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12:00 AM
 | 
Feb 21, 2011
 |  BioCentury  |  Product Development

Aveo's VEGF 3-step

Aveo, Astellas hope tivozanib can replace Avastin in RCC, other solid tumors

After going public last year based on tivozanib's potential as front-line therapy for advanced renal cell carcinoma, Aveo Pharmaceuticals Inc. partnered with Astellas Pharma Inc. last week to expand the pan-VEGF receptor tyrosine kinase inhibitor into other solid tumors. Aveo hopes the deal will accelerate the timetable for testing its theory that tivozanib offers the potency and selectivity to be both a safer, more convenient tyrosine kinase inhibitor, and a potential replacement for Roche's Avastin bevacizumab.

Tivozanib is a small molecule TKI against VEGF receptor 1 (FLT1), VEGF receptor 2 (KDR/Flk-1; VEGFR-2) and VEGF receptor 3 (FLT4). It is in Phase III testing as front-line therapy for advanced RCC. Aveo licensed ex-Asian rights from Kirin Brewery Co. Ltd. in 2007.

The RCC arena is teeming with oral VEGF receptor tyrosine kinase inhibitors (TKIs). Three products are already on the market: Pfizer Inc.'s Sutent sunitinib; Nexavar sorafenib from Onyx Pharmaceuticals Inc. and Bayer AG; and GlaxoSmithKline plc's Votrient pazopanib.

A fourth, Pfizer's axitinib, has generated Phase III data but is not being evaluated in the front-line setting (see BioCentury, Dec. 13, 2010).

VEGF receptor TKIs have proven useful for treating RCC because the tumors are relatively hypervascular and thus particularly dependent on the VEGF pathway for survival, according to Aveo President and CEO Tuan Ha-Ngoc. In addition, a majority of patients with RCC express a mutation that results in overexpression of the VEGF gene.

A better mousetrap

Ha-Ngoc believes tivozanib (AV-951) might provide the right combination of efficacy and tolerability to allow it to replace Sutent as the top choice front-line therapy for advanced RCC.

The keys, he said, are tivozanib's potency and selectivity.

At the American Society of Clinical Oncology meeting in 2009, Aveo presented a poster showing that the agent inhibits phosphorylation of all three VEGF receptors more potently than all three of the marketed VEGF receptor TKIs and axitinib.

Tivozanib's IC50 values - its half maximal inhibitory concentration - for VEGF receptors 1, 2 and 3 are 0.21, 0.16 and 0.24 nM, respectively. In contrast, none of the three marketed drugs is capable of...

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