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On September 20, 2021, the US Food and Drug Administration (FDA) accelerated the approval of Tivdak (also known as tisotumab vedotin-tftv) jointly developed by Seagen and Genmab A/S, which is a first-in-class and the only approved second-line Antibody-drug Conjugate (ADC) for the treatment of adult patients with recurrent or metastatic cervical cancer. It is reported that Tivdak's accelerated approval is based on tumor remission and remission persistence data, and subsequent full approval may depend on the verification and description of clinical benefits in validation trials.
TIVDAK is a first-in-class antibody-drug conjugate directed to Tissue Factor (TF), which is a protein involved in tumor signal transduction and angiogenesis. It is overexpressed in most cervical cancer patients and many other solid tumors (including ovarian, lung, pancreas, colorectal, and head and neck cancers). Based on the high expression and rapid internalization of TF factor in many solid tumors, TF has become an ideal target for the development of ADC drugs. Recurrent and/or metastatic cervical cancer previously treated usually shows a very limited objective response rate (ORR) to standard therapies. This approval was based on the clinical trial results of 101 patients with recurrent or metastatic cervical cancer. They received at most two pre-systemic treatments, including at least one platinum-based therapeutic regimen. The results showed that Tivdak achieved an objective remission rate of 24 % (95 % CI, 15.9–33.3), and the median duration of response (DOR) was 8.3 months.
Fig. 1 Mechanism of action of tisotumab vedotin-tftv.
The active pharmaceutical ingredient of Tivdak is tisotumab vedotin, which is composed of human anti-TF IgG1-kappa antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable vc (valine-citrulline) linker. The monoclonal antibody is produced in a mammalian cell cline (Chinese hamster ovary). MMAE and the linker are produced by chemical synthesis. Each monoclonal antibody molecule carries an average of 4 MMAE molecules. Tivdak has an approximate molecular weight of 153 kDa.
Fig 2. The structure formula of Tivdak.
Tisotumab vedotin has an encouraging antitumor activity and controllable safety in a variety of tumor types, which makes it a promising candidate for cancer therapy in patients with known tissue factors. However, continuous evaluation of safety and tolerability is required. Currently, Tivdak is being jointly developed by Seagen and Genmab A/S as a monotherapy or combined with other therapies to treat recurrent and/or metastatic cervical cancer, ovarian cancer and other solid tumors. In addition, both parties are also evaluating the dosing regimen once a week or once every three weeks.
