Tarextumab

近期《Nature Reviews Drug Discovery》发表了一篇关于抗血管生成药物的综述，抗血管生成药物对于人们来说可能相对较为熟悉了，特别是以2004年2月26日，人源化抗VEGF单克隆抗体贝伐单抗(Avastin)问世为分界点，抗血管生成药物逐步在肿瘤，眼科中展现出了广泛的应用。尤其是眼科，抗VEGF单一疗法能够显著改善新生血管性AMD和糖尿病性黄斑水肿(DME)患者的视力和生活质量，阿柏西普更是代表着这类眼科疾病治疗的黄金标准。而在肿瘤中靶向VEGF的疗法也成为了多种联用手段的优选方案，其中抗血管生成＋肿瘤免疫检查点抑制剂的组合的治疗效果尤其令人瞩目。而在VEGF在眼科和肿瘤的应用之外，还有其他靶点和其他应用方式可能为血管生成药物的开发提供更广泛的适应途径，该综述对其进行了简单介绍。本文将在该综述的新靶点基础上进一步拓展。非VEGF抗血管生成靶点临床前研究表明，阻断VEGF-VEGFR信号通常会通过缺氧的可能机制引发其他促血管生成因子的过度产生，如FGFs、ANGs、肝细胞生长因子(HGF)、整联蛋白和PDGFs。这些额外的促血管生成因子不是基于抗VEGF的抗血管生成药物的靶点，因此可能提供耐药机制。此外，一些炎性细胞的浸润，也可以产生对VEGF靶点的耐药性。因此应对VEGF的耐药性，理论上来看非VEGF靶点可能提供一种补偿机制，通过使血管生成转向非VEGF依赖性来规避抗VEGF抗体的作用。但不幸的是，没有确凿的证据表明将非VEGF与VEGF一起靶向治疗能提供任何额外的益处。这也是为什么目前的研究还在临床探索阶段。ANG/Tie2血管生成素（ANG）家族与Tie2通路也参与血管形成的重要阶段，如血管重塑和成熟。Ang/Tie2轴使用酪氨酸激酶进行信号转导，在病理过程中ANG2释放更多，因此目前对Ang靶点的开发主要集中在ANG2。Ang2的表达在血管重塑和炎症过程中由内皮细胞增加和释放。Ang2作为血管生成的自分泌早期启动因子，首先破坏静止血管的稳定性，从而使VEGF驱动血管生成新生血管的增殖和趋化迁移。此外，Ang2还激活表达Tie2的单核细胞/巨噬细胞(TEMs ),它们具有自身的促血管生成、促肿瘤发生、促转移和免疫抑制功能，也有关于肿瘤细胞表达Ang2的报道。图：ANG/Tie2通路相关管线统计 来源：doi:10.15252/emmm.36866.88868688666迄今为止，抗Ang2疗法的临床测试仅限于晚期癌症疾病的评估，这些研究显示出令人失望的结果。然而，有临床前证据表明，在围手术期新辅助或辅助治疗中，调节Ang2功能或Tie1/Tie2受体的药物可能更有希望治疗或抑制早期微转移疾病。这种方法的潜在危险警告包括Ang2阻断或Tie2激活增强癌细胞肝转移的可能性。未来将Ang/Tie调节剂与其他疗法(如VEGF/VEGFR2途径抑制剂、常规(或节律)化疗或免疫疗法)相结合的研究可能值得进一步的临床前验证和未来的临床试验评估，以治疗早期疾病。虽然在癌症方面受挫，Ang-2和VEGF-A在驱动血管不稳定方面具有协同作用，来自临床前研究的数据表明，Ang-2阻断与抗VEGF治疗的组合可以有效地减少渗漏、病理性新生血管形成和炎症，从而潜在地改善视网膜和脉络膜疾病的结果。而这一临床转化已经得到很好的落实。其中特别是罗氏的VEGF/Ang2双抗Faricimab已经成功上市，并在AMD、DME等疾病中达到了终点，提升了给药间隔。国内信达的IBI324，奥赛康/蔼睦医疗的ASKG712（ AM712）也是同靶点的有利竞争者。HIF抑制剂HIF（缺氧诱导因子）是一种异二聚体转录因子，由HIF1α和HIF1β亚单位组成。HIF1α由缺氧诱导，HIF1β的组成型表达不依赖于氧水平。由于缺氧是实体瘤的特征之一，这会使得HIF途径经常被激活。除了缺氧，基因突变导致的VHL功能失活（一种肿瘤抑制基因）——例如在RCCs亚群（肾透明细胞癌亚群）和VHL综合征(希佩尔-林道综合征——一种以各种器官的异常血管增生和肿瘤为特征的遗传疾病)——也能够通过稳定作用显著增加HIF表达。重要的是，HIF在促进肿瘤发生和耐药性方面也有多重作用。有趣的是该靶点还是2019年诺贝尔生理学奖的明星靶点，由19年生理学奖得主格雷格·塞门扎（Gregg L. Semenza）发现，并因为他在这方面（理解了细胞在分子水平上感受氧气的基本原理）的贡献而获奖。实际上，HIF-1抑制剂的治疗效果已经在临床前和临床研究中反复得到证实。值得注意的是，阻断哺乳动物雷帕霉素靶蛋白(mTOR)可以抑制HIF 1α-VEGF介导的血管生成途径，表明联合应用mTOR抑制剂和抗VEGF治疗可增强临床疗效。事实上，mTOR抑制剂依维莫司确实改善了接受一线VEGFR靶向TKI lenvatinib治疗的转移性肾细胞癌患者的无进展生存期。最令人瞩目的要属默沙东的Belzutifan (MK-6482，以前称为PT2977)，该药物的疗效令人印象深刻，该药物在)治疗二三线VHL突变型肾细胞癌患者的临床中观察到36.1%的患者对Belzutifan有部分反应，62.3%的患者病情稳定。这一临床数据使得该药物在2021年8月获得FDA批准。然而，在一些研究中，HIF-1抑制剂偶尔不能表现出良好的治疗效果，这也是目前需要解决的问题。一般认为，HIF-1抑制剂的开发方向是①优化HIF-1抑制剂的药代动力学和药效学性质，②寻找多种HIF-1抑制剂的良好组合，③开发一种并行的伴随诊断方法，④通过与其他抗癌策略相结合而协同获得治疗效果。图：处于研发阶段的HIF-1抑制剂 来源：doi:10.3390/cancers13112813Notch抑制剂NOTCH受体是跨膜细胞表面蛋白，控制细胞间通讯、胚胎发生和组织定向。Notch信号控制不同生理过程的稳态，其改变可引起不同的病理状态或疾病，包括遗传性综合征或获得性恶性肿瘤。而目前人类癌症中NOTCH受体的大多数致癌性改变发生在NOTCH1基因。NOTCH1受体及其配体DLL4是血管生成的重要调节因子。DLL4在肿瘤中的高表达发生在血管内皮细胞中，并与存活率降低相关。DLL 4–Notch 1和VEGF–VEGFR 2信号通路在肿瘤微血管网络的形成中相互调节。但是DLL 4–Notch 1的临床转化却并不顺利，尽管具有有效的抗肿瘤活性，但DLL4抑制剂在肝脏、心脏、肺和皮肤中表现出广泛的毒性。OncoMed公司在I期癌症研究中，测试了人源化抗-DLL4抗体demcizumab，但胰腺癌和肺癌的II期研究因毒性和缺乏疗效而中止。又例如MedImmune（后被阿斯利康收购）的DLL4单抗MEDI0639也因为种种原因而被从管线中砍去。还有，RO4929097，MRK003，tarextumab等Notch-DLL4通路抑制剂均未给出较为积极的临床数据。此外，也有研究想要通过Notch1的更上游通路来解决毒性问题，例如SERCA抑制可以有效地控制NOTCH1的运输，并且这种阻断可以在临床前白血病模型中实现，而不会引起明显的心脏毒性，不过SERCA抑制尚且等待临床转化。