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发表于 2019-10-23 10:40:44 | 显示全部楼层 |阅读模式
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 楼主| 发表于 2019-10-23 10:46:42 | 显示全部楼层
Tivozanib(FOTIVDA®)是一种口服,每日一次的血管内皮生长因子(VEGF)酪氨酸激酶抑制剂(TKI),由Kyowa Hakko Kirin发现并在欧洲被批准用于治疗成年晚期肾细胞癌(RCC)的成年患者联盟以及挪威,新西兰和冰岛。它是所有三种VEGF受体的强效,选择性和长效半衰期抑制剂,旨在优化VEGF阻断作用,同时将脱靶毒性降至最低,从而有可能提高疗效,并最大程度地减少剂量。1,2减少临床前模型中调节性T细胞的产生,与免疫调节疗法结合使用时可潜在增强活性。

作为北美注册计划的一部分,目前正在3期TIVO-3试验中研究tivozanib,这是一项随机,对照,多中心,开放标签的研究,用于比较tivozanib与索拉非尼在难治性晚期RCC患者中的作用。已经对Tivozanib的多种肿瘤类型进行了研究,包括肾细胞癌,肝细胞癌,结直肠癌和乳腺癌。 TIVO-3试验的阳性结果公布于2018年11月。基于这些阳性结果,以及2019年9月宣布的预先确定的总体存活率分析令人鼓舞的结果,公司计划与美国食品药品监督管理局会面在2019年第四季度讨论tivozanib在RCC中的适当发展方向,并在这些讨论之后提供有关tivozanib在RCC中可能提交新药申请的最新信息。 AVEO还正在评估tivozanib与Bristol-Myers Squibb的PD-1抑制剂OPDIVO®(nivolumab)和阿斯利康的PD-L1抑制剂IMFINZI®(durvalumab)分别用于RCC和肝细胞癌。 Tivozanib在VEGF TKI中具有独特的耐受性,使其成为与免疫疗法结合使用的潜在独特候选者。

2015年12月,AVEO与EUSA Pharma签订了独家许可协议,授予tivozanib欧洲用于肿瘤适应症的权利。该协议还包括北美以外的许多其他地区,包括南美和南非,以及其他潜在的迹象。 2017年8月,AVEO宣布欧洲委员会(EC)批准了FOTIVDA®(tivozanib)用于治疗欧盟以及挪威,新西兰和冰岛的RCC成年患者。替沃扎尼适用于患有晚期RCC的成年患者的一线治疗,以及先前用细胞因子疗法治疗晚期RCC的疾病进展后未发生血管内皮生长因子受体(VEGFR)和mTOR途径抑制剂的成年患者。 2017年9月,AVEO宣布EUSA Pharma根据与AVEO的FOTIVDA®(tivozanib)的多领域许可协议,选择了TiNivo 1/2期研究以及未来潜在的组合开发。根据协议条款,EUSA可以将研究数据用于监管或商业目的,以换取总计200万美元的研究与开发经费。

实体瘤中的VEGF
血管内皮生长因子(VEGF)通路在血管生成中起着重要作用,而血管生成对癌症至关重要。血管生成是新血管的形成,对于内皮细胞的增殖,迁移和存活至关重要。有五个已知的VEGF配体(A,B,C,D,PLGF)和三个VEGF受体(1、2和3)。每个配体对三种VEGF受体显示出独特但重叠的结合曲线。

为了最佳地抑制VEGF途径,有效阻断所有三种VEGF受体可能至关重要,因为每种受体在癌症血管生成中均起着重要作用:

VEGF受体1对于调节内皮细胞存活和血管形态发生至关重要。
VEGF受体2被认为是内皮细胞增殖和迁移的主要受体。和,
VEGF受体3促进内皮发芽和血管网络形成。
临床前研究表明,替沃扎尼是所有三种VEGF受体的强效,选择性,长半衰期抑制剂,旨在优化VEGF阻断作用,同时将脱靶毒性降至最低。


Tivozanib (FOTIVDA®) is an oral, once-daily, vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) discovered by Kyowa Hakko 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 modifications.1,2 Tivozanib has been shown to significantly reduce regulatory T-cell production in preclinical models, enabling potentially enhanced activity when used in combination with immune modulating therapy.

As part of a North American registration plan, tivozanib is currently 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. Tivozanib has been investigated in several tumor types, including renal cell, hepatocellular, colorectal and breast cancers. Positive topline results from the TIVO-3 trial were announced in November 2018. Based on these positive topline results, as well as encouraging results from a prespecified overall survival analysis announced in September 2019, the Company plans to meet with the U.S. Food and Drug Administration to discuss the appropriate path forward for tivozanib in RCC in the fourth quarter of 2019, and to provide an update regarding the potential submission of a New Drug Application for tivozanib in RCC following these discussions. AVEO is also evaluating tivozanib in combination with Bristol-Myers Squibb’s PD-1 inhibitor OPDIVO® (nivolumab) and AstraZeneca’s PD-L1 inhibitor IMFINZI® (durvalumab) in RCC and hepatocellular carcinoma, respectively. Tivozanib’s distinct tolerability profile among VEGF TKIs makes it a potentially unique candidate for use in combination with immunotherapy.

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 August 2017, AVEO announced that the European Commission (EC) approved FOTIVDA® (tivozanib) for the treatment of adult patients with RCC in the European Union plus Norway, New Zealand, and Iceland. Tivozanib is indicated for the first line treatment of adult patients with advanced RCC and for adult patients who are vascular endothelial growth factor receptor (VEGFR) and mTOR pathway inhibitor-naïve following disease progression after one prior treatment with cytokine therapy for advanced RCC. 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.

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.
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