Clinical Testing of an Insulin Analog

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。该I期STTR申请由Thermalin Diabetes， Inc.与凯斯西储大学（Case Western Reserve University）联合提交，旨在支持用于胰岛素泵的超稳定、超速效胰岛素类似物的临床前测试和商业开发。这种胰岛素类似物（命名为Thermalin）的新型物理化学特性使植入式腹腔胰岛素泵的长期使用成为可能。这项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认为是实验性的。一个主要的问题是，目前的胰岛素制剂在腹腔内37℃的泵库中储存1-3个月时，其稳定性有限。这种不稳定性导致异常的蛋白质聚集，由于泵的部分或完全阻塞而经常损害胰岛素的输送。使用速效胰岛素类似物（HumalogTM（礼来公司）和NovalogTM（诺和诺德公司））时，这个问题更为严重，它们良好的药代动力学特性为外部胰岛素泵的使用提供了显著的优势。Thermalin是一种单体单链胰岛素类似物，在37℃的搅拌条件下体外难聚集和降解6个月。虽然其热力学稳定性明显高于野生型人胰岛素或目前批准用于人的胰岛素类似物，但Thermalin的受体结合亲和力及其在1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。在细胞培养中没有观察到与IGF受体交叉结合的不良增加或异常的有丝分裂性。这些初步结果强烈表明，Thermalin将被证明是一种用于植入系统的“完美泵胰岛素”，结合了快速的药代动力学和在37℃下轻度搅拌的高蛋白浓度下储存在泵库中的长期稳定性。Thermalin的设计基于生物物理化学的一般原理，并分析了胰岛素的结构及其非天然聚集和化学降解途径。要求支持GLP生产Thermalin，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，(b)能够在猪体内评估其效力，药代动力学和药效学，这是胰岛素类似物研究的标准模型。公共卫生相关性：我们建议开发一种用于植入式胰岛素泵的超稳定和超速效胰岛素类似物。有了这项技术，1型糖尿病患者每年可能只需要3到4次注射（以补充泵库），而不是每天3到4次注射。鉴于现有的胰岛素制剂往往会在体温下降解数周，通常会阻塞泵，我们的产品（命名为“Thermalin”）稳定超过6个月，预计在长期植入式泵治疗中具有最佳的耐久性和最佳的快速作用。

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.