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

描述(申请人提供)：可溶膳食胰岛素类似物和NPH微晶悬浮液的预混合配方为单靠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成本效益高的基础团注方案。这种每天两次的产品(瓶装或预装笔)占 &gt；在发达国家的销售额为20亿美元，而它们在发展中国家的使用正在迅速增长。市场领先者是诺和诺德公司(NovoMix(R)30，其中天门冬氨酸胰岛素30%作为可溶性六聚体锌，70%作为NPH微晶悬浮液)和Eli Lilly and Co(Humalog(R)预混胰岛素，其中25%作为可溶性六角体胰岛素，75%作为NPH微晶悬浮液；也有50/50的产品可供选择)。尽管这些产品很受欢迎，在适当的患者中也有临床实用价值，但它们的制造复杂，不能与其他胰岛素产品混合，固定在基础推注比上，并且在室温以上容易降解。一旦打开，钢笔和瓶子必须分别在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配方，它的制造更简单、成本更低，其药代动力学特性可调，在&gt；100？F温度下超稳定，我们的产品基于基于单链胰岛素(SCI)平台的创新结构方法。我们的SCI类似物在动物模型中显示了药效学概况，该模型概括了当前预混合胰岛素产品的概况。它的超稳定性将在旅行中提供便利，实现邮购递送，并加强应急准备；在发展中国家，这种产品将绕过胰岛素冷链递送的成本和复杂性。因此，我们预计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好处。我们预计，与目前的胰岛素NPH混合产品相比，Thermarin双相产品将提供显著的成本节约。这一节省将来自三个因素：(A)通过消除冷藏需要而简化运输和交付；(B)延长瓶装瓶子的保质期 (C)通过减少后发酵过程来简化生产过程。这个第一阶段的项目将通过概念验证测试采用Thermarin两相药物。这种新颖的分子平台由凯斯西储大学(M.A.Weiss教授)发明，并授权Thermarin糖尿病有限责任公司使用，可显著延长保质期，并在高温下保持效力。申请者B·弗兰克博士(PI)是Humalog(R)的联合发明人，他之前在礼来公司工作过。合作研究将由C.T.Roberts，Jr.教授进行。(俄勒冈健康科学大学)和A.Cherrington教授(狗的PK/PD，Vanderbilt大学学院)。Thermarin糖尿病有限责任公司拥有该IP的独家许可证，该IP由CWRU拥有。

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.