PFI:BIC Bioengineering Glucagon-like Peptide 1 Analogs and a Formulation for Oral Delivery to Treat Diabetes

Tufts大学的PFI：BIC项目将研究新发现的肽激素胰高血糖素样肽-1（GLP-1）的口服活性类似物，以确定是否有可能将其用于治疗2型糖尿病（T2 D）。GLP-1通过与其受体（GLP-1 R）相互作用降低进食后的血糖，GLP-1 R信号增加胰岛素分泌，减少胰高血糖素分泌，减缓胃排空和增加饱腹感。可以说，GLP-1 R激动剂是实现T2 D管理中推荐血糖目标的最有效治疗方法。然而，目前可用的GLP-1 R激动剂艾塞那肽和利拉鲁肽具有需要注射的缺点，特别是对于慢性药物。目标是开发GLP-1类似物的固体剂量制剂，其结合了口服给药的便利性和治疗优势。 通过口服递送的肽激素的消化受到胃肠道（GI）蛋白酶和GI道的吸收屏障的挑战。此外，GLP-1的活性寿命由于血液和组织中二肽基肽酶-4（DPP 4）和中性内肽酶（NEP）的蛋白水解降解而大大缩短。该项目的早期技术导向研究始于Bachovchin博士及其同事发现如何使GLP-1对GI蛋白酶，DPP 4和NEP的破坏更具抵抗力。将使用肽化学和肠溶包衣片剂中的制剂组合来实现临床使用所需的口服生物利用度和降糖效力。所述方法也适用于可能具有治疗意义的其它肽激素。在这种情况下，Bachovchin团队修改了食欲抑制肽胃泌酸调节素，以提供对DPP 4和NEP的抗性，而不破坏体内平衡功能所需的受体激动剂活性。该项目更广泛的影响在于它有助于解决一个巨大的、代价高昂的公共卫生问题。超过一半的T2 D患者未能达到推荐的血糖控制目标，导致医疗并发症的发生率很高。随着糖尿病患者人数在2025年上升到估计的3亿，这个问题将变得更加严重。美国糖尿病协会-欧洲糖尿病研究协会一致认为GLP-1类似物可能是最有效的治疗方法;但市场渗透率表明，目前只有少数患者受益。避免注射减少了艾塞那肽和利拉鲁肽的处方。开发方便的口服制剂中的GLP-1类似物将克服这一障碍，并与生活方式的改变相结合，可能有助于减缓或预防越来越多的青少年患者和糖尿病前期患者的疾病进展，因为他们没有症状，不太可能接受长期注射。对于Unigene Laboratories，Inc.，在该项目过程中预期的进展将进一步验证PeptelligenceTM平台用于口服递送的肽基药物的固体剂量制剂的多功能性，并且反过来增加其作为服务的市场可售性。对于Arisaph和Unigene来说，如果成功，将产生一种候选药物，可以通过合作进行的研究和开发进行临床开发并最终商业化。该项目的合作伙伴是1）领导机构：塔夫茨大学医学院（生物化学系）; 2）主要小企业合作伙伴：Unigene Laboratories Inc.（Boonton，NJ）和Arisaph Pharmaceuticals（Boston，MA）。

This PFI:BIC project from Tufts University will investigate newly discovered orally active analogs of the peptide hormone, glucagon-like peptide-1(GLP-1), to see whether it is possible to adapt them for use in the treatment of type 2 diabetes (T2D). GLP-1 reduces blood glucose after eating by interactions with its receptor (GLP-1R) that signal increased insulin secretion, reduced glucagon secretion, slowed gastric emptying and increased satiety. GLP-1R agonists provide, arguably, the most effective therapeutic approach for achieving recommended blood-glucose targets in the management of T2D. However, the currently available GLP-1R agonists, exenatide and liraglutide, suffer the drawback, especially for chronic medication, of requiring injection. The goal is to develop a solid-dose formulation of a GLP-1 analog that combines convenience of oral administration with the therapeutic advantages. The digestion of peptide hormones via oral delivery is challenged by gastrointestinal (GI) proteases and the absorption barrier of the GI tract. In addition, the active lifetime of GLP-1 is greatly shortened by proteolytic degradation as a result of dipeptidyl peptidase-4 (DPP4) and neutral endopeptidase (NEP) in the blood and tissues. The early-stage technology-oriented research of this project starts with the discovery by Dr. Bachovchin and co-workers of how to make GLP-1 more resistant to destruction by GI proteases, DPP4, and NEP. A combination of peptide chemistry and formulation in enteric-coated tablets will be used to achieve the oral bioavailability and glucose-lowering potency required for clinical use. The methods are also applicable to other peptide hormones of possible therapeutic interest. In this vein, the Bachovchin team has modified the appetite-suppressing peptide oxyntomodulin to provide resistance to DPP4 and NEP without disruption of the receptor-agonist activity required for homeostatic function. The broader impacts of this project lie in its contribution to the solution of a large, costly public health problem. More than half of T2D patients fail to achieve recommended targets for glycemic control, leading to high rates of medical complications. The problem will grow as the number of diabetics rises to an estimated 300 million in 2025. The American Diabetes Association-European Association for the Study of Diabetes consensus recognizes GLP-1 analogs as potentially the most effective treatment; but market penetration suggests only a minority of patients currently receive their benefit. Avoidance of injections reduces prescription of exenatide and liraglutide. Development of a GLP-1 analog in convenient oral formulation would overcome this hurdle and in combination with lifestyle changes might help to slow or prevent disease progression in the increasing numbers of juvenile patients and prediabetics, who, because they are asymptomatic, are less likely to accept long-term injections. For Unigene Laboratories, Inc., the advances anticipated in the course of this project will further validate the versatility of the Peptelligence (TM) platform for solid-dose formulation of peptide-based drugs for oral delivery, and in turn increase its marketability as a service. For Arisaph and Unigene, given success, a drug candidate will result that could be clinically developed and eventually commercialized by research and development conducted in partnership.Partners at the inception of the project are 1) Lead Institution: Tufts University School of Medicine (Department of Biochemistry); and 2) Primary Small Business Partners: Unigene Laboratories Inc.(Boonton, NJ) and Arisaph Pharmaceuticals (Boston, MA).