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

开发一种口服疗法来模拟胃绕道手术的抗糖尿病作用

• 批准号: 10174918
• 负责人: Jerzy Szewczyk
• 金额: $ 99.97万
• 依托单位: BIOKIER, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-17 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10174918
• 关键词: Acute; Address; Adoption; Affect; Age; Agreement; Amino Acids; Animals; Antidiabetic Drugs; Blood Glucose; Body Weight decreased; Butyrates; Bypass; Carbohydrates; Catheters; Chronic; Clinical Research; Clinical Trials; Colon; Controlled Study; Data; Development; Diabetes Mellitus; Disease; Dose; Double-Blind Method; Eating; Effectiveness; Enteroendocrine Cell; Epidemic; Fatty Acids; Fermentation; Formulation; Funding; Glucose; Glutamine; Glycosylated hemoglobin A; Health; Health Benefit; Hormone secretion; Hormones; Human; Impairment; Industry Standard; Insulin; Insulin Resistance; Intestinal Bypasses; Intestines; L Cells; Life; Long-Term Effects; Mediating; Metabolic; Methods; Modeling; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Nutritional; Obesity; Operative Surgical Procedures; Oral; Patients; Peptide YY; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Physicians; Physiological; Physiology; Placebos; Plasma; Positioning Attribute; Process; Public Health; Randomized; Rattus; Regulation; Respondent; Risk; Safety; Satiation; Small Intestines; Sodium Butyrate; Symptoms; Tablets; Testing; Therapeutic; Triglycerides; Validation; arm; bariatric surgery; base; blood glucose regulation; capsule; clinical development; clinical practice; colon bacteria; commercialization; delivered meals; design; diabetic; diabetic patient; diabetic rat; dietary; dietary supplements; fasting glucose; glucagon-like peptide 1; human data; improved; innovation; insulin sensitivity; interest; medical food; novel; obese patients; patient population; pre-clinical; preclinical study; prevent; recruit; response; side effect; stability testing; success; therapeutically effective

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.

概括 血糖稳态和食物摄入均受肠内分泌L-分泌的肠道激素的调节 受营养物质刺激后肠道下部的细胞。这一过程在糖尿病中受到损害，但可以通过以下方法恢复： 将氨基酸和脂肪酸等膳食营养物质输送到下肠道，例如胃绕道手术后 手术和结肠中碳水化合物的发酵过程，两者都可以解决糖尿病。虽然这些 将营养物质输送到下肠道的方法存在并发症，其功效和效果的持久性是 优于现有药物。 BioKier 已经确定了一种简单、直接且安全的方法来提供关键的之一 向结肠提供营养，以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将一种肠道激素促分泌剂的营养物质输送到结肠。 绕过上消化道吸收的靶向制剂。 BioKier 的单剂量研究表明 通过导管将特定营养物质直接输送到糖尿病动物和人类的结肠，恢复了口腔功能 葡萄糖诱导的肠道激素反应。此外，完全使用丁酸盐口服制剂进行长期治疗 在行业标准 ZDF 大鼠模型中阻止了糖尿病的发展，提供了临床前证据 概念。此外，口服、缓释、结肠靶向的 L-谷氨酰胺对胰岛素有显着影响 敏感性，在 T2D 患者中给药 4 周（快速通道的第二阶段）。虽然单剂量的 L- 谷氨酰胺导致 L 细胞和 GLP-1 的刺激，4 周结束时对 GLP-1 切片没有观察到影响 T2D 患者的 BID 治疗。重复向结肠输送 L-谷氨酰胺可提高 L-谷氨酰胺的利用率 L-谷氨酰胺由结肠细菌产生。相反，丁酸盐的作用也显示出刺激 GLP-1 分泌 BioKier的临床前和临床研究，都是长期持续的。除了结肠靶向的效果外 BioKier 在大鼠模型中的丁酸盐片剂具有结肠发酵衍生的验证性人体数据 丁酸盐。虽然非常有效，但在结肠中产生丁酸盐的发酵方法并不适合 由于发酵具有严重的胃肠道副作用，因此被广泛使用。建立在验证的基础上 由于 II 期配方和丁酸盐已知的长期影响，我们重点关注 IIB 期应用 口服片剂中针对结肠的丁酸盐。为了进行人体测试，BioKier 的结肠丁酸盐配方， BKR-017 将进行生产、验证和稳定性测试，以用于临床开发（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 BKR-017 在 T2D 患者中的应用，间接与 BKR-013（L-谷氨酰胺）获得的结果进行比较。目标3，更大 剂量范围研究将确定商业用途的有效剂量。迄今为止的进展吸引了 一些营养和制药合作伙伴的兴趣表明了临床研究的结果 该申请的资助对于讨论将该产品推向市场的商业协议至关重要。