最有希望的一种开发方向似乎在于DLL 4/VEGF双抗，Mereo BioPharma在收购了OncoMed公司后开始开发DLL 4/VEGF双抗 OMP-305B83（Navicixizumab），2020年Mereo与鼎航医药展开了合作，由鼎航医药获得全球开发和商业化Navi的独家授权。TRIGR Therapeutics（后被Compass Therapeutics收购）也开发了一款VEGF和DLL4双抗药物ES104（TR009），后来将大中华区权益授权给了科望医药。目前正在国内开展针对不可手术切除的局部晚期或转移性结直肠癌（CRC）的1/2期临床试验(NCT05167448)。ES104是目前我国唯一进入临床试验的靶向VEGF和DLL4的双特异性抗体候选药物。图：DLL 4/VEGF双抗作用机理 来源：科望医药官网PlGF胎盘生长因子（PlGF）是个有些争议的靶点，不少研究呈现出完全矛盾的结果，目前对于它在促进肿瘤生长、血管生成和转移中的作用仍不清楚。一些临床前研究表明，PlGF与VEGF具有相同的冗余功能，用抗PlGF抗体抑制PlGF可抑制原发性肿瘤的生长和转移。其他的一些研究却得出了相互矛盾的发现，例如，显示在多种癌症模型中发现PlGF阻断反而会缺少抗血管生成作用。此外，著名的眼科用药阿柏西普可以同时靶向VEGF（A）、PlGF和VEGFB，但阿柏西普在肿瘤用药的疗效还不如贝伐单抗。尽管阿柏西普在多种肿瘤中进行了临床研究，但它只获得了FDA对二线CRC治疗的批准。Oncurious NV开发了一款PlGF单抗TB-403（ RO5323441 ）不过临床开发并不太顺利，与贝伐单抗联合治疗实体瘤的临床研究被终止。此外，TB-403与ranibizumab (Lucentis)联合用于眼科疾病，如新生血管性AMD和DME，但是这些研究似乎也停止了。对于TB-403近期的好消息只有在原位髓母细胞瘤（MB）展现出了较为安全的初步结果，结果据称令人鼓舞：11名复发MB受试者中的7名疾病稳定，这在7名受试者中的4名中稳定持续超过100天。有趣的是，已有研究表明，至少在某些情况下，由于PlGF-VEGF异二聚体的形成，PlGF表达减少而不是促进肿瘤生长，而异二聚体在刺激血管生成方面不如VEGF有效。FGFR成纤维细胞生长因子受体(FGFR)是由四个不同基因(FGFR 1-4)编码的酪氨酸激酶受体(RTKs)家族。这些受体共享相同的典型蛋白质结构，它们的信号轴参与细胞增殖、分化、组织建模和血管生成。第一代非选择性FGFR tki与受体催化位点的ATP结合域结合，但不是激酶选择性的，也靶向其他RTK，如VEGFRs和PDGFRs。这些抑制剂具有同时靶向肿瘤血管生成和增殖的优点，但是它们显示出对FGFR信号通路的适度作用，同时具有多种副作用，这限制了它们在临床实践中的应用。尽管如此，这些治疗药物中的一些已被批准用于治疗几种肿瘤类型，通常与化疗联合使用或在一线治疗失败后使用。为了克服由于非选择性抑制剂的脱靶效应引起的并发症，已经开发了第二代选择性FGFR tki，由于该受体家族不同成员的结构同源性，大多数TKI能够靶向一种以上的FGFR。但目前只有少数进入临床试验。与非选择性TKIs相比，这些选择性治疗剂的副作用减少了，最显著的副作用表现为FGF23途径的调节，随之发生钙和磷代谢的改变，如高磷血症和组织钙化。与TKIs相比，中和性抗FGFR单克隆抗体的特征在于更高的特异性，由于没有脱靶效应，这可能降低药物毒性。总结——目前尚且离不开VEGF最后，该综述对目前的新靶点进行了总结。尽管进行了广泛的临床前和临床努力，但没有令人信服的证据表明靶向血管生成途径而非VEGF在癌症或眼科疾病中提供治疗益处。虽然HIF和mTOR抑制剂已被批准用于治疗肾细胞癌，但它们的作用至少部分是由VEGF抑制介导的。该综述期望，综述内提到的靶点能够改善目前的情况。扩展阅读:VEGF靶向药物革新参考来源：Shirai Y, Chow CCT, Kambe G, Suwa T, Kobayashi M, Takahashi I, Harada H, Nam JM. An Overview of the Recent Development of Anticancer Agents Targeting the HIF-1 Transcription Factor. Cancers (Basel). 2021 Jun 4;13(11):2813. doi: 10.3390/cancers13112813. PMID: 34200019; PMCID: PMC8200185.Khan KA, Wu FT, Cruz-Munoz W, Kerbel RS. Ang2 inhibitors and Tie2 activators: potential therapeutics in perioperative treatment of early stage cancer. EMBO Mol Med. 2021 Jul 7;13(7):e08253. doi: 10.15252/emmm.201708253. Epub 2021 Jun 14. PMID: 34125494; PMCID: PMC8261516.Choueiri TK, Bauer TM, Papadopoulos KP, Plimack ER, Merchan JR, McDermott DF, Michaelson MD, Appleman LJ, Thamake S, Perini RF, Zojwalla NJ, Jonasch E. Inhibition of hypoxia-inducible factor-2α in renal cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis. Nat Med. 2021 May;27(5):802-805. doi: 10.1038/s41591-021-01324-7. Epub 2021 Apr 22. Erratum in: Nat Med. 2021 Oct;27(10):1849. PMID: 33888901; PMCID: PMC9128828.Pagliaro L, Marchesini M, Roti G. Targeting oncogenic Notch signaling with SERCA inhibitors. J Hematol Oncol. 