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

摘要 各年龄段肥胖率的上升突显了糖尿病发病率的急剧上升 在美国。根据疾控中心的数据，2018年有3420万人患有糖尿病，占美国人口的10.5%。 医疗保健系统的总成本估计为3270亿美元。医学界已经认识到 理想情况下，糖尿病治疗应该同时控制血糖和减轻体重。的使命 泛乐治疗公司将开发一种创新的、同类最佳的口服多肽药物，用于治疗 糖尿病和肥胖症使用我们专有的多肽装订化学。这个项目的目标是开发一种 化学修饰GIPR/GLP-1R双激动剂每日一次口服治疗卵巢癌 糖尿病和肥胖症。在我们的初步研究中，我们确定了两个显示有偏向的双重GIP的装订多肽 和GLP-1受体激动剂，以及显著提高的蛋白分解稳定性和体内强劲的葡萄糖- 降低药效。在这个SBIR第一阶段的应用中，我们有两个具体的目标：(1)合成和评价 含脂质修饰化学吻合器的GIPR/GLP-1R嵌合双激动剂改善口腔功能 生物利用度；(2)药物动力学、血糖控制、体重减轻、 以及口服GIPR/GLP-1R双激动剂对DIO小鼠代谢的影响。我们 预计会鉴定出一种含有脂肪酸二元酸的联芳基多肽，其PAPP值要高出100倍 在Caco-2细胞单层转运实验中比Semagluide(必要时使用渗透促进剂)更有效 在口服葡萄糖耐量试验(OGTT)中，降糖效果大于或等于赛马谷肽。另外，我们 预期含有脂质的装订多肽的口服生物利用度比口服半谷氨酸甘油高25%。 腹膜糖耐量试验(IPGTT)中空腹血糖水平的降低，以及体重的20% 在DIO小鼠中，与安慰剂相比，PO给药后减少。第一期工程圆满完成 这些研究应为今后促进可持续发展的第二阶段研究奠定坚实的基础。

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.