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

• 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
• 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

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（由申请方提供）：可溶性餐时胰岛素类似物和NPH微晶混悬液的预混制剂为单独基础胰岛素治疗无法有效控制的2型糖尿病（T2 DM）患者提供了一种简化且具有成本效益的基础-餐时方案。这种每天两次的产品（小瓶或预填充在笔中）占 在发达国家的销售额超过20亿美元，在发展中国家的使用也在迅速增长。市场领导者是Novo-Nordisk（NovoMix（r）30，其中门冬胰岛素30%配制为可溶性锌六聚体，70%配制为NPH微晶混悬液）和Eli Lilly and Co（Humanitary（r）预混胰岛素，其中赖脯胰岛素25%配制为可溶性锌六聚体，75%配制为NPH微晶混悬液;也可提供50/50产品）。 尽管这些产品在适当的患者中很受欢迎并具有临床效用，但它们的制造复杂，不能与其他胰岛素产品混合，基础-餐时比率固定，并且在室温以上会降解。一旦打开，注射笔和小瓶必须分别在10天和28天后丢弃。 我们已经发明了一种超稳定的双相胰岛素类似物制剂，其制造更简单且更便宜，其药代动力学性质可调，并且在>100 ° F的温度下超稳定。我们的产品被指定为Thermalin双相，基于单链胰岛素（SCI）平台的创新结构方法。我们的SCI类似物在动物模型中表现出的药效学特征概括了当前预混胰岛素产品的特征。它的超稳定性将为旅行提供便利，使邮购交付成为可能，并加强应急准备;在发展中国家，这种产品将规避胰岛素输送冷链的成本和复杂性。因此，我们预计该产品将对发达国家和发展中国家的2型糖尿病患者产生广泛的益处。 我们预计，与目前的胰岛素NPH混合产品相比，Thermalin双相胰岛素将显著节省成本。这一节省将来自三个因素：（a）通过消除对冷藏的需要而简化运输和交付，（B）延长包装中小瓶的保存期，（b）减少对冷藏的需求，（c）减少对冷藏的需求，（d）减少对冷藏的需求，（e）减少对冷藏的需求，（f）减少对冷藏的需求，（g）减少对 （c）通过减少后发酵处理简化制造过程。该第一阶段项目将通过概念验证测试对Thermalin双相进行测试。这种新型的分子平台，发明于凯斯西储大学（教授M.A.韦斯）和许可的Thermalin糖尿病，有限责任公司，赋予了一个显着延长保质期与保留效力在高温下。申请人B博士Frank（PI）在Eli Lilly的职业生涯中曾是Humanitarian（r）的共同发明者。合作研究将由C教授进行。T.小罗伯茨（细胞信号传导和促有丝分裂;俄勒冈州健康科学大学）和A. Cherrington（犬PK/PD;范德比尔特大学）。Thermalin Diabetes，LLC拥有该知识产权的独家许可，该知识产权归CWRU所有。