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 在此直接到相的II SBIR应用中，我们建议提高一类稳定的第一类开发 胰岛素类似物T-1123，在U-100和U-500公式中均具有超高的时间交流。这 T-1123的分子设计结合了几种协同稳定性增强的取代，使锌 - 免费的，非尚面的公式。这些公式表现出对两者的抗药性提高 与销售的胰岛素产品相比，化学降解。我们的初步研究探讨了一般 蛋白质设计的原理，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，有丝分裂性和效力。在这些研究中，我们证明了（a）超增强滥用 在猪毛囊钳研究中，U-100和U-500的动力学均可用于T-1123的动力学 与U-100Fiasp®，（b）在动物模型中T-1123降低葡萄糖的效力的可比 人胰岛素和培养基胰岛素类似物，（c）T-1123的化学和物理稳定性增强，（d） T-1123的有丝分裂效力不比人类胰岛素大。在第二阶段，我们建议（1）确定 与超高PK/PD和物理/化学稳定性建立标准有关的T-1123形成； （2） 要确定制造规模条件，请将这项技术转移到合同制造组织 并产生足以支持所有毒理学研究的T-1123的工程； （3）到 完成最终的T-1123 U-100公式的临床前毒理学测试。我们预料到这一点 达到这些II期里程碑将有利地将Thermalin Inc.定位为启动IIB期或 投资者资助的临床安全/有效性试验，并吸引公司合作伙伴以进一步发展T- 1123。我们设想T-1123的U-100和U-500公式都将满足重要的，未满足的需求 在糖尿病患者中。 T-1123的U-100公式将与现有胰岛素兼容 泵，包括一次性贴片泵。这具有商业意义，因为T-1123明显 增强稳定性将在填充油管泵和贴片泵储层时进行预填充 生产。 U-500超优化效果公式，使我们可以共同开发 填充和一次性闭环糖尿病管理系统邮票的大小-Stamppump™。 Thermalin在NIDDK的支持下开发了该设备的初始原型（1R43DK121639- 01）和DARPA（STTR W911NF-19-C-0029）。此外，对现有的预填充笔的微小修改 设备可以支持足够准确的U-500 T-1123向严重胰岛素抵抗的患者递送， 他们必须服用非常大的胰岛素胰岛素剂量。以后的T2DM患者子集 不成比例的包括服务不足的少数民族和阿巴拉契亚的粗糙贫困人口 - 人群减少 生命跨越原本受影响的社会。如果可以广泛访问，则T-1123及其相关的交付设备 因此，可以减轻所有糖尿病人群中医疗保健结果的明显分布。