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

 描述（由申请方提供）：在营养物刺激下肠中的肠内分泌细胞（L细胞）后，肠道激素的分泌促进葡萄糖稳态和摄食调节。这一过程在糖尿病中受损，但当膳食化合物如氨基酸和脂肪酸向下消化道的输送得到促进时，这一过程得以恢复。在胃肠道给药后观察到营养物输送到下消化道的这种效果。 旁路手术和结肠中碳水化合物的发酵期间，这两者都可以导致糖尿病的解决。这些将营养物质输送到下消化道的方法并非没有并发症，尽管它们产生的疗效往往上级现有的药物。目前市售的抗糖尿病药物在功效、效果的持久性和安全性方面存在缺陷，因此，制药工业一直在寻找新的方法来恢复受损的肠道激素分泌。BioKier已经确定了一种简单、直接、安全的方法，将一种关键营养素输送到结肠，这种方法可以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的概念涉及通过结肠靶向制剂将营养素作为肠道激素促分泌素输送到结肠的方法，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素直接输送到结肠， 糖尿病动物和人恢复了口服葡萄糖诱导的肠道激素反应。在糖尿病易感大鼠模型中，用代表性营养素的口服制剂进行长期治疗完全防止了糖尿病的发展，并支持了该方法可能导致开发可销售的治疗剂的概念。基于急性临床研究的先导选择数据，L-谷氨酰胺被配制成口服、缓释、结肠靶向胶囊，用于在2型糖尿病患者中进行测试。为了进行人体试验，需要在动物中检测谷氨酰胺制剂的安全性;正如在SBIR申请的I期中在犬中进行的BKR 013胶囊局部毒性和毒代动力学研究中所提出的那样。II期包括进行I期临床试验，以评价BKR-013在糖尿病药物初治的2型糖尿病患者中的药代动力学、血浆GLP-1和胰岛素生物标志物反应以及安全性。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递送。迄今取得的进展吸引了一些潜在的 制药合作伙伴谁已表明临床研究的结果将由本申请资助是至关重要的讨论许可协议。

 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.