Clinical Testing of an Insulin Analog

胰岛素类似物的临床测试

• 批准号: 7613905
• 负责人: MICHAEL Aaron WEISS
• 金额: $ 25.5万
• 依托单位: THERMALIN DIABETES, LLC
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7613905
• 关键词: Adhesives; Affinity; Agitation; Alloxan; Amyloid; Asparagine; Binding; Biological; Biological Assay; Blood Glucose; Body Temperature; Buffers; Catheters; Cell Culture Techniques; Cells; Certification; Chemicals; Clinical Data; Clinical Trials; Cresol; Cresols; Data; Development; Diabetes Mellitus; Disulfides; Dose; Drug Formulations; Drug Kinetics; Epidemiology; Family suidae; Fermentation; Future; Glycerol; Goals; Greater sac of peritoneum; Hepatic; Human; Hypoglycemia; Implant; Implantable Pump; In Vitro; Incidence; Indiana; Inflammatory; Injection of therapeutic agent; Insulin; Insulin Infusion Systems; Insulin, Lispro, Human; Insulin-Dependent Diabetes Mellitus; Insulin-Like Growth Factor Receptor; Intervention; Lead; Letters; Link; Measurement; Modeling; Modification; Non-Insulin-Dependent Diabetes Mellitus; Obstruction; Operative Surgical Procedures; Pathway interactions; Patients; Peritoneal; Pharmacodynamics; Phase; Physiological; Pichia; Poison; Polymers; Problem Solving; Procedures; Property; Proteins; Protocols documentation; Pump; Quality of life; Rattus; Recombinants; Refractory; Regulation; Relative (related person); Replacement Therapy; Risk; Safety; Saline; Sampling; Small Business Technology Transfer Research; Streptozocin; Structure; Study models; System; Technology; Temperature; Testing; Thermodynamics; United Kingdom; Universities; Yeasts; Zinc; absorption; analog; base; biophysical chemistry; blood glucose regulation; chemical stability; deamidation; density; design; diabetes control; diabetic; diabetic rat; glycemic control; good laboratory practice; immunogenic; in vivo; interest; intraperitoneal; medical schools; monomer; novel; polypeptide; pre-clinical; prevent; prospective; protein aggregation; protein function; psychologic; public health relevance; receptor binding; research clinical testing; response; sodium phosphate; stability testing; surfactant

DESCRIPTION (provided by applicant): The central goal of insulin replacement therapy in the treatment of Type 1 diabetes mellitus (T1DM) is tight control of blood glucose concentration. This Phase I STTR application, submitted by Thermalin Diabetes, Inc., in conjunction with Case Western Reserve University, seeks support for the pre-clinical testing and commercial development of an ultra-stable and ultra-fast-acting insulin analog for use in insulin pumps. The novel physico- chemical features of this insulin analog (designated Thermalin) promise to make feasible the long-term use of implantable intraperitoneal insulin pumps. This technology promises to enhance the safety and efficacy of insulin replacement therapy. Clinical trials have established the potential of implantable insulin pumps in the treatment of diabetes mellitus, but such pumps are presently regarded experimental by the FDA. A major problem is posed by the limited stability of present insulin formulations as stored for 1-3 months within the pump reservoir at 37oC within the peritoneal cavity. Such instability causes aberrant protein aggregation, which frequently impairs insulin delivery due to partial or complete obstruction of the pump. This problem is more severe with use of rapid- acting insulin analogs (HumalogTM (Lilly) and NovalogTM (Novo-Nordisk)), whose favorable pharmacokinetic properties otherwise offer significant advantages for use in external insulin pumps. Thermalin is a monomeric single-chain insulin analog refractory to aggregation and degradation in vitro for > 6 months on agitation at 37oC. Whereas its thermodynamic stability is markedly higher than wild-type human insulin or insulin analogs currently approved for human use, the receptor-binding affinity of Thermalin and its biological activity in diabetic rat model of Type I diabetes mellitus are essentially identical to that of wild-type human insulin. No adverse increase in cross-binding to the IGF receptor or aberrant mitogenicity in cell culture is observed. These preliminary results strongly suggest that Thermalin will prove to be a "perfect pump insulin" for an implantable system, combining rapid pharmacokinetics with long-term stability at high protein concentration as stored in a pump reservoir with gentle agitation at 37oC. Design of Thermalin was based on general principles of biophysical chemistry together with analysis of the structure of insulin and its pathways of non-native aggregation and chemical degradation. Support is requested for the GLP manufacture of Thermalin in quantities (10 grams) sufficient (a) to permit rigorous testing of its chemical and physical stability and (b) to enable in vivo assessment of its potency, pharmacokinetics, and pharmacodynamics in pigs, a standard model for studies of insulin analogs. PUBLIC HEALTH RELEVANCE: We propose to develop an ultra-stable and ultra-fast-acting insulin analog for use in implantable insulin pumps. With this technology, patients with Type I diabetes mellitus may need only 3 or 4 injections per year (to refill the pump reservoir) rather than 3 or 4 injections per day. Whereas existing insulin formulations tend to degrade at body temperature over a period of weeks, often obstructing the pump, our product (designated "Thermalin") is stable for more than 6 months and is predicted to have both optimal durability and optimal rapid action for long-term implantable pump therapy.

描述（由申请人提供）： 胰岛素替代疗法治疗 1 型糖尿病 (T1DM) 的中心目标是严格控制血糖浓度。这一 I 期 STTR 申请由 Thermalin Diabetes, Inc. 与凯斯西储大学联合提交，寻求对用于胰岛素的超稳定、超速效胰岛素类似物的临床前测试和商业开发的支持泵。这种胰岛素类似物（称为 Thermalin）的新颖理化特性有望使植入式腹膜内胰岛素泵的长期使用成为可能。该技术有望提高胰岛素替代疗法的安全性和有效性。临床试验已经证实了植入式胰岛素泵在治疗糖尿病方面的潜力，但这种泵目前被 FDA 视为实验性的。一个主要问题是现有胰岛素制剂在腹膜腔内37℃的泵储存器内储存1-3个月时稳定性有限。这种不稳定性会导致异常的蛋白质聚集，这通常会由于泵的部分或完全阻塞而损害胰岛素的输送。使用速效胰岛素类似物（HumalogTM（礼来）和 NovalogTM（诺和诺德））时，这个问题更加严重，其良好的药代动力学特性为外部胰岛素泵的使用提供了显着的优势。 Thermalin 是一种单体单链胰岛素类似物，在 37oC 搅拌下在体外超过 6 个月不会聚集和降解。虽然其热力学稳定性明显高于目前批准用于人类使用的野生型人胰岛素或胰岛素类似物，但 Thermalin 的受体结合亲和力及其在 I 型糖尿病大鼠模型中的生物活性与野生型人胰岛素基本相同。型人胰岛素。没有观察到与 IGF 受体交叉结合的不利增加或细胞培养物中异常有丝分裂性。这些初步结果强烈表明，Thermalin 将被证明是用于植入系统的“完美泵胰岛素”，它将快速药代动力学与高蛋白质浓度下的长期稳定性结合起来，储存在泵储库中并在 37oC 下轻轻搅拌。 Thermalin 的设计基于生物物理化学的一般原理以及胰岛素结构及其非天然聚集和化学降解途径的分析。请求支持 Thermalin 的 GLP 生产，其数量（10 克）足以 (a) 允许对其化学和物理稳定性进行严格测试，以及 (b) 能够在猪体内评估其效力、药代动力学和药效学，胰岛素类似物研究的标准模型。公共健康相关性：我们建议开发一种超稳定、超速效的胰岛素类似物，用于植入式胰岛素泵。利用这项技术，I 型糖尿病患者每年可能只需注射 3 或 4 次（以重新填充泵储液器），而不是每天注射 3 或 4 次。现有的胰岛素制剂往往会在几周内因体温而降解，常常会阻塞泵，而我们的产品（称为“Thermalin”）可稳定超过 6 个月，预计将具有最佳的耐久性和长期的最佳快速作用长期植入泵治疗。