Tivozanib (VEGFR 123 TKI)

Tivozanib (FOTIVDA®) is an oral, once-daily, next-generation vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) discovered by Kyowa Kirin and approved for the treatment of adult patients with advanced renal cell carcinoma (RCC) in the European Union plus Norway, New Zealand and Iceland. It is a potent, selective and long half-life inhibitor of all three VEGF receptors and is designed to optimize VEGF blockade while minimizing off-target toxicities, potentially resulting in improved efficacy and minimal dose modifications1,2. Tivozanib has been shown to significantly reduce regulatory T-cell production in preclinical models3 and has demonstrated synergy in combination with nivolumab (anti PD-1) in a Phase 2 study in RCC4. Tivozanib has been investigated in several tumor types, including renal cell, hepatocellular, colorectal, ovarian and breast cancers.

As part of a North American registration plan, tivozanib is being studied in the Phase 3 TIVO-3 trial, a randomized, controlled, multi-center, open-label study to compare tivozanib to sorafenib in subjects with refractory advanced RCC. In November 2018, AVEO announced that the TIVO-3 trial met its primary endpoint of demonstrating a significant improvement in progression free survival (PFS) and that the study also demonstrated a significant improvement in the secondary endpoint of overall response rate (ORR). In May 2020, the Company announced the final hazard ratio for the study’s secondary endpoint of OS. On June 1, 2020, the U.S. Food and Drug Administration (FDA) accepted for filing the New Drug Application (NDA) for tivozanib as a treatment for relapsed or refractory RCC and assigned a Prescription Drug User Fee Act (PDUFA) target action date of March 31, 2021.

Tivozanib Mechanism of Action

In December 2015, AVEO entered into an exclusive licensing agreement with EUSA Pharma granting European rights to tivozanib for oncology indications. The agreement also includes a number of additional territories outside North America, including South America and South Africa, and additional potential indications. In September 2017, AVEO announced that EUSA Pharma, under its multi-territory licensing agreement with AVEO for FOTIVDA® (tivozanib), opted into the Phase 1/2 TiNivo study and potential future combination development. Under terms of the agreement, EUSA may utilize data from the study for regulatory or commercial purposes in exchange for a research and development funding payment totaling $2.0 million.

VEGF In Solid Tumors

The vascular endothelial growth factor (VEGF) pathway plays a significant role in angiogenesis, which is critical in cancer. Angiogenesis, the formation of new blood vessels, is essential for endothelial cell proliferation, migration and survival. There are five known VEGF ligands (A, B, C, D, PLGF) and three VEGF receptors (1, 2 and 3). Each ligand exhibits distinct but overlapping binding profiles for the three VEGF receptors.

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To optimally inhibit the VEGF pathway it may be critical to effectively block all three VEGF receptors as each plays an important role in cancer angiogenesis:

  • VEGF receptor 1 is critical for the modulation of endothelial cell survival and vessel morphogenesis;
  • VEGF receptor 2 is thought to be the predominant receptor for endothelial cell proliferation and migration; and,
  • VEGF receptor 3 promotes endothelial sprouting and vascular network formation.

Preclinical studies have demonstrated tivozanib is a potent, selective, long half-life inhibitor of all three VEGF receptors that is designed to optimize VEGF blockade while minimizing off-target toxicities.

1. Fotivda (Tivozanib) SmPC August 2017
2. Motzer RJ, Nosov D, Eisen T, et al. J Clin Oncol 2013; 31(30): 3791-9.
3. Pawlowski N et al. AACR 2013. Poster 3971
4. Barthelemy et al. ESMO 2018. Poster 878P

Tivozanib is an investigational drug and has not yet been approved by the U.S. Food and Drug Administration (FDA).