Pharmacological evaluation of MLR-1023: Studies to confirm efficacy, establish a

描述(申请人提供)：该项目的目标是开发MLR-1023的生物标记物，以验证Lyn Kinase作为治疗II型糖尿病(T2D)的分子靶点，并使用该生物标记物了解药代动力学/药效学(PK/PD)断开，以便在临床试验中优化给药方案。这些目标将通过显示MLR-1023目标参与和该参与在细胞和T2D的可翻译啮齿动物模型中的动力学来实现。结果将被转化为人类临床研究。T2D是美国的一种流行病，每年都在恶化。该疾病影响了8.3%的美国人，一些人预计到2025年这一比例将翻一番。T2D是2007年第七大死亡原因，也是包括失明和截肢在内的许多其他疾病的主要原因。这种疾病对医疗体系造成了巨大的损失，仅在2007年就造成了约1740亿美元的医疗成本。尽管FDA已经批准了许多治疗T2D的方法，但还没有安全的药物来治疗这种疾病最重要的病理生理因素之一：胰岛素受体不敏感。口服活性候选药物MLR-1023有可能成为这样的药物。以前的研究揭示了两个可能限制临床试验成功设计和执行的问题，以及对这些问题的理解 试验结果。首先，目前还没有办法在临床上监测分子靶标的参与。这种缺乏监测靶点结合的机制给验证分子靶点作为治疗T2D的方法带来了挑战。其次，MLR-1023在啮齿动物模型中显示出较短的药代动力学半衰期和较长的药效学反应。这种PK/PD断开给临床试验设计最佳给药方案带来了挑战。我们建议开发一种用于MLR-1023/Lyn激酶激活的靶标生物标记物来解决这些问题。生物标记物将允许通过了解靶点参与和临床疗效之间的关系的程度来全面解释临床试验结果。此外，这样的生物标记物将对验证靶点作为治疗T2D的方法至关重要，并将推动下一代化合物的研究和发现。其次，生物标记物将补充PK数据，并有助于设计最佳临床剂量范例。尽管梅尼奥尔已有MLR-1023的现有IND，但必须解决这些问题，以最大限度地提高第二阶段临床试验的成功概率。将在这些研究中检验的假设是，MLR-1023在MLR-1023从循环中消失后很长时间内引发Lyn激酶的持久激活，从而导致持久的降糖效果。在拟议的研究中，我们将进行体外和体内实验，以确定MLR-1023介导的Lyn激酶信号转导事件。这些研究将以Lyn激酶下游底物的磷酸化事件的形式提供数据，这些数据反过来将为分子靶标生物标记物用于临床研究提供基础。

DESCRIPTION (provided by applicant): The goals of this project are to develop a biomarker for MLR-1023 in order to validate Lyn kinase as a molecular target for treatment of Type II diabetes (T2D) and use the biomarker to understand the pharmacokinetic/pharmacodynamic (PK/PD) disconnect in order to optimize a dosing regimen in clinical trials. These goals will be accomplished by showing MLR-1023 target engagement and kinetics of that engagement in cells and in a translatable rodent model of T2D. Results will be translated to human clinical studies. T2D is an epidemic in the U.S. that is worsening every year. The disease affects 8.3% of Americans, a rate that some expect to double by 2025. T2D was the seventh leading cause of death in 2007 and is a leading cause of a host of other disorders, including blindness and amputations. The disease takes a massive toll on the healthcare system, having caused about $174 billion in healthcare costs in 2007 alone. Although a host of therapies have been approved by FDA for T2D, there are no safe drugs that address one of the most important pathophysiological factors of the disease: insulin receptor insensitivity. The orally active drug candidate, MLR- 1023 has potential to be such a drug. Previous studies exposed two issues that could limit successful design and execution of clinical trials, as well as understanding those trials' results. First, at present there is no way to monitor molecular target engagement in the clinic. This absence of a mechanism for monitoring target engagement presents challenges in validating the molecular target as a treatment for T2D. Second, MLR-1023 exhibits a short pharmacokinetic half-life but a long-lasting pharmacodynamic response in rodent models. This PK/PD disconnects produces challenges in designing an optimal dosing regimen for clinical trials. We propose developing a target-linked biomarker for MLR-1023/ Lyn kinase activation to address these issues. A biomarker will permit the full interpretation of clinical trial results by understanding the extent of the relationship between target engagement and clinical efficacy. Further, such a biomarker would be critical in validating the target as a treatment for T2D and would drive research and discovery of next-generation compounds. Second, a biomarker would supplement PK data and aid in the design of an optimal clinical dosing paradigm. Although Melior has an existing IND for MLR- 1023, these issues must be addressed to maximize the probability of success in Phase II clinical trials. The hypothesis that will be tested in these studies is that MLR-1023 elicits a long-lasting activation of Lyn kinase well after the disappearance of MLR-1023 from circulation, which leads to the long-lasting glucose lowering effect. In the proposed studies, we will conduct in vitro and in vivo experiments in order to identify MLR-1023-mediated Lyn kinase signaling events. These studies will provide data in the form of phosphorylation events of downstream substrates of Lyn kinase that in turn will provide the basis for a molecular target-linked biomarker to be used in clinical studies.