An Ultra-Stable Insulin Analog with Intrinsic Basal-Bolus Action

具有内在基础推注作用的超稳定胰岛素类似物

基本信息

批准号：
8780579
负责人：
Bruce Hill Frank
金额：
$ 30万
依托单位：
THERMALIN DIABETES, LLC
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-24 至 2016-09-23
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8780579
关键词：
Accounting Animal Model Biological Assay Blood Glucose Bolus Infusion Cancer cell line Canis familiaris Cell Line Chemicals Clinical Cold Chains Collaborations Complex Conscious Cost Savings Crystallization Development Diabetes Mellitus Disadvantaged Dose Drug Formulations Drug Kinetics Emergency Situation Engineering Enzyme-Linked Immunosorbent Assay Exhibits Fermentation Gel Chromatography Health Sciences High temperature of physical object Human Hybrids Hypoglycemia Insulin Insulin Receptor Insulin, Aspart, Human Insulin, Lispro, Human Insulin-Like Growth Factor I Ions Isoelectric Point Isophane Insulin Lasers Licensing Life Ligands MCF7 cell Mail Order Marketing Measurement Metabolic syndrome Modeling Molecular N-terminal Nature Non-Insulin-Dependent Diabetes Mellitus Normal Pressure Hydrocephalus Obesity Oregon Patients Peptide Signal Sequences Pharmacodynamics Phase Phosphorylation Pichia Prevalence Process Property Protamines Protein Isoforms Proteins Proteolytic Processing Protocols documentation Readiness Refrigeration Regimen Relative (related person)Rodent Model Sales Savings Schools Signal Transduction Solubility Solutions Sprague-Dawley Rats Structure Suspension substance Suspensions Temperature Testing Travel Universities Vial device Yeasts Zinc analog basal insulin base career cost cost effective design fast protein liquid chromatography glargine in vivo innovation light scattering manufacturing process meetings novel pandemic disease peptidyl-Lys metalloendopeptidase protein function public health relevance receptor receptor binding response three dimensional structure

项目摘要

DESCRIPTION (provided by applicant): Pre-mixed formulations of soluble prandial insulin analogs and NPH micro-crystalline suspensions provide a simplified and cost-effective basal-bolus regimen for patients with Type 2 diabetes mellitus (T2DM) not effectively controlled by basal insulin therapy alone. Such twice-daily products (in vials or pre-filled in pens) account for >$2B in sales in the developed world, and their use is rapidly growing in the developing world. The market leaders are Novo-Nordisk (NovoMix(r) 30 in which insulin aspart is formulated 30% as a soluble zinc hexamer and 70% as an NPH micro-crystalline suspension) and Eli Lilly and Co (Humalog(r) Premixed Insulin in which insulin lispro is formulated 25% as a soluble zinc hexamer and 75% as an NPH micro-crystalline suspension; a 50/50 product is also available). Despite their popularity and clinical utility with appropriate patients, these products are complicated to manufacture, not mixable with other insulin products, fixed in their basal-bolus ratio, and subject to degradation above room temperature. Once opened, pens and vials must be discarded after 10 and 28 days, respectively. We have invented an ultra-stable biphasic insulin analog formulation that would be simpler and less expensive to manufacture, tunable in its pharmacokinetic properties, and ultra-stable at temperatures >100 ¿F. Designated Thermalin-biphasic, our product builds on an innovative structural approach based on a single-chain insulin (SCI) platform. Our SCI analog exhibits a pharmacodynamics profile in an animal model that recapitulates the profile of current pre-mixed insulin products. Its ultra-stability would provide convenience during travel, enable mail-order delivery, and enhance emergency preparedness; in the developing world such a product would circumvent the cost and complexity of the cold chain of insulin delivery. Accordingly, we anticipate that this product would be of broad benefit t patients with Type 2 diabetes mellitus in the developed and developing worlds. We anticipate that Thermalin-biphasic will provide a significant cost savings relative to current insulin NPH- mix products. This savings would accrue from three factors: (a) simplification of transport and delivery through elimination of the need for refrigeration, (b) extended shelf life of vials in the hands of patients, and (c) simplification of the manufacturing process through reduction in post-fermentation processing. This Phase I project will take Thermalin-biphasic through proof-of-concept testing. This novel molecular platform, invented at Case Western Reserve University (Prof. M.A. Weiss) and licensed to Thermalin Diabetes, LLC, confers a dramatic extension of shelf life with retention of potency at high temperatures. The applicant, Dr. B. Frank (PI), was co-inventor of Humalog(r) during his prior career at Eli Lilly. Collaborative studies in will be conducted by Prof. C. T. Roberts, Jr. (cellular signaling and mitogenicity; Oregon Health Sciences University) and Prof. A. Cherrington (PK/PD in dogs; Vanderbilt University School). Thermalin Diabetes, LLC has an exclusive license to the IP, which is owned by CWRU.

描述（由申请人提供）：可溶性餐时胰岛素类似物和 NPH 微晶悬浮液的预混合制剂为基础胰岛素治疗无法有效控制的 2 型糖尿病 (T2DM) 患者提供了一种简化且具有成本效益的基础推注方案仅此类每日两次的产品（装在小瓶中或预装在笔中）就占了。在发达国家的销售额超过 20 亿美元，其在发展中国家的使用正在迅速增长，市场领导者是诺和诺德 (NovoMix(r) 30)，其中门冬胰岛素的配方中 30% 为可溶性锌六聚体，70% 为可溶性锌六聚体。作为 NPH 微晶悬浮液）和 Eli Lilly and Co（Humalog(r) 预混胰岛素，其中赖脯胰岛素配制为 25% 可溶性胰岛素）锌六聚体和 75% 的 NPH 微晶悬浮液也可提供，尽管它们在适当的患者中很受欢迎并具有临床实用性，但这些产品制造起来很复杂，不能与其他胰岛素产品混合，并固定在其中。基础-推注比例，并且一旦打开，笔和小瓶必须分别在 10 天和 28 天后丢弃。制造起来会更简单、更便宜，其药代动力学特性可调，并且在温度> 100 ¿ F. 我们的产品被命名为 Thermalin-biphasic，它建立在基于单链胰岛素 (SCI) 平台的创新结构方法之上。我们的 SCI 类似物在动物模型中表现出药效学特征，概括了当前预混合胰岛素产品的特征。其超稳定性将为旅行提供便利，实现邮购交付并增强应急准备；在世界范围内开发此类产品将规避胰岛素输送冷链的成本和复杂性。该产品将为发达国家和发展中国家的 2 型糖尿病患者带来广泛的益处，我们预计，相对于目前的 NPH 胰岛素混合产品，Thermalin 双相产品将显着节省成本。这种节省来自三个因素： (a) 通过消除冷藏需求简化运输和交付， (b) 延长小瓶在包装内的保质期（c）通过减少发酵后处理来简化制造过程。该第一阶段项目将通过概念验证测试来验证Thermalin-biphasic，这是由凯斯西储大学发明的。 M.A. Weiss 教授）并获得 Thermalin Diabetes, LLC 的许可，可显着延长保质期并在高温下保持效力。申请人 B. Frank 博士 (PI) 是他之前在礼来公司 (Eli Lilly) 工作期间是 Humalog(r) 的共同发明人。C. T. Roberts, Jr. 教授（细胞信号传导和有丝分裂；俄勒冈健康科学大学）和 A. Cherrington 教授（PK/狗的 PD；Thermalin Diabetes, LLC 拥有该知识产权的独家许可，由 CWRU 所有。