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AV-951 – THE ANTI-ANGIOGENIC DRUG

AV-951: Introduction

Angiogenesis is the natural biological system for the formation of vascular networks, tumor growth requires materials and energy to grow, a vascular system therefore develops to supply the growing tumor with oxygen and molecules required for cellular construction. Factors affecting angiogenesis include transforming growth factors (TGF-beta), angiogenin, vascular endothelial growth factor (VEGF), fibroblast growth factors (FGF), epidermal growth factor (EGF) as well as TGF-beta and TNF-alpha which either directly or indirectly affect angiogenic processes. The development of small molecule anti- angiogenesis compounds has been reported extensively in literature. Of which the potent AV-951 VEGFR inhibitor, (a multiple tyrosine kinase inhibitor) has been shown to inhibit VEGF receptors 1,2 and 3 as well as c-KIT and PDGFR. AV-951 PDGFR inhibitor is an oral inhibitor given once daily that has demonstrated great potential in renal carcinomas at phase 1, 2 and 3 levels. It is also being investigated in a variety of other tumor types.

AG-951 PHARMACOLOGY AND PROPERTIES:

AV-951 structure is described as a derivative of Quinoline substituted urea and its is being developed by AVEO biopharmaceuticals and its collaborator Astellas Pharma Inc. AV-951 is marketed under the trade name Tivozanib and is available in high purity from a limited number of AV-951 suppliers. AV-951 price varies greatly between suppliers ranging from $113 – 400 for a 10 mg vial, to buy AV-951 researchers are advised to shop carefully to obtain the best value for money. For AV-951 stability powders and stock solutions it is recommended that they are all stored at  or below -20°C and freeze/thaw cycles is kept to a minimum. AV-951 solubility is documented as being relatively good in DMSO with concentrations of 5 mg/ml being achievable with slight warming. AV-951 is not soluble in water or ethanol to any degree above 50 – 100 µM. AV-951 IC50 with regards to VEGFR (1, 2&3) ranges from 6.5 -30 nM while the IC50 values of AV-951 c-Kit inhibitor with regards to PDGFR(α&β), KIT, TIE2 and EPHB2 range from 24 –78 nM.

Av-951: pre-clinical

AV-951 has been demonstrated to inhibit VEGFR tyrosine kinases, more specifically it targets all three VEGFR isoforms at concentrations significantly lower than many of its competitor compounds. AV-951 has shown significant tumor inhibition in several different xerograph rat models and has demonstrated a similar inhibition in human tumour xenographs, including lung, breast, colon, ovarian, pancreas, and prostate cancer. [1;2]

AV-951 Clinical Trials

Clinically AV-951 has been reported in the treatment of renal cell carcinoma. At phase 1 stage the MTD was established with minimal toxicity at 1.5 mg per day on a schedule of four weeks on, 2 weeks off [3;4]. At the Phase 2 level with the developed dose and schedule a response rate of >25% was seen, survival was significantly improved over standard treatments. In terms of the toxicity of AV-951 significant improvements compared to standard treatments were reported with low occurrences of toxicities normally associated with TKI’s.  A Phase 3 trial are comparing Av-951 with Sorafenib in renal cell carcinoma was reported in 2011 indicating the AV-951 efficacy was greater in Renal cell carcinoma. AV-951 demonstrated a 20% increase in progression free survival which was increased to 35% in the subpopulation of naive patients.when comparing progression free survival. Evaluations of Av-952 in other cancer forms are also ongoing for breast, colorectal and lung cancers. [3;5-9]. Further evaluation in solid tumors are also been conducted in a series of trials to assess patient screening by biomarkers to increase efficiency of treatment.

References

 

   1.   Nakamura K, Taguchi E et al. KRN951, a highly potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, has antitumor activities and affects functional vascular properties. Cancer Res 2006; 66(18):9134-9142.

   2.   Murakami M, Iwai S et al. Signaling of vascular endothelial growth factor receptor-1 tyrosine kinase promotes rheumatoid arthritis through activation of monocytes/macrophages. Blood 2006; 108(6):1849-1856.

   3.   Bhargava P, Robinson MO. Development of second-generation VEGFR tyrosine kinase inhibitors: current status. Curr Oncol Rep 2011; 13(2):103-111.

   4.   De LA, Normanno N. Tivozanib, a pan-VEGFR tyrosine kinase inhibitor for the potential treatment of solid tumors. IDrugs 2010; 13(9):636-645.

   5.   Gross-Goupil M, Massard C et al. Targeted Therapies in Metastatic Renal Cell Carcinoma: Overview of the Past Year. Curr Urol Rep 2011.

   6.   Gupta S, Fishman M. Progress and contrasts of the development of tivozanib for therapy of kidney cancer. Expert Opin Pharmacother 2011; 12(18):2915-2922.

   7.   Eskens FA, de Jonge MJ et al. Biologic and clinical activity of tivozanib (AV-951, KRN-951), a selective inhibitor of VEGF receptor-1, -2, and -3 tyrosine kinases, in a 4-week-on, 2-week-off schedule in patients with advanced solid tumors. Clin Cancer Res 2011; 17(22):7156-7163.

   8.   Coppin C, Kollmannsberger C et al. Targeted therapy for advanced renal cell cancer (RCC): a Cochrane systematic review of published randomised trials. BJU Int 2011; 108(10):1556-1563.

   9.   Negrier S, Raymond E. Antiangiogenic treatments and mechanisms of action in renal cell carcinoma. Invest New Drugs 2011.

Related Products

Cat.No. Product Name Information
S1207 Tivozanib (AV-951) Tivozanib (AV-951, KRN-951) is a potent and selective VEGFR inhibitor for VEGFR1/2/3 with IC50 of 30 nM/6.5 nM/15 nM, and also inhibits PDGFR and c-Kit, low activity observed against FGFR-1, Flt3, c-Met, EGFR and IGF-1R. Phase 3.

Related Targets

VEGFR