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

本申请提出将我们对肝细胞癌的生物标志物组的鉴定转化为 商业和临床应用。我们已经确定了一个特定的翻译后修饰，在HCC中改变。 这种改变是在HCC中产生和分泌的蛋白质上发现的N-连接聚糖组成的变化 细胞许多含有这种聚糖改变的蛋白质已经被鉴定并获得专利。我们强大 初步证据表明，当与现有的生物标志物结合时， 临床因素对HCC和肝硬化患者有很好的区分能力。 重要的是，我们的生物标志物的努力集中在检测早期病变，使用我们目前的 生物标志物组，其是由岩藻糖基化激肽原、α- 甲胎蛋白（AFP）、碱性磷酸酶（ALK）、天冬氨酸转氨酶（AST）、年龄和性别。称为 激肽原面板，它具有0.97的受试者操作曲线下面积（AUROC），用于区分早期 肝硬化的HCC分期。在该小组的独立外部验证中，在三个独立的队列中， 该组在早期HCC检测中的AUROC为0.92至0.97。因此，我们对这种生物标志物的热情 面板很高。为了充分了解任何生物标志物的临床和商业效益， 验证研究，是适当的权力是必不可少的。因此，该应用程序的两个目标是验证 在HCC诊断时检测早期HCC的激肽原组（目的1），并确定 当个体在发展HCC之前及时变为生物标志物阳性时（目标2）。完成时 这两个目标，Glycotest将验证这个生物标志物面板，并有信心在其性能。 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.这些测试将被销售给那些照顾有风险的患者群体的专家并由他们订购 治疗肝癌和肝纤维化LDT是在由美国食品药品监督管理局监管的单一"CLIA实验室"中开发和运行的测试。 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的商业模式已被许多其他美国公司成功地使用， 将商业化检测作为多个疾病领域的服务产品。公司将建立内部 销售和营销能力最初集中在主要有影响力的医疗中心和关键意见领袖网站 以及西海岸和东海岸的地理区域，并将推行建立医疗保险的战略， 它与外部专家合作开发的补偿。

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.