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

使用 U100 或 U500 超快速的新型稳定胰岛素破坏胰岛素输送

基本信息

批准号：
10262961
负责人：
Mervyn Dodson Michael
金额：
$ 157.08万
依托单位：
THERMALIN, INC.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2023-05-10
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10262961
关键词：
Address Adherence Adolescent Advanced Development African American Animal Model Appalachian Region Bolus Infusion Buffers Canis familiaris Caring Cell Culture Techniques Cells Chemicals Clinical Closure by clamp Communities Contracts Development Devices Diabetes Mellitus Diffusion Dose Drug Kinetics Elements Engineering Excipients Exhibits Family suidae Formulation Funding Glucose Glucose Clamp Glycosylated hemoglobin A Heteronuclear NMR Hispanic Americans Human In Vitro Indigenous American Insulin Insulin Infusion Systems Insulin Resistance Insulin, Lispro, Human Insulin-Dependent Diabetes Mellitus Kinetics Lasers Longevity Malignant Neoplasms Maximum Tolerated Dose Metabolic Methods Minor Minority Modification Molecular Mutagenesis National Institute of Diabetes and Digestive and Kidney Diseases Non-Insulin-Dependent Diabetes Mellitus Obesity Pain Patients Pharmacodynamics Pharmacology Pharmacology Study Phase Polishes Population Populations at Risk Positioning Attribute Postage Stamps Process Production Property Protein Engineering Proteins Proteomics Protocols documentation Pump Recombinants Research Resistance Risk Rural Safety Salts Signal Transduction Small Business Innovation Research Grant Small Business Technology Transfer Research Societies Spectrum Analysis Sprague-Dawley Rats Structure Subgroup System Technology Technology Transfer Testing Time Toxicology Tribes Tube Underserved Population Universities Vulnerable Populations X-Ray Crystallography Zinc absorption age group analog base biophysical properties care outcomes cell bank chemical stability clinical material clinical toxicology design diabetes management efficacy trial glycemic control health disparity immunogenicity improved in silico innovation interest invention light scattering manufacturing scale-up member miniaturize novel patient subsets pharmacokinetics and pharmacodynamics phase 1 study pre-clinical prototype self assembly underserved minority

项目摘要

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.

项目概要在这个直接进入第二阶段的 SBIR 应用中，我们建议推进一流的、稳定的开发胰岛素类似物 T-1123，在 U-100 和 U-500 配方中均具有超快速的时间作用特性。 T-1123 的分子设计结合了多种增强稳定性的协同取代基，使锌- 游离的、非六聚体配方这些配方表现出对物理和化学物质的更好的耐受性。与市售胰岛素产品相比，我们的初步研究利用了一般性。 “调整”与其药理学相关的胰岛素关键分子特性的蛋白质设计原则：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 制剂在猪正常血糖钳夹研究中的动力学 - 结果如下与 U-100 Fiasp® 相当，(b) T-1123 在动物模型中的降血糖效力与人胰岛素和餐时胰岛素类似物，(c) 增强 T-1123 的化学和物理稳定性，以及 (d) T-1123 的促有丝分裂效力不大于人胰岛素。在第二阶段，我们建议 (1) 最终确定。与超快速 PK/PD 和物理/化学稳定性的既定标准相关的 T-1123 配方 (2) 为了最终确定制造规模扩大的条件，将该技术转移给合同制造组织并生产足以支持所有 IND 毒理学研究的 T-1123 工程批次 (3) 我们预计最终的 T-1123 U-100 配方将进行完整的临床前毒理学测试。实现这些 II 期里程碑将有利于 Thermalin Inc. 启动 IIb 期或投资者资助的临床安全性/有效性试验，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 制剂将解决重要的、未满足的需求 T-1123 的 U-100 配方将与现有胰岛素兼容。泵，包括一次性贴片泵，这具有商业利益，因为 T-1123 显着。增强的稳定性将能够在使用时预填充管式泵和贴片泵储液器 U-500 超速效配方使我们能够共同开发小型化的预- 邮票大小的一次性闭环糖尿病管理系统——StampPump™。该设备的初始原型是由 Thermalin 在 NIDDK (1R43DK121639- 01) 和 DARPA (STTR W911NF-19-C-0029) 此外，对现有预填充笔进行了细微修改。设备可以支持足够准确地向患有严重胰岛素抵抗的患者输送 U-500 T-1123，需要大量注射胰岛素并因此造成疼痛的人，属于后者的 T2DM 患者。不成比例地包括服务不足的少数民族和阿巴拉契亚的农村贫困人口 - 人口减少如果 T-1123 及其相关的输送设备能够广泛使用，则可以延长其在富裕社会的寿命。因此可以减轻所有糖尿病患者医疗保健结果的显着差异。