Development of DT-110 as an oral therapeutic for type 2 diabetes

 描述（由申请人提供）：2型糖尿病是一种慢性衰弱性疾病，到2030年有可能达到大流行水平。目前，全球有近3.5亿人患有糖尿病，超过70%的2型糖尿病患者死于心血管疾病。然而，迄今为止，没有特定的糖尿病药物被认为在最小化与2型糖尿病相关的心血管疾病风险方面具有上级优势。因此，开发还降低心血管疾病风险的新的抗糖尿病药物将是非常期望和需要的。正在开发的产品是DT-110，一种三肽，作为治疗2型糖尿病的口服治疗剂。技术创新是将三肽作为口服剂型应用于治疗人类疾病。在我们的I期研究中，我们发现DT-110激活G蛋白偶联受体D（MrgprD）信号通路，该通路尚未报道与代谢疾病有关。由于MrgprD的激活已被证明在心血管系统中发挥保护作用，我们的研究结果表明，DT-110除了控制血糖水平外，还可能对心血管系统产生有益作用，因此，可能成为第一种抗糖尿病药物，可以最大限度地降低与2型糖尿病相关的心血管疾病的风险。本SBIR的长期目标是完成DT-110的临床前研究，提交IND，并将其作为一类能够降低2型糖尿病相关心血管疾病风险的新型抗2型糖尿病药物进行商业化。DT-110的作用机制与目前可用的2型糖尿病药物不同。在II期研究中，我们将验证DT-110特异性作用于这种新的信号通路以有效降低2型糖尿病患者的血糖水平并保护心血管系统的假设。该II期SBIR的具体目的是：1）检查DT-110在控制转基因小鼠的葡萄糖水平和调节血管舒张中的治疗作用，2）开发肠溶包衣DT-110，3）确定DT-110在大型动物模型中的降血糖作用。本研究将为我们了解DT-110的新作用机制及其在各种动物模型中的疗效提供重要信息，以支持IND申请，并最终 从而成功地开发出一种治疗2型糖尿病新药，该药物还可能对心血管系统具有保护作用。

 DESCRIPTION (provided by applicant): Type 2 diabetes is a chronic debilitating disease that threatens to reach pandemic level by 2030. Nearly 350 million people worldwide are currently affected by diabetes and more than 70% of patients with type 2 diabetes die of cardiovascular causes. However, no particular diabetes medication to date is considered superior in the minimization of the risk of cardiovascular diseases associated with type 2 diabetes. Therefore, development of new anti-diabetic drugs that also decreases the risk of cardiovascular diseases will be highly desirable and needed. The product being developed is DT-110, a tripeptide, as an oral therapeutic for treatment of type 2 diabetes. Technological innovation is the application of tripeptide as an oral dosage form to treat human diseases. In our phase I study, we found that DT-110 activates G protein coupled receptor D (MrgprD) signaling pathway that has not been reported to be linked to metabolic diseases. Since activation of MrgprD has been shown to play a protective role in cardiovascular system, our results suggest that DT-110 may have beneficial effects on cardiovascular system in addition to controlling blood glucose levels, and therefore, potentially be a first anti-diabetic drug that can minimize the risk of cardiovascular diseases associated with type 2 diabetes. The long-term goal of this SBIR is to complete the preclinical study on DT-110, file IND, and commercialize it as a new class of anti-type 2 diabetes drugs capable of reducing the risk of cardiovascular diseases associated with type 2 diabetes. The mechanism of action of DT-110 is different from that of the currently available medications for type 2 diabetes. In the Phase II study, we will test the hypothesis that DT-110 specifically acts on this novel signaling pathway to effectively lower the blood glucose levels and protecting cardiovascular system in the patients with type 2 diabetes. Specific aims of this Phase II SBIR are 1) to examine the therapeutic roles of DT-110 in controlling glucose levels and in regulation of blood vessel vasodilation in the genetically modified mice, 2) to develop an enteric coated DT-110, and 3) to determine the blood glucose lowering effect of DT-110 in a large animal model. This study will provide significant information for our understanding of novel mechanism of action of DT-110 and its efficacy in various animal models to support IND filing, and ultimately lead to successful development of a new drug for treatment of type 2 diabetes, which may also has a protective effect on cardiovascular system.