Development of an oral therapeutic to mimic the anti-diabetic effects of gastric bypass surgery

 描述(申请人提供)：葡萄糖稳态和食物摄入量的调节都是通过营养刺激下肠道内分泌细胞(L细胞)后分泌的肠道激素来促进的。这一过程在糖尿病患者中受到损害，但当促进氨基酸和脂肪酸等饮食化合物向下肠道输送时，这一过程就会恢复。这种向下肠道输送营养物质的效果是在胃过后观察到的 搭桥手术和在结肠中发酵碳水化合物的过程中，这两种情况都可以导致糖尿病的解决。这些将营养物质输送到下肠道的方法并不是没有并发症，尽管它们产生的效果往往优于现有的药物。目前市场上的抗糖尿病药物在有效性、效果持久性和安全性方面都存在不足，因此制药业一直在寻找新的方法来恢复受损的胃肠激素分泌。BioKier已经确定了一种简单、直接、安全的方法，可以将一种关键营养物质输送到结肠，这种方法可以开发用于治疗糖尿病和其他以L细胞刺激受损为特征的疾病。BioKier的概念包括通过结肠靶向配方将营养物质作为肠道激素促分泌剂输送到结肠，用于治疗糖尿病和其他疾病。BioKier进行的急性研究表明，通过导管将特定营养物质直接输送到结肠 糖尿病动物和人类恢复了口服葡萄糖诱导的胃肠激素反应。口服一种具有代表性的营养素的长期治疗完全防止了糖尿病易患大鼠模型的糖尿病发展，并支持了这种方法可能导致开发一种市场上的治疗方法的概念。基于急性临床研究的铅选择数据，L-谷氨酰胺被制成口服、缓释、结肠靶向胶囊，用于2型糖尿病患者的试验。为了进行人体试验，谷氨酰胺制剂需要在动物身上进行安全性测试；正如BKR 013胶囊在狗身上的局部毒性和毒代动力学研究中SBIR应用的第一阶段所建议的那样。第二阶段包括进行第一阶段临床试验，以评估药物动力学、血浆GLP-1和胰岛素生物标记物反应，以及BKR-013在糖尿病药物--幼稚2型糖尿病患者中的安全性。终点是评估L-谷氨酰胺的生物利用度，并测量生物标志物以确认结肠特异性给药。到目前为止，进展已经吸引了几个潜在的兴趣 已经表明将由这项申请资助的临床研究结果的制药合作伙伴对许可协议的讨论至关重要。

 DESCRIPTION (provided by applicant): Glucose homeostasis and regulation of food intake are both promoted by the secretion of gut hormones following nutrient stimulation of enteroendocrine cells (L-cells) in the lower gut. This process is impaired in diabetes but is restored when delivery of dietary compounds such as amino acids and fatty acids to the lower gut is facilitated. This effect of delivery of nutrients to the lower gut is observed after gastric bypass surgery and during fermentation of carbohydrates in the colon, both of which can result in resolution of diabetes. These approaches to deliver nutrients to the lower gut are not without complications, although their resulting efficacy is often superior to existing drugs. Currently marketed anti-diabetes drugs have deficiencies in efficacy, durability of effect, and safety, and the pharmaceutical industry has, therefore, been looking for novel approaches to restore impaired gut-hormone secretion. BioKier has identified a simple, direct, safe method to deliver one of the key nutrients to the colon in a way that can be developed for the treatment of diabetes and other conditions characterized by impaired L-cell stimulation. BioKier's concept involves the approach of delivering nutrients as gut hormone secretagogues to the colon via a colon-targeting formulation for the treatment of diabetes and other disorders. Acute studies conducted by BioKier showed that direct delivery via catheter of specific nutrients to the colon of diabetic animals and humans restored the oral glucose-induced gut hormone response. Chronic treatment with an oral formulation of a representative nutrient completely prevented the development of diabetes in a diabetes-prone rat model and supported the concept that the approach could lead to development of a marketable therapeutic. Based on lead-selection data from the acute clinical studies, L-glutamine was formulated in an oral, sustained-release, colon-targeted capsule for testing in type 2 diabetes patients. In order to conduct human testing, the glutamine formulation needs to be tested in animals for safety; as is proposed in Phase I of the SBIR application in a local toxicity and toxicokinetic study of BKR 013 capsules in dogs. Phase II involves conduct of a Phase 1 clinical trial to evaluate pharmacokinetics, plasma GLP-1 and insulin biomarker responses, and safety of BKR-013 in diabetes drug-naïve type 2 diabetes patients. Endpoints are to assess the bioavailability of L-glutamine and measure biomarkers to confirm colon- specific delivery. Progress thus far has attracted the interest of several potential pharmaceutical partners who have indicated the results of the clinical study to be funded by this application are crucial to discussions of a licensing agreement.