2021 Jan 6;14(1):8. doi: 10.1186/s13045-020-01015-9. PMID: 33407740; PMCID: PMC7789735.Saulnier-Sholler G, Duda DG, Bergendahl G, Ebb D, Snuderl M, Laetsch TW, Michlitsch J, Hanson D, Isakoff MS, Bielamowicz K, Kraveka JM, Ferguson W, Carmeliet P, De Deene A, Gijsen L, Jain RK. A Phase I Trial of TB-403 in Relapsed Medulloblastoma, Neuroblastoma, Ewing Sarcoma, and Alveolar Rhabdomyosarcoma. Clin Cancer Res. 2022 Sep 15;28(18):3950-3957. doi: 10.1158/1078-0432.CCR-22-1169. PMID: 35833850; PMCID: PMC9481695.Ghedini GC, Ronca R, Presta M, Giacomini A. Future applications of FGF/FGFR inhibitors in cancer. Expert Rev Anticancer Ther. 2018 Sep;18(9):861-872. doi: 10.1080/14737140.2018.1491795. Epub 2018 Jul 2. PMID: 29936878.Cao, Y., Langer, R. & Ferrara, N. Targeting angiogenesis in oncology, ophthalmology and beyond. Nat Rev Drug Discov (2023). https://doi-org.libproxy1.nus.edu.sg/10.1038/s41573-023-00671-z

BOSTON--(BUSINESS WIRE)--AVEO Oncology (Formerly known as AVEO Pharmaceuticals, Inc.) (Nasdaq: AVEO) today announced that the National Comprehensive Cancer Network (NCCN) has updated its Clinical Practice Guidelines to include FOTIVDA® (tivozanib) as a recommended regimen for subsequent therapy. The subsequent therapy category follows the first-line treatment regimen recommendations for patients with clear cell histology renal cell carcinoma (ccRCC). On March 10, 2021, the U.S. Food and Drug Administration (FDA) approved FOTIVDA for the treatment of adults with relapsed or refractory advanced renal cell carcinoma (RCC) following two or more prior systemic therapies. FOTIVDA is an oral, next-generation vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI). “FOTIVDA’s addition to the NCCN Guidelines provides further validation for its potential to serve as an important evidence-based, well tolerated treatment option for patients with relapsed or refractory advanced RCC,” said Michael Bailey, president and chief executive officer of AVEO. “As previously announced, launch efforts are now underway, and we are committed to bringing this promising therapy to as many appropriate patients as possible.” The NCCN Clinical Practice Guidelines are the recognized standard for clinical policy in cancer care and are developed through review of evidence and recommendations from physicians and oncology researchers. The current NCCN RCC guidelines categorically make treatment recommendations for first-line or subsequent therapy options for RCC patients. FOTIVDA is now recommended by the NCCN Guidelines as a subsequent therapy for patients with ccRCC who have received two or more prior systemic therapies (Category 2a). FOTIVDA’s addition to the NCCN Guidelines follows its recent U.S. FDA approval, which was based on AVEO’s pivotal Phase 3 study, TIVO-3, comparing FOTIVDA to sorafenib in relapsed or refractory advanced RCC following two or more prior systemic therapies. The approval was also supported by three additional trials in RCC and included safety data from over 1,000 clinical trial subjects. About FOTIVDA® (tivozanib) FOTIVDA® (tivozanib) is an oral, next-generation vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI). It is a potent, selective inhibitor of VEGFRs 1, 2, and 3 with a long half-life designed to improve efficacy and tolerability. AVEO received U.S. Food and Drug Administration (FDA) approval for FOTIVDA on March 10, 2021 for the treatment of adult patients with relapsed or refractory advanced renal cell carcinoma (RCC) following two or more prior systemic therapies. FOTIVDA was approved in August 2017 in the European Union and other countries in the territory of its partner EUSA Pharma (UK) Limited for the treatment of adult patients with advanced RCC. FOTIVDA has been shown to significantly reduce regulatory T-cell production in preclinical models1. FOTIVDA was discovered by Kyowa Kirin. INDICATIONS FOTIVDA is indicated for the treatment of adult patients with relapsed or refractory advanced renal cell carcinoma (RCC) following two or more prior systemic therapies. IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Hypertension and Hypertensive Crisis: Control blood pressure prior to initiating FOTIVDA. Monitor for hypertension and treat as needed. For persistent hypertension despite use of anti-hypertensive medications, reduce the FOTIVDA dose. Cardiac Failure: Monitor for signs or symptoms of cardiac failure throughout treatment with FOTIVDA. Cardiac Ischemia and Arterial Thromboembolic Events: Closely monitor patients who are at increased risk for these events. Permanently discontinue FOTIVDA for severe arterial thromboembolic events, such as myocardial infarction and stroke. Venous Thromboembolic Events: Closely monitor patients who are at increased risk for these events. Permanently discontinue FOTIVDA for severe venous thromboembolic events. Hemorrhagic Events: Closely monitor patients who are at risk for or who have a history of bleeding. Proteinuria: Monitor throughout treatment with FOTIVDA. For moderate to severe proteinuria, reduce the dose or temporarily interrupt treatment with FOTIVDA. Thyroid Dysfunction: Monitor before initiation and throughout treatment with FOTIVDA. Risk of Impaired Wound Healing: Withhold FOTIVDA for at least 24 days before elective surgery. Do not administer for at least 2 weeks following major surgery and adequate wound healing. The safety of resumption of FOTIVDA after resolution of wound healing complications has not been established. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Discontinue FOTIVDA if signs or symptoms of RPLS occur. Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. Allergic Reactions to Tartrazine: The 0.89 mg capsule of FOTIVDA contains FD&C Yellow No.5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible patients. ADVERSE REACTIONS The most common (≥20%) adverse reactions were fatigue, hypertension, diarrhea, decreased appetite, nausea, dysphonia, hypothyroidism, cough, and stomatitis, and the most common Grade 3 or 4 laboratory abnormalities (≥5%) were sodium decreased, lipase