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

总结 葡萄糖稳态和食物摄入均受肠内分泌L- 下消化道中的细胞受到营养素的刺激。这一过程在糖尿病中受损，但随着糖尿病的发生而恢复。 将膳食营养素如氨基酸和脂肪酸输送到下消化道，如胃旁路手术后 手术和结肠中碳水化合物的发酵过程中，这两种方法都可以解决糖尿病。虽然这些 将营养物质输送到下消化道的方法具有并发症，它们的功效和效果的持久性 上级现有药物。BioKier已经确定了一种简单，直接和安全的方法来提供其中一个关键 营养素的结肠治疗糖尿病和其他条件的特点是受损的L-细胞刺激。 BioKier的概念包括通过结肠向结肠输送一种营养素，这种营养素是一种肠道激素促分泌素， 靶向制剂，其绕过吸收性上消化道。BioKier的单剂量研究表明， 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， 葡萄糖诱导的肠道激素反应。此外，长期治疗与口服制剂的丁酸完全 在工业标准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 在T2 D患者中给药4周时的敏感性（快速通道II期）。而单剂量的L- 谷氨酰胺导致L-细胞和GLP-1的刺激，在4周结束时对GLP-1切片没有观察到影响 T2 D患者的BID治疗。重复向结肠输送L-谷氨酰胺导致增加的 L-谷氨酰胺通过结肠细菌。相反，丁酸盐的作用，也显示刺激GLP-1分泌 在BioKier的临床前和临床研究中，是长期持续的。除了结肠靶向治疗的效果外， 在大鼠模型中，BioKier具有结肠发酵来源的证实性人体数据。 丁酸盐。虽然非常有效，但在结肠中产生丁酸的发酵方法并不适合 由于发酵的严重胃肠道副作用而被广泛使用。在验证 鉴于II期制剂和丁酸盐的已知长期效应，我们将重点关注IIB期申请 结肠靶向丁酸盐的口服片剂。为了进行人体测试，BioKier的结肠丁酸盐配方， BKR-017将进行生产、验证和稳定性试验，用于临床开发（目标1）。目标2涉及 开展一项2a期临床试验，以评价胰岛素敏感性、血浆GLP-1和胰岛素反应以及安全性 间接比较BKR-013（L-谷氨酰胺）获得的结果。目标3，更大的 剂量范围研究将确定用于商业用途的有效剂量。迄今为止的进展吸引了 几个营养和制药合作伙伴的兴趣表明了临床研究的结果， 这一申请的资金是至关重要的商业协议的讨论，把产品推向市场。

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.