Hexalog: A Rapid-Acting Ultra-Concentrated Insulin Formulation

Hexalog：速效超浓缩胰岛素制剂

• 批准号: 8592724
• 负责人: Bruce Hill Frank
• 金额: $ 16.48万
• 依托单位: THERMALIN DIABETES, LLC
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8592724
• 关键词: Adolescent; Adrenal Cortex Hormones; Binding; Biochemical; Biological Assay; Blood capillaries; Breast Cancer Cell; Budgets; Cancer cell line; Cell Culture Techniques; Characteristics; Charge; Clinical; Clinical Research; Crystallization; Diabetes Mellitus; Disadvantaged; Discrimination; Dose; Drug Formulations; Drug Kinetics; Electrostatics; Engineering; Euglycemic Clamping; Exhibits; Family suidae; Future; Glucose Clamp; Glycosylated hemoglobin A; Gray unit of radiation dose; Health; Health system; Hour; Human; Hyperinsulinism; Hypoglycemia; Injection of therapeutic agent; Insulin; Insulin Infusion Systems; Insulin Receptor; Insulin Resistance; Insulin, Lispro, Human; Insulin-Dependent Diabetes Mellitus; Insulin-Like Growth Factor Receptor; Isophane Insulin; Kinetics; Lantus; Lasers; Lead; Left; Licensing; Life; Lipodystrophy; MCF7 cell; Mediating; Membrane Proteins; Miniaturization; Minority; Mitochondria; Modeling; Mutagenesis; National Institute of Diabetes and Digestive and Kidney Diseases; Non-Insulin-Dependent Diabetes Mellitus; Nude Mice; Obesity; Octreotide; Pain; Patients; Peer Review; Pharmacodynamics; Phase; Physical condensation; Positioning Attribute; Preparation; Prevention; Property; Proteins; Pump; Relative (related person); Resistance; Safety; Secondary to; Shapes; Signal Transduction; Small Business Innovation Research Grant; Solubility; Solutions; Speed; Surface; Syndrome; Testing; Thermodynamics; TimeLine; Trypsin; Universities; Zinc; absorption; analog; base; capillary; carcinogenesis; carcinogenicity; career; compliance behavior; design; experience; glargine; glycemic control; improved; in vivo; innovation; insulin secretion; light scattering; mouse model; novel; prevent; programs; receptor; receptor binding; subcutaneous; ward

DESCRIPTION (provided by applicant): We seek to develop a rapid-acting U-500 insulin analog formulation for patients with Type 2 and Type 1 diabetes mellitus (T2DM and T1DM). Such a novel product would improve treatment in two contexts: (i) for T2DM patients with marked insulin resistance (as associated with "diabesity," secondary to corticosteroid treatment, the mitochondrial diabetes syndrome MIDD, or lipodystrophies), a rapid-acting U-500 formulation would enhance safety, convenience, and efficacy of prandial or pump therapy and could, by reducing injection volume- associated pain, improve patient compliance; (ii) for patients without insulin resistance (i.e., the majority of patients with T1DM) or for T2DM patients who want the convenience of a patch-pump, a rapid acting U-500 formulation would extend by fivefold the reservoir life of current disposable pumps and/or would enable miniaturization of these disposable pumps without decreasing reservoir life. An innovative structural approach is proposed based on "electrostatic engineering." Only a single U-500 product is currently available (Lilly Humulin R U-500, containing wild-type human insulin); its pharmacokinetic and pharmacodynamic (PK/PD) properties are so prolonged that they resemble U- 100 NPH insulin. Experimental U-500 versions of Humalog likewise exhibit prolonged PK/PD and so are suboptimal for prandial or pump use. The key barrier to design of a rapid-acting U-500 formulation is posed by concentration-dependent hexamer-hexamer interactions. Such interactions retard disassembly of insulin hexamers in the subcutaneous depot and so block capillary absorption. The insulin hexamer is doughnut-shaped. Linear stacking of successive hexamers (the predominant mode of crystal packing) is mediated by trimer-related protein surfaces at the top and bottom of the doughnut. We have discovered that a rapid-acting U-500 formulation (designated Hexalog-1) is made possible by combining the "lispro" substitutions of Humalog? with a two-residue acidic extension of the B-chain: residues GluB31 and GluB32. Compatible with native potency, these negative charges are positioned to cause electrostatic repulsion between opposing hexamer surfaces. As a further potential benefit, the acidic extension (opposite in charge from the ArgB31-ArgB32 extension in the reportedly mitogenic basal analog insulin glargine; Lantus?) reduces cross-binding to the mitogenic IGF receptor. Speed of disassembly may be further enhanced by an optional chloro-aromatic substitution at the para position of PheB24 (Hexalog-Cl). Dr. B. Frank (PI) was co-inventor of Humalog? during his prior career at Eli Lilly. Thermalin Diabetes, LLC has an exclusive license to U500- related IP, which is owned by CWRU. Project Description

描述（由申请人提供）：我们寻求为 2 型和 1 型糖尿病（T2DM 和 T1DM）患者开发一种速效 U-500 胰岛素类似物制剂。这种新产品将改善两种情况的治疗：（i）对于具有明显胰岛素抵抗（与继发于皮质类固醇治疗的“糖尿病”、线粒体糖尿病综合征 MIDD 或脂肪营养不良相关）的 T2DM 患者，一种速效 U- 500配方将增强膳食或泵治疗的安全性、便利性和有效性，并且可以通过减少注射量相关的疼痛来提高患者的依从性； (ii) 对于无胰岛素抵抗的患者（即大多数 T1DM 患者）或 T2DM 患者 对于那些想要贴片泵的便利性的人来说，速效 U-500 配方可以将当前一次性泵的储液器寿命延长五倍和/或可以在不缩短储液器寿命的情况下实现这些一次性泵的小型化。提出了一种基于“静电工程”的创新结构方法。目前只有一种 U-500 产品（Lilly Humulin R U-500，含有野生型人胰岛素）；其药代动力学和药效学 (PK/PD) 特性非常持久，类似于 U-100 NPH 胰岛素。 Humalog 的实验性 U-500 版本同样表现出延长的 PK/PD，因此对于膳食或泵使用来说不是最佳选择。设计速效 U-500 制剂的主要障碍是浓度依赖性六聚体-六聚体相互作用。这种相互作用阻碍了皮下储库中胰岛素六聚体的分解，从而阻碍了毛细血管的吸收。胰岛素六聚体是甜甜圈形状的。连续六聚体的线性堆积（晶体堆积的主要模式）是由甜甜圈顶部和底部的三聚体相关蛋白质表面介导的。我们发现速效 U-500 制剂（称为 Hexalog-1）可以通过结合 Humalog 的“lispro”替代品来实现。具有 B 链的两个残基酸性延伸：残基 GluB31 和 GluB32。与天然效力兼容，这些负电荷的位置可在相对的六聚体表面之间引起静电排斥。作为进一步的潜在益处，酸性延伸（与据报道的促有丝分裂基础类似物甘精胰岛素中的 ArgB31-ArgB32 延伸相反的电荷；Lantus？）减少了与促有丝分裂 IGF 受体的交叉结合。通过在 PheB24 (Hexalog-Cl) 的对位进行可选的氯代芳香族取代，可以进一步提高分解速度。 B. Frank 博士（PI）是 Humalog 的共同发明人？在他之前在礼来公司的职业生涯中。 Thermalin Diabetes, LLC 拥有 U500 相关 IP 的独家许可，该 IP 归 CWRU 所有。项目描述