increased, and phosphate decreased. DRUG INTERACTIONS Strong CYP3A4 Inducers: Avoid coadministration of FOTIVDA with strong CYP3A4 inducers. USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. Females and Males of Reproductive Potential: Can impair fertility. Hepatic Impairment: Adjust dosage in patients with moderate hepatic impairment. Avoid use in patients with severe hepatic impairment. To report SUSPECTED ADVERSE REACTIONS, contact AVEO Pharmaceuticals, Inc. at 1-833-FOTIVDA (1-833-368-4832) or FDA at 1-800-FDA-1088 or . Please see FOTIVDA Full Prescribing Information which is available at . About Advanced Renal Cell Carcinoma According to the American Cancer Society’s 2021 statistics, renal cell carcinoma (RCC) is the most common type of kidney cancer, which is among the ten most common cancers in both men and women. Approximately 73,750 new cases of kidney cancer will be diagnosed annually and about 14,830 people will die from this disease. In patients with late-stage disease, the five-year survival rate is 13%. Agents that target the vascular endothelial growth factor (VEGF) pathway have shown significant antitumor activity in RCC.2 According to a 2019 publication, 50% of the approximately 10,000 patients who progress following two or more lines of therapy choose not to receive further treatment,3 which may be attributable to tolerability concerns and a lack of data to support evidence-based treatment decisions in this highly relapsed or refractory patient population. About AVEO Pharmaceuticals, Inc. AVEO is an oncology-focused biopharmaceutical company committed to delivering medicines that provide a better life for cancer patients. AVEO’s strategy is to focus its resources toward the development and commercialization of its product candidates in North America, while leveraging partnerships to support development and commercialization in other geographies. AVEO’s lead candidate, FOTIVDA® (tivozanib), received U.S. Food and Drug Administration (FDA) approval on March 10, 2021 for the treatment of adult patients with relapsed or refractory renal cell carcinoma (RCC) following two or more prior systemic therapies. FOTIVDA® was approved in August 2017 in the European Union and other countries in the EUSA territory for the treatment of adult patients with advanced RCC. AVEO has previously reported promising early clinical data on ficlatuzumab (anti-HGF IgG1 mAb) in head and neck cancer, pancreatic cancer and acute myeloid leukemia and is conducting a randomized Phase 2 confirmatory clinical trial of ficlatuzumab for the potential treatment of head and neck cancer. AVEO’s pipeline of product candidates also includes AV-380 (anti-GDF15 IgG1 mAb). AVEO has previously reported the acceptance of its investigational new drug application in the U.S. for AV-380 and its initiation of a Phase 1 clinical trial for the potential treatment of cancer cachexia. AVEO’s earlier-stage pipeline includes monoclonal