Narmafotinib

HIGHLIGHTS Amplia's highly selective FAK inhibitor AMP945, when used in combination with FOLFIRINOX, enhances survival in a preclinical model of pancreatic cancer FOLFIRINOX is the most widely used treatment for pancreatic cancer patients in the US, Canada and most European countries This new data supports clinical studies investigating the combination of AMP945 in a second major treatment regimen in pancreatic cancer Amplia has filed a patent to cover the use of FAK inhibitors in combination with FOLFIRINOX and related treatment regimes MELBOURNE, Australia, May 29, 2023 /PRNewswire/ -- Amplia Therapeutics Limited (ASX: ATX) ("Amplia" or the "Company") is pleased to announce new data showing the efficacy of its investigational FAK inhibitor, AMP945, in a preclinical model of pancreatic cancer, when used in combination with FOLFIRINOX treatment. FOLFIRINOX, a combination of four chemotherapies used in the treatment of pancreatic cancer patients, is currently a widely-used treatment in many major markets around the world including the US. New data from preclinical studies conducted in the laboratory of Prof. Paul Timpson at the Garvan Institute of Medical Research in Sydney, demonstrate that mice treated with AMP945 in addition to FOLFIRINOX show improved overall survival compared to those treated with FOLFIRINOX alone. The data, available in the Meeting Abstracts for the forthcoming American Society of Clinical Oncology meeting in Chicago, USA, (here)[1] describe studies in mice bearing pancreatic cancer tumours derived from a human patient. AMP945 was given in the days preceding FOLFIRINOX treatment (given on a 12-day cycle) resulting in a statistically significant increase in survival (up to 35% approx.) compared to FOLFIRINOX-only treated mice. Dr Chris Burns, Amplia's CEO and Managing Director commented: "The exciting results from this mouse study further indicate the potential of AMP945 in pancreatic cancer treatment when used in combination with standard-of-care therapies. In light of this data, we have filed a patent to cover the use of FAK inhibitors, and particularly AMP945, in combination with FOLFIRINOX and related treatment regimes." With this data, and the Company's previously reported preclinical data demonstrating the benefit of combining AMP945 with gemcitabine and nab-paclitaxel, AMP945 has shown promising activity in models of pancreatic cancer with the two most common first-line chemotherapy regimens for treatment of the disease. Prof. Nick Pavlakis, a medical oncologist at the Royal North Shore Hospital in Sydney, and an investigator in the current ACCENT trial, commented: "FOLFIRINOX is employed under certain conditions in Australia and more broadly in the USA and Europe, and the data from this study, coupled with the developing safety and tolerability data from Amplia's current ACCENT trial, provide strong support to undertake a future clinical study of AMP945 with FOLFIRINOX." This ASX announcement was approved and authorised for release by the Board of Amplia Therapeutics. About AMP945 AMP945 is an orally bioavailable small molecule FAK inhibitor with a best-in-class profile. The compound is currently undergoing a Phase 1b/2a trial in pancreatic cancer patients in combination with gemcitabine and nab-paclitaxel (the ACCENT trial) in Australia. More information about the ACCENT trial, including a list of participating sites, can be found via our website and