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

MLR-1023 的药理学评价：研究确​​认疗效，建立

• 批准号: 8713549
• 负责人: Andrew Gerard Reaume
• 金额: $ 22.5万
• 依托单位: MELIOR DISCOVERY, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8713549
• 关键词: AKT2 gene; Address; Adipocytes; Adverse effects; Affect; Agonist; American; Amputation; Animals; Biological Assay; Biological Markers; Blindness; Blood Circulation; Blood Glucose; Cause of Death; Cells; Clinic; Clinical; Clinical Research; Clinical Trials; Data; Diet; Disease; Dose; Drug Kinetics; Epidemic; Evaluation; Event; Exhibits; FDA approved; Fatty acid glycerol esters; Glucose; Goals; Half-Life; Health Care Costs; Healthcare Systems; Human; Hypertension; In Vitro; Insulin; Insulin Receptor; Insulin Resistance; Kinetics; Life; Link; Liver; Longitudinal Studies; Malignant neoplasm of urinary bladder; Measurement; Mediating; Molecular Target; Monitor; Mus; Needle biopsy procedure; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Patients; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase II Clinical Trials; Phosphorylation; Phosphotransferases; Pioglitazone; Probability; Receptor Activation; Regimen; Research; Risk; Rodent; Rodent Model; Side; Signal Transduction; Subgroup; Testing; Therapeutic; Tissues; Translating; Ulcer; Weight Gain; base; cardiovascular risk factor; clinical efficacy; design; diabetic; drug candidate; in vivo; insulin secretion; insulin sensitizing drugs; insulin signaling; next generation; public health relevance; receptor; research clinical testing; research study; response; rosiglitazone; success

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.

描述（由申请方提供）：本项目的目的是开发MLR-1023的生物标志物，以验证林恩激酶作为治疗II型糖尿病（T2 D）的分子靶点，并使用生物标志物了解药代动力学/药效学（PK/PD）断开，以优化临床试验中的给药方案。这些目标将通过显示MLR-1023靶标接合和该接合在细胞中和在T2 D的可翻译啮齿动物模型中的动力学来实现。结果将转化为人类临床研究。T2 D在美国是一种流行病，每年都在恶化。这种疾病影响了8.3%的美国人，一些人预计到2025年这一比例将翻一番。T2 D是2007年第七大死亡原因，也是许多其他疾病的主要原因，包括失明和截肢。这种疾病对医疗保健系统造成了巨大的损失，仅在2007年就造成了约1740亿美元的医疗保健费用。尽管FDA已经批准了许多治疗T2 D的方法，但没有安全的药物可以解决该疾病最重要的病理生理因素之一：胰岛素受体不敏感性。口服活性药物候选物MLR- 1023具有成为这样的药物的潜力。以前的研究揭示了两个问题，可能会限制成功的设计和执行的临床试验，以及了解这些 试验结果。首先，目前还没有办法监测临床中的分子靶点接合。缺乏监测靶点结合的机制对验证分子靶点作为T2 D治疗提出了挑战。其次，MLR-1023在啮齿动物模型中表现出较短的药代动力学半衰期，但具有持久的药效学反应。这种PK/PD脱节给设计临床试验的最佳给药方案带来了挑战。我们建议开发MLR-1023/林恩激酶激活的靶向相关生物标志物来解决这些问题。生物标志物将允许通过了解靶点参与和临床疗效之间的关系程度来全面解释临床试验结果。此外，这种生物标志物在验证靶点作为T2 D治疗方法方面至关重要，并将推动下一代化合物的研究和发现。其次，生物标志物将补充PK数据，并有助于设计最佳临床给药模式。尽管Melior已有MLR- 1023的IND，但必须解决这些问题，以最大限度地提高II期临床试验的成功概率。将在这些研究中检验的假设是，在MLR-1023从循环中消失后，MLR-1023激发林恩激酶的持久活化，这导致持久的降糖作用。在拟定的研究中，我们将进行体外和体内实验，以鉴定MLR-1023介导的林恩激酶信号传导事件。这些研究将以林恩激酶下游底物的磷酸化事件的形式提供数据，这反过来将为临床研究中使用的分子靶标相关生物标志物提供基础。