antibodies in oncology development, including AV-203 (anti-ErbB3 mAb) and AV-353 (anti-Notch 3 mAb). AVEO is committed to creating an environment of diversity and inclusion. Cautionary Note Regarding Forward-Looking Statements This press release contains forward-looking statements of AVEO within the meaning of the Private Securities Litigation Reform Act of 1995 that involve substantial risks and uncertainties. All statements, other than statements of historical fact, contained in this press release are forward-looking statements. The words “anticipate,” “believe,” “design,” “expect,” “hope,” “intend,” “may,” “plan,” “potential,” “could,” “should,” “would,” “seek,” “look forward,” “advance,” “goal,” “strategy,” or the negative of these terms or other similar expressions, are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. These forward-looking statements include, among others, statements about: AVEO’s ability to successfully sell and distribute FOTIVDA (tivozanib) to patients in the U.S. and to ensure it is available to as many patients as possible; the potential for FOTIVDA as a treatment option for patients with relapsed or refractory advanced RCC; the potential for FOTIVDA as a subsequent therapy for patients with ccRCC as recommended by NCCN Guidelines; the potential efficacy, safety, and tolerability of tivozanib, both as a stand-alone drug candidate and in combination with other therapies in several indications; the potential of the AVEO ACE Patient Support program to make patient access to FOTIVDA simple and to offer comprehensive services to patients regardless of insurance or financial circumstances; AVEO’s execution of its clinical and regulatory strategy for tivozanib; AVEO’s plans and strategies for current and future clinical trials of tivozanib, ficlatuzumab and AV-380 and for commercialization of FOTIVDA in the U.S.; the advancement of AVEO’s pipeline, including the advancement of ficlatuzumab in multiple clinical studies; the potential outcomes from studies of ficlatuzumab to provide AVEO with opportunities to pursue regulatory strategies; the potential clinical utility of ficlatuzumab and AV-380 in areas of unmet need and AVEO’s strategy, prospects, plans and objectives for FOTIVDA and its product candidates and for AVEO generally. AVEO has based its expectations and estimates on assumptions that may prove to be incorrect. As a result, readers are cautioned not to place undue reliance on these expectations and estimates. Actual results or events could differ materially from the plans, intentions and expectations disclosed in the forward-looking statements that AVEO makes due to a number of important factors, including risks relating to: AVEO’s ability to successfully implement its strategic plans, including its ability to successfully commercialize FOTIVDA and to obtain and maintain market and third party payor acceptance of FOTIVDA; AVEO’s ability to raise the substantial