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

• 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
• 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

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.

项目摘要 在这个直接到第二阶段SBIR应用中，我们建议推进一流的稳定的 胰岛素类似物T-1123，在U-100和U-500制剂中均具有超快速时间-作用曲线。的 T-1123的分子设计结合了几种协同稳定性增强取代， 游离的、非基于六聚体的制剂。这些制剂表现出改善的对两种物理性质的耐受性。 和化学降解。我们的初步研究利用了 蛋白质设计的原则，以“调整”与其药理学相关的胰岛素的关键分子特性： 稳定性、自组装、促有丝分裂性和效力。在这些研究中，我们证明了（a）超快速吸收 在猪正葡萄糖钳夹研究中T-1123 U-100和U-500制剂的动力学-结果 与U-100 Fiasp®相当，（B）T-1123在动物模型中的降糖功效与U-100 Fiasp ®相当 人胰岛素和餐时胰岛素类似物，（c）T-1123的化学和物理稳定性增强，和（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）完成 与超快速PK/PD和物理/化学稳定性的既定标准相关的T-1123制剂;（2） 为了最终确定生产规模扩大的条件，将该技术转让给合同生产组织 并生产足以支持所有IND毒理学研究的T-1123工程批次;（3） 完成最终T-1123 U-100制剂的临床前毒理学试验。我们预计 这些第二阶段的里程碑的实现将有利地定位赛莫林公司。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.我们设想，T-1123的U-100和U-500制剂将满足重要的未满足的需求。 在糖尿病患者中。T-1123的U-100制剂将与现有胰岛素相容 泵，包括一次性贴片泵。这是商业利益，因为T-1123明显 增强的稳定性将使得能够在注射时预填充管状泵和贴片泵储器。 制造。U-500超速效配方，使我们能够共同开发一种小型化，预 一个邮票大小的填充式一次性闭环糖尿病管理系统-StampPump ™。 该设备的初始原型已由Thermalin在NIDDK的支持下开发（1 R43 DK 121639- 01)和DARPA（STTR W911NF-19-C-0029）。此外，对现有预充式注射笔进行微小修改 装置可以支持将U-500 T-1123足够准确地输送给具有严重胰岛素抵抗的患者， 这些患者需要服用非常大且因此疼痛的大剂量胰岛素。后一个T2 DM患者亚组 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， 在一个富裕的社会里，如果广泛使用，T-1123及其相关输送装置 因此，可以减轻所有糖尿病患者在医疗保健结果方面的显著差异。