with a high unmet medical need.