additional funds required to achieve its goals, including those goals pertaining to the commercialization of FOTIVDA; AVEO’s ability, and the ability of its licensees, to demonstrate to the satisfaction of applicable regulatory agencies such as the FDA the safety, efficacy, and clinically meaningful benefit of AVEO’s product candidates, and risks relating to the timing and costs of seeking and obtaining regulatory approvals; AVEO’s dependence on third-party vendors for the development, manufacture and supply of FOTIVDA and its product candidates; and AVEO’s ability to enter into and maintain its third party collaboration and license agreements, and its ability, and the ability of its strategic partners, to achieve development and commercialization objectives under these arrangements; AVEO’s and its collaborators’ ability to successfully enroll and complete clinical trials; AVEO’s ability to maintain compliance with regulatory requirements applicable to FOTIVDA and its product candidates; AVEO’s ability to obtain and maintain adequate protection for intellectual property rights relating to FOTIVDA and its product candidates; unplanned capital requirements; uncertainties related to AVEO’s ability to access future borrowings under the Hercules loan agreement, which turns on the achievement of milestones related to the commercialization of FOTIVDA in the U.S., which milestones may not be achieved; adverse general economic, political and industry conditions; the potential adverse effects of the COVID-19 pandemic on AVEO’s business continuity, financial condition, results of operations, liquidity and ability to successfully and timely enroll, complete and read-out data from its clinical trials; competitive factors; and those risks discussed in the sections titled “Risk Factors” and “Management’s Discussion and Analysis of Financial Condition and Results of Operations—Liquidity and Capital Resources” included in AVEO’s quarterly and annual reports on file with the Securities and Exchange Commission (SEC) and in other filings that AVEO makes with the SEC. The forward-looking statements in this press release represent AVEO’s views as of the date of this press release, and subsequent events and developments may cause its views to change. While AVEO may elect to update these forward-looking statements at some point in the future, it specifically disclaims any obligation to do so. You should, therefore, not rely on these forward-looking statements as representing AVEO's views as of any date other than the date of this press release. Any reference to AVEO’s website address in this press release is intended to be an inactive textual reference only and not an active hyperlink. References Pawlowski N et al. AACR 2013. Poster 3971 J Angulo and O Shapiro, Cancers (Basel) 2019 Sep; 11(9): 1227. [10.3390/cancers11091227] Decision Resources. RCC landscape and forecast. December 12, 2019. View source version on businesswire.com: