Translation of a biomarker panel for the early detection of hepatocellular carcinoma

这项申请建议将我们对肝细胞癌生物标记物小组的识别转化为 商业和临床应用。我们已经确定了一种特定的翻译后修饰，这种修饰在肝癌中发生了改变。 这一变化是在肝细胞癌中制造和分泌的蛋白质上发现的N-连接多糖组成的变化 细胞。许多含有这种糖链改变的蛋白质已经被鉴定并申请了专利。我们的强者 初步证据表明，其中一些蛋白质，当与现有的生物标志物和 临床因素对肝细胞癌和肝硬变有很好的区分能力。 重要的是，我们的生物标记物努力集中在使用我们的现有技术检测早期病变上 BioMarker Panel，这是一种简单的Logistic回归算法，由岩藻糖化激肽原、α-激肽原和岩藻糖化激肽原组成。 胎儿蛋白(AFP)、碱性磷酸酶(ALK)、天冬氨酸氨基转移酶(AST)、年龄和性别。被称为 激肽原面板，它在接受者操作曲线(AUROC)下的面积(AUROC)为0.97用于区分早期 从肝硬变分期为肝细胞癌。在该小组的独立外部验证中，在三个独立的队列中， Panel对早期肝细胞癌的AUROC为0.92~0.97。因此我们对这个生物标记物的热情 面板处于高位。为了充分了解任何生物标记物的临床和商业利益，大规模临床 具有适当动力的验证性研究至关重要。因此，此应用程序的两个目标是验证 在肝癌诊断时检测早期肝癌的激肽原面板(目标1)并确定 当一个人在发展为肝细胞癌之前生物标记物呈阳性时(目标2)。在完成时 这两个目标，Glycotest将验证这一生物标志物小组，并对其表现充满信心。 Glycotest的战略重点是将其测试商业化，作为实验室开发测试(LDT)服务 产品。这些测试将由护理高危患者群体的专家销售和订购 用于治疗肝癌和纤维化--肝硬变。LDT是在单一的CLIA实验室中开发和运行的测试，由 医疗保险和医疗补助服务中心(CMS)通过临床实验室改进修正案 (CLIA)。LDT商业模式已经被许多其他美国公司成功使用，这些公司已经 将测试商业化，作为多个疾病领域的服务产品。公司将建立一个内部 销售和营销能力最初集中在主要的有影响力的医疗中心和关键的意见领袖网站 以及西海岸和东海岸地理区域，并将推行建立医疗保险的战略 这是它与外部专家合作制定的。

This application proposes to translate our identification of a biomarker panel for hepatocellular carcinoma to commercial and clinical use. We have identified a specific post-translation modification that is altered in HCC. This alteration is a shift in the composition of N-linked glycans found on proteins made in and secreted by HCC cells. Many of the proteins containing this glycan alteration have been identified and patented. Our strong preliminary evidence has shown that some of these proteins, when combined with existing biomarkers and clinical factors, have excellent discriminatory ability between those with HCC and those with cirrhosis. Importantly, our biomarker efforts have focused on the detection of early stage lesions using our current biomarker panel, which is a simple logistic regression algorithm composed of fucosylated kininogen, alpha- fetoprotein (AFP), alkaline phosphatase (ALK), aspartate aminotransferase (AST), age and gender. Called the kininogen panel, it had an area under the receiver operator curve (AUROC) of 0.97 for the differentiation of early stage HCC from cirrhosis. In an independent external validation of this panel, in three independent cohorts this panel had an AUROC of 0.92 to 0.97 in the detection of early stage HCC. Thus our enthusiasm for this biomarker panel is high. To fully understand the clinical and commercial benefits of any biomarker, a large scale clinical validation study that is appropriate powered is essential. Hence, the two goals of this application are to validate the kininogen panel for the detection of early stage HCC at the time of HCC diagnosis (Aim 1) and determine when in time an individual becomes biomarker positive prior to developing HCC (Aim 2). At the completion of these two aims, Glycotest will have validated this biomarker panel and have confidence in its performance. Glycotest's strategy is focused on commercialization of its tests as Laboratory Developed Test (LDT) service products. These tests will be marketed to and ordered by specialists who care for the patient populations at risk for liver cancers and fibrosis-cirrhosis. LDTs are tests developed and run in a single "CLIA lab" regulated by the Center for Medicare & Medicaid Services (CMS) through the Clinical Laboratory Improvement Amendments (CLIA). The LDT business model has been used successfully by many other US companies that have commercialized tests as service products in multiple disease areas. The Company will establish an internal selling and marketing capability focused initially on major influential medical centers and key opinion leader sites as well as the west coast and east coast geographical areas, and will pursue a strategy for establishing Medicare reimbursement that it has developed in collaboration with external experts.