Disrupting Insulin Delivery with a Novel, Stabilized Insulin that is Ultra-rapid at U100 or U500

项目摘要 在这个直接到第二阶段的SBIR应用中，我们建议推进一流、稳定的 胰岛素类似物T-1123，在U-100和U-500配方中都具有超快的时间-作用曲线。这个 T-1123的分子设计结合了几个协同增强稳定性的取代基，使锌能够- 免费、不含六聚体的配方。这些配方显示出更好的抵抗力 与市面上销售的胰岛素产品相比，具有更强的化学降解性。我们的初步研究利用了将军 与胰岛素药理学相关的蛋白质设计原则，以“调整”胰岛素的关键分子特性： 稳定性、自组装、有丝分裂和效力。在这些研究中，我们证明了(A)超快速吸收 T-1123的U-100和U-500制剂在猪正糖钳夹研究中的动力学-结果是 与U-100 FIAsp®相当，(B)T-1123在动物模型中的降血糖效力与U-100相当 人胰岛素和膳食胰岛素类似物，(C)增强T-1123的化学和物理稳定性，和(D) T-1123的促有丝分裂能力不高于人胰岛素。在第二阶段，我们建议(1)敲定 T-1123的配方与超快速PK/PD和物理/化学稳定性的既定标准有关；(2) 要最终确定制造放大条件，请将该技术转让给合同制造组织 并生产一批工程批量的T-1123，足以支持所有支持IND的毒理学研究； 完成最终T-1123 U-100配方的临床前毒理学测试。我们预料到 达到这些第二阶段的里程碑将有利于Thermarin Inc.启动第二阶段b-或 投资者资助的临床安全/疗效试验，并吸引企业合作伙伴进一步开发T- 1123。我们预计T-1123的U-100和U-500配方都将满足重要的、未得到满足的需求 在糖尿病患者中。T-1123的U-100配方将与现有的胰岛素兼容 泵，包括一次性补丁泵。这具有商业利益，因为T-1123的S明显 增强的稳定性将使管式泵和补丁泵的储油层在 制造。U-500超快速作用配方，使我们能够共同开发一种小型化、预制式 一枚邮票大小的充填和一次性闭环糖尿病管理系统--StampPump™。 该设备的初始原型由Thermarin在NIDDK(1R43DK121639- 01)和DARPA(STTRW911NF-19-C-0029)。此外，对现有预填充笔的细微修改 设备可以支持足够准确地向严重胰岛素抵抗患者输送U-500 T-1123， 他们被要求服用非常大的剂量的胰岛素，因此很痛苦。这是T2 DM患者的后一亚群 不成比例地包括服务不足的少数民族和阿巴拉契亚地区的农村贫困人口--人口减少 生活在一个其他方面都很富裕的社会里。如果广泛使用，T-1123及其相关输送设备 因此，可能会缓解所有糖尿病患者在医疗保健结果方面的明显差异。

Project Summary In this Direct-to-Phase II SBIR application we propose to advance development of a first-in-class, stabilized insulin analog, T-1123, that has an ultra-rapid time-action profile in both U-100 and U-500 formulations. The molecular design of T-1123 combines several synergistic stability-enhancing substitutions that enable zinc- free, non-hexamer-based formulations. These formulations demonstrate improved resistance to both physical and chemical degradation compared to marketed insulin products. Our preliminary studies exploited general principles of protein design to “tune” critical molecular properties of insulin pertinent to its pharmacology: stability, self-assembly, mitogenicity, and potency. In these studies we demonstrated (a) ultra-rapid absorption kinetics for both U-100 and U-500 formulations of T-1123 in swine euglycemic clamp studies—results that are comparable with U-100 Fiasp®, (b) glucose-lowering potency of T-1123 in animal models that is comparable to human insulin and the prandial insulin analogs, (c) enhanced chemical and physical stability of T-1123, and (d) mitogenic potency of T-1123 that no greater than human insulin. In Phase II we propose to (1) to finalize the formulation of T-1123 in relation to established criteria for ultra-rapid PK/PD and physical/chemical stability; (2) to finalize manufacturing scale-up conditions, transfer this technology to a contract manufacturing organization and produce an engineering lot of T-1123 sufficient to support all IND-enabling toxicology studies; (3) to complete pre-clinical toxicology testing of the finalized T-1123 U-100 formulation. We anticipate that attainment of these Phase II milestones would favorably position Thermalin Inc. to initiate Phase IIb- or investor-funded clinical safety/efficacy trials and to attract a corporate partner to further the development of T- 1123. We envision that both U-100 and U-500 formulations of T-1123 will address important, unmet needs among people with diabetes mellitus. The U-100 formulation of T-1123 will be compatible with existing insulin pumps, including disposable patch pumps. This is of commercial interest because T-1123’s markedly augmented stability would enable pre-filling of tubed pump and patch pump reservoirs at the time of manufacture. The U-500 ultra-rapid-acting formulation, enables our co-development of a miniaturized, pre- filled and disposable closed-loop diabetes management system the size of a postage stamp—StampPump™. Initial prototypes of this device have been developed by Thermalin with support from NIDDK (1R43DK121639- 01) and DARPA (STTR W911NF-19-C-0029). Additionally, minor modifications to existing pre-filled pen devices could support sufficiently accurate delivery of U-500 T-1123 to patients with severe insulin resistance, who are required to take very large and thus painful bolus doses of insulin. This latter subset of T2DM patients disproportionately includes underserved minorities and the rural poor of Appalachia—populations with reduced life spans in an otherwise affluent society. If broadly accessible, T-1123 and its associated delivery devices may therefore mitigate marked disparities in health-care outcomes in all populations with diabetes.