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

摘要 葡萄糖动态平衡和摄食量都受到肠道内分泌L分泌的胃肠激素的调节-- 在营养物质的刺激下，下层肠道中的细胞。这一过程在糖尿病患者中受损，但在糖尿病患者中恢复 将膳食营养物质，如氨基酸和脂肪酸输送到下部肠道，如胃旁路手术后 手术和在结肠中发酵碳水化合物，这两种方法都可以解决糖尿病。而这些 向下肠道输送营养的方法有并发症，其有效性和效果的持久性是 优于现有药物。BioKier已经确定了一种简单、直接和安全的方法来提供其中一种密钥 营养素到结肠治疗糖尿病等以L细胞刺激受损为特征的疾病。 BioKier的概念包括通过结肠将一种营养物质--一种肠道激素促分泌剂--输送到结肠。 靶向配方，绕过吸收的上肠道。BioKier的单剂研究表明 通过导管将特定的营养物质直接输送到糖尿病动物和人类的结肠恢复了口腔 葡萄糖诱导的胃肠激素反应。此外，慢性治疗完全用丁酸盐的口服配方 在行业标准的ZDF大鼠模型中预防糖尿病的发展，提供了临床前证据 概念。此外，口服、缓释、结肠靶向L-谷氨酰胺对胰岛素有显著影响 敏感性，在T2D患者服药4周时(快速通道第二阶段)。而单剂L- 谷氨酰胺对L细胞和GLP-1有刺激作用，4周末对GLP-1无影响 T2D患者的治疗。L-谷氨酰胺反复给药至结肠，可增加对 L-谷氨酰胺由结肠菌引起。相反，丁酸的作用也显示出刺激GLP-1的分泌 在BioKier的临床前和临床研究中，都是长期持续的。除了结肠靶向治疗的影响外 在大鼠模型中，BioKier有确凿的人体数据与结肠发酵衍生的 丁酸盐。虽然在结肠中产生丁酸的发酵方法非常有效，但它并不适用。 由于发酵会产生严重的胃肠道副作用而被广泛使用。的验证为基础。 鉴于丁酸盐在第二阶段的配方和已知的长期效果，我们将重点放在第二阶段的应用上 关于口服片剂中结肠靶向丁酸盐。为了进行人体测试，BioKier的结肠丁酸盐配方， BKR-017将用于临床开发，将进行制造、验证和稳定性测试(目标1)。目标2涉及 进行2a期临床试验以评估胰岛素敏感性、血浆GLP-1和胰岛素反应，以及安全性 以间接比较BKR-013(L-谷氨酰胺)在T2D患者中的检测结果。AIM 3，更大的 剂量范围研究将确定商业使用的有效剂量。到目前为止的进展吸引了 已表明临床研究结果的几个营养和制药合作伙伴的兴趣 由该应用程序提供资金，对于讨论将该产品推向市场的商业协议至关重要。

SUMMARY Glucose homeostasis and food intake are both regulated by gut hormones secreted from enteroendocrine L- cells in the lower gut following stimulation by nutrients. This process is impaired in diabetes but is restored with delivery of dietary nutrients such as amino acids and fatty acids to the lower gut, such as after gastric bypass surgery and during fermentation of carbohydrates in the colon, both of which resolve diabetes. While these approaches to deliver nutrients to the lower gut have complications, their efficacy and durability of effect is superior to existing drugs. BioKier has identified a simple, direct, and safe method to deliver one of the key nutrients to the colon to treat diabetes and other conditions characterized by impaired L-cell stimulation. BioKier's concept involves delivering a nutrient that is a gut hormone secretagogue to the colon via a colon- targeting formulation that bypasses the absorptive upper gut. BioKier's single-dose studies have shown that direct delivery of specific nutrients via catheter to the colon of diabetic animals and humans restored the oral glucose-induced gut hormone response. Also, chronic treatment with an oral formulation of butyrate completely prevented the development of diabetes in the industry standard ZDF rat model, providing preclinical proof of concept. Furthermore, oral, sustained-release, colon targeted L-glutamine had significant effects on insulin sensitivity, when dosed for 4 weeks in T2D patients (Phase II of the Fast-Track). While a single dose of L- glutamine resulted in stimulation of L-cells and GLP-1, no effect was seen on GLP-1 section at end of a 4-week BID treatment in T2D patients. Repeated delivery of L-glutamine to the colon resulted in increased utilization of L-glutamine by colonic bacteria. On the contrary, the effects of butyrate, also shown to stimulate GLP-1 secretion in BioKier's preclinical and clinical studies, are sustained long-term. In addition to the effects of colon-targeted butyrate tablets in the rat model, BioKier has confirmatory human data with colonic fermentation-derived butyrate. Although very effective, the fermentation approach to generating butyrate in the colon is not suitable for widespread utilization due to the severe GI side effects of fermentation. To build on the validation of the formulation in Phase II and the known long-term effects of butyrate, we are focusing this Phase IIB application on colon-targeted butyrate in an oral tablet. To conduct human testing, BioKier's colonic butyrate formulation, BKR-017, will be manufactured, validated and stability tested for clinical development (Aim 1). Aim 2 involves conduct of a Phase 2a clinical trial to evaluate insulin sensitivity, plasma GLP-1 and insulin responses, and safety of BKR-017 in T2D patients to indirectly compare to results obtained with BKR-013 (L-glutamine). Aim 3, a larger dose-ranging study will determine an effective dose for commercial use. Progress thus far has attracted the interest of several nutritional and pharmaceutical partners who have indicated the results of the clinical study to be funded by this application are crucial to discussions of a commercial agreement to bring the product to market.