Development of Orally Administered Peptide Hormones for Treatment of Diabetes and Obesity

用于治疗糖尿病和肥胖症的口服肽激素的开发

• 批准号: 10323876
• 负责人: Qing Lin
• 金额: $ 30万
• 依托单位: TRANSIRA THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10323876
• 关键词: Agonist; Agreement; Biological Assay; Biological Availability; Biological Markers; Blood Glucose; Caco-2 Cells; Centers for Disease Control and Prevention (U.S.); Chemicals; Chemistry; Chronic; Communities; Development; Diabetes Mellitus; Diagnosis; Drug Kinetics; Enhancers; Epidemic; Evaluation; Exhibits; Foundations; Future; GIPR gene; Glucose; Glucose tolerance test; Goals; Hand; Healthcare Systems; In Vitro; Incidence; Insulin; Lead; Legal patent; Lipids; Manufacturer Name; Medical; Metabolic; Metabolic Diseases; Mission; Mus; New York; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; OGTT; Obese Mice; Obesity; Oral; Peptides; Permeability; Pharmacotherapy; Phase; Placebos; Plasma; Population; Positioning Attribute; Prodrugs; Publishing; Reporting; Research; Research Contracts; Serum; Small Business Innovation Research Grant; Sodium; Solid; Tablets; Technology; Therapeutic; Time; Triglycerides; United States; Universities; absorption; adiponectin; age group; blood glucose regulation; chemical stability; comparative efficacy; cost; design; diet-induced obesity; dosage; driving force; drug candidate; efficacy study; fasting glucose; good laboratory practice; improved; in vivo; innovation; monolayer; mouse model; peptide drug; peptide hormone; phase 1 study; phase 2 study; pre-clinical; pre-clinical assessment; preclinical evaluation; preclinical study; programs; receptor; statistics; success

ABSTRACT The rising obesity rate across all age groups underlines the dramatic increase in the incidence of diabetes in the United States. According to CDC, 34.2 million people or 10.5% of U.S. population have diabetes in 2018, with an estimated total cost of $327 billion to the healthcare system. The medical community has recognized that diabetes treatments should ideally lead to both blood glucose control and bodyweight loss. The mission of Transira Therapeutics is to develop an innovative best-in-class oral peptide drug for the treatment of the diabetes and obesity using our proprietary peptide stapling chemistry. The goal of this project is to develop a chemically modified peptide dual agonist of GIPR/GLP-1R as a once-daily oral drug for the treatment of diabetes and obesity. In our preliminary studies, we identified two stapled peptides that show biased dual GIP and GLP-1 receptor agonists along with the drastically improved proteolytic stability and robust in vivo glucose- lowering efficacy. In this SBIR phase I application, we have two specific aims: (1) Synthesis and evaluation of the chimeric GIPR/GLP-1R peptide dual agonists containing a lipid-modified chemical stapler for improved oral bioavailability; and (2) Preclinical assessment of the pharmacokinetics, glucose control, bodyweight reduction, and other metabolic effects of the orally administered GIPR/GLP-1R peptide dual agonist in DIO mice. We expect to identify one fatty diacid-containing biaryl-stapled peptide that exhibits Papp value >100 times greater than semaglutide (with a permeation enhancer if necessary) in the Caco-2 cell monolayer transport assay and glucose-lowering efficacy greater than or equal to semaglutide in oral glucose tolerance test (OGTT). Also, we expect the lipid-containing stapled peptide to show greater oral bioavailability than oral semaglutide, >25% decrease in fasting glucose levels in intraperitoneal glucose tolerance test (IPGTT), and >20% bodyweight reduction after PO administration compared to placebo in DIO mice. The successful completion of the phase I studies should lay a solid foundation for the IND-enabling phase II studies in the future.

抽象的 所有年龄段肥胖率的上升凸显了糖尿病发病率的急剧上升 在美国。根据 CDC 的数据，2018 年有 3420 万人（占美国人口的 10.5%）患有糖尿病， 医疗保健系统的估计总成本为 3270 亿美元。医学界已经认识到 理想情况下，糖尿病治疗应同时控制血糖和减轻体重。的使命 Transira Therapeutics 将开发一种创新的一流口服肽药物，用于治疗 使用我们专有的肽装订化学来治疗糖尿病和肥胖症。该项目的目标是开发一个 化学修饰的 GIPR/GLP-1R 肽双重激动剂，每日一次口服药物，用于治疗 糖尿病和肥胖症。在我们的初步研究中，我们鉴定了两种显示有偏差的双 GIP 的钉合肽 和 GLP-1 受体激动剂，以及显着改善的蛋白水解稳定性和强大的体内葡萄糖- 降低功效。在这个 SBIR 第一阶段应用中，我们有两个具体目标：（1）合成和评估 嵌合 GIPR/GLP-1R 肽双重激动剂，含有脂质修饰的化学缝合器，可改善口腔 生物利用度； (2) 药代动力学、血糖控制、体重减轻的临床前评估， 以及口服 GIPR/GLP-1R 肽双重激动剂对 DIO 小鼠的其他代谢影响。我们 期望鉴定出一种含有脂肪二酸的联芳基钉合肽，其 Papp 值大于 100 倍 在 Caco-2 细胞单层转运测定中比索马鲁肽（必要时使用渗透增强剂）和 口服葡萄糖耐量试验（OGTT）中降糖功效大于或等于索马鲁肽。另外，我们 预计含脂钉合肽的口服生物利用度高于口服索马鲁肽，>25% 腹膜内葡萄糖耐量试验 (IPGTT) 中空腹血糖水平下降，且体重>20% DIO 小鼠中 PO 给药后与安慰剂相比减少。一期工程顺利完成 研究将为未来的IND II期研究奠定坚实的基础。