at ClinicalTrials.gov under the identifier NCT05355298. About FOLFIRINOX FOLFIRINOX is combination chemotherapy consisting of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin used in the treatment of pancreatic cancer. In Australia, FOLFIRINOX is reserved for younger, fitter patients whereas in other countries (e.g. US, UK, Canada, France) it is standard-of-care therapy where it has been shown to result in a median overall survival of 11.1 months. Related chemotherapies such as FOLFOX and FOLFIRI are used to treat colorectal cancer and other gastric cancers. About Amplia Therapeutics Limited Amplia Therapeutics Limited is an Australian pharmaceutical company advancing a pipeline of Focal Adhesion Kinase (FAK) inhibitors for cancer and fibrosis. FAK is an increasingly important target in the field of cancer immunology and Amplia has a particular development focus in fibrotic cancers such as pancreatic cancer. FAK also plays a significant role in a number of chronic diseases, such as idiopathic pulmonary fibrosis (IPF). For more information visit and follow Amplia on Twitter (@ampliatx) and LinkedIn. SOURCE Amplia Therapeutics

2022年10与18日，应世生物在19届国际黑色素瘤学会（SMR）年会上，公布在研管线IN10018的一项在美国和澳大利亚开展Ib期恶性黑色素瘤临床研究初步结果。数据显示，IN10018在治疗葡萄膜黑色素瘤（Uveal Melanoma，UM）和NRAS突变黑色素瘤患者中，表现出极具潜力的抗肿瘤疗效和良好可控的安全性。关于IN10018IN10018是一种高效和高选择性的黏着斑激酶（FAK）抑制剂，为应世生物从勃林格殷格翰引进，获得其全球开发及商业运营权。N10018目前已在超过250多例患者用药，尤其在铂耐药类卵巢癌和黑色素瘤中，显示出良好的安全性和极具潜力的疗效信号。正在开发用于包括铂耐药复发卵巢癌、黑色素瘤、三阴性乳腺癌、头颈部肿瘤、KRAS G12C突变肿瘤、胰腺癌等多种缺乏有效治疗手段的实体瘤适应症。其中，IN10018联合脂质体多柔比星（PLD）治疗铂耐药复发卵巢癌已于2021年8月获得了FDA的快速通道认证，并于2022年4月获得NMPA突破性治疗药物认定。值得注意的是，N10018有望通过调节肿瘤微环境（TME）来克服肿瘤相关的纤维化屏障并增强局部免疫反应。因此，可与不同疗法相联合。根据临床前数据，IN10018在临床前与化疗、靶向治疗、免疫治疗、放射治疗等多种治疗方式都具有良好的协同作用。这也是应世生物的主要布局侧重点。关于黏着斑激酶FAK信号通路来源：Nat Rev CancerFAK是一种非受体酪氨酸激酶，是介导细胞与细胞之间，细胞与细胞外基质信号转导的重要胞内分子，与肿瘤细胞生存、增殖、凋亡、迁移及血管生成等密切相关。它的表达在多种肿瘤类型中是上调的，包括蛋白高表达以及过度激活，存在于几乎所有的肿瘤组织当中，例如常见的肺癌、胃癌、结直肠癌、子宫癌以及黑色素瘤等等。研究人员发现，在临床前模型中抑制FAK信号通路可以有效地扭转之前因耐药性而导致的化疗和靶向治疗失败，并提高免疫治疗对实体瘤的反应和疗效。临床进展IN10018临床进展来源：应世生物官网此次会议公布的这项Ib期研究，旨在评估IN10018单药或与MEK抑制剂Cobimetinib （Cobi）联合治疗UM或NRAS突变黑色素瘤患者的安全性和抗肿瘤疗效。该研究正在美国和澳大利亚共计8个中心进行。截至2022年6月30日，共有45名UM或NRAS突变黑色素瘤患者入组，其中93%患者在此前接受过免疫检查点抑制剂治疗。IN10018 100 mg QD单药或与Cobi 60 mg 联用被确定为推荐剂量。Cobi由罗氏研发上市，此前公司与罗氏达成IN10018与Cobi联合治疗的全球临床开发合作。在UM患者中，IN10018单药治疗在10例疗效可评估患者中的中位无进展生存期（mPFS） 为 2.73个月；IN10018 联用Cobi治疗在8名疗效可评估患者中的mPFS为6.52个月。在NRAS突变黑色素瘤患者中，IN10018单药治疗在7例理疗学可评估患者中的mPFS为 2.79个月，其中有1例PR。更令人振奋的结果来自于IN10018 联用Cobi治疗NRAS突变黑色素瘤患者，在13例可评估患者中报告5例 PR和5例SD，ORR 为38.5%（5/13），DCR为76.9%（10/13），中位PFS为5.45个月。安全性方面，IN10018与Cobi联合治疗与IN10018单药相当，未观察到有毒性的叠加。FAK竞争格局现阶段FAK抑制剂主要通过抑制FAK磷酸化，阻断信号传导发挥作用。根据其发挥作用的机制不同可分为两大类：ATP依赖和非依赖的FAK抑制剂。目前多种ATP依赖的小分子FAK抑制剂已进入临床试验用于治疗肿瘤。根据药渡数据检索，布局FAK抑制剂的企业并不多，临床进展大多处于I、II期。以全球研发状态来看，进度最快的是Defactinib、AMP-945处于临床II期，在国内方面，苏州亚盛也有布局FAK抑制剂，处于临床I期。Defactinib第一个进入临床试验的是辉瑞研发的PF-562271，是一种ATP竞争性抑制剂，靶向FAK和富含脯氨酸的酪氨酸酶2（Pyk2）。Defactinib相比其前体PF-562271，药效学更优，辉瑞在2012年将其转让给Verastem。2021年，Defactinib单独或联合化疗药物对晚期卵巢癌、胰腺导管腺癌、恶性胸膜间皮瘤和KRAS突变的非小细胞肺癌治疗均已进入II期临床试验。但在恶性胸膜间皮瘤适应症上，Defactinib虽然安全性良好，但是由于缺乏治疗效果而终止。另有数据表明，Defactinib可以明显增强卵巢癌细胞对紫杉醇的敏感性。AMP-945Amplia Therapeutics于2021年公布了AMP-945的I期临床试验结果，结果表明，口服AMP945可导致活性pFAK的降低，并且FAK抑制的程度与药物水平相关。这些数据将用于进一步完善AMP945的剂量水平，为胰腺癌患者的II期临床试验提供数据支持。该项II期试验于2021年11月完成试验设计。此外，Amplia还计划于2022年末开展AMP945关于肺纤维化适应症的临床试验。APG-2449APG-2449是由亚盛医药自主研发的FAK/ALK/ROS1多酶抑制剂，目前处于临床I期。临床前研究数据表明，在临床前卵巢癌肿瘤模型中，APG-2449通过抑制FAK的功能从而使卵巢癌对化疗药物再次敏感。联合治疗中可减少肿瘤干细胞的数量，显示出协同抗肿瘤活性，因此，APG-2449联合化疗药物具有治疗卵巢癌具有发展潜力。参考来源应世生物官网